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Horwitz, Mitchell Eric

Overview:

Allogeneic stem cell transplantation using umbilical cord blood grafts; Allogenic stem cell transplantation for Sickle Cell Disease; Prevention of acute graft versus host disease through donor stem cell graft manipulation; Improving immune recovery following alternative donor stem cell transplantation using donor graft manipulation or third party thymus transplantation.

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1992

M.D. — Rush University

Medical Resident, Medicine

Northwestern University

Grants:

Blood and Marrow Transplant Clinical Trials Network

Administered By
Pediatrics, Blood and Marrow Transplantation
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2001
End Date
June 30, 2024

GNOS 201312100

Administered By
Duke Cancer Institute
AwardedBy
Washington University in St. Louis
Role
Principal Investigator
Start Date
May 05, 2017
End Date
May 22, 2022

A Multicenter, Randomized, Phase III Registratoin Trial of Transplantation of NiCord, Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor Cells, versus Unmanipulated Umbilical Cord Blo

Administered By
Duke Cancer Institute
AwardedBy
Gamida Cell Ltd
Role
Principal Investigator
Start Date
October 15, 2016
End Date
October 14, 2021

BMT CTN Protocol 1501

Administered By
Duke Cancer Institute
AwardedBy
National Marrow Donor Program
Role
Principal Investigator
Start Date
October 15, 2016
End Date
October 14, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2021

Phase I/II study to compare BEGEDINA vs conventional therapy in pts with GvHD

Administered By
Duke Cancer Institute
AwardedBy
Adienne SA
Role
Principal Investigator
Start Date
December 15, 2015
End Date
December 14, 2020

Phase III RECRUIT Study CTN 1505

Administered By
Duke Cancer Institute
AwardedBy
University of Texas Health Science Center at Houston
Role
Principal Investigator
Start Date
June 30, 2015
End Date
June 30, 2017
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Publications:

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.

B Cell Receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy, since Notch has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from HCT patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B cell maturation/effector molecules. Examination of the molecular underpinnings of this 'NOTCH2-BCR axis' in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4/IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells, without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1, a gene expression pattern associated with mature follicular B cells, and also attained increased CpG responsiveness. Together we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.

Authors
Poe, JC; Jia, W; Su, H; Anand, S; Rose, JJ; Tata, PV; Suthers, AN; Jones, CD; Kuan, PF; Vincent, BG; Serody, JS; Horwitz, ME; Ho, VT; Pavletic, SZ; Hakim, FT; Owzar, K; Zhang, D; Blazar, BR; Siebel, CW; Chao, NJ; Maillard, I; Sarantopoulos, S
MLA Citation
Poe, JC, Jia, W, Su, H, Anand, S, Rose, JJ, Tata, PV, Suthers, AN, Jones, CD, Kuan, PF, Vincent, BG, Serody, JS, Horwitz, ME, Ho, VT, Pavletic, SZ, Hakim, FT, Owzar, K, Zhang, D, Blazar, BR, Siebel, CW, Chao, NJ, Maillard, I, and Sarantopoulos, S. "An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD." Blood (August 29, 2017).
PMID
28851699
Source
epmc
Published In
Blood
Publish Date
2017
DOI
10.1182/blood-2017-05-782466

Evaluation of Hematopoietic Stem Cell Mobilization Rates with Early Plerixafor Administration for Adult Stem Cell Transplantation.

The addition of plerixafor to high-dose colony-stimulating growth factor has been shown to improve stem cell mobilization rates in autologous transplant patients with multiple myeloma and non-Hodgkin lymphoma. This study evaluates the change in administration time of plerixafor to determine if cell mobilization rates are similar between the US Food and Drug Administration-approved administration time of 11 hours before apheresis and an earlier administration time of 16 hours before apheresis. Medical records of patients age ≥ 18 years undergoing autologous stem cell transplantation requiring the use of plerixafor after at least 4 days of granulocyte colony-stimulating factor therapy to complete stem cell mobilization from January 1, 2010 through September 30, 2014 were retrospectively reviewed. The primary outcome was CD34+ cell mobilization success rates when plerixafor was administered 11 ± 2 hours (standard administration group) compared with 16 ± 2 hours before cell apheresis (early administration group), as defined as collection of  ≥2 × 106 CD34+ cells/kg. Secondary outcomes included the number of plerixafor therapy days required to collect a total of ≥2 × 106 CD34+ cells/kg, the number of apheresis cycles required to achieve ≥2 × 106 CD34+ cells/kg, the median CD34+ cells/kg collected in each apheresis session, and the rates of reported adverse events that occurred in the standard administration time group compared with the early administration time group. Of the 197 patients included, 114 patients received plerixafor 11 ± 2 hours before apheresis and 83 patients received plerixafor 16 hours ± 2 hours before apheresis. Ninety-four percent of patients in the early administration group achieved successful stem cell mobilization compared with 81.6% in the standard administration group (P = .0111). The median number of plerixafor days to reach the collection goal of  ≥2 × 106 CD34+ cells/kg was 1 day for each group (P = .323), and the median number of apheresis days to reach the collection goal was 2 days for the standard administration group compared with 1 day for the early administration group (P = .0156). Most adverse events were similar between the 2 groups except for fever, which occurred in 4.8% of the patients in the early administration group and none of the patients in the standard administration group. This study demonstrates plerixafor effectively mobilizes peripheral blood stem cells when given at an early administration time of 16 hours before apheresis compared with standard administration of 11 hours before apheresis. However, further prospective studies could strengthen these results.

Authors
Stover, JT; Shaw, JR; Kuchibhatla, M; Horwitz, ME; Engemann, AM
MLA Citation
Stover, JT, Shaw, JR, Kuchibhatla, M, Horwitz, ME, and Engemann, AM. "Evaluation of Hematopoietic Stem Cell Mobilization Rates with Early Plerixafor Administration for Adult Stem Cell Transplantation." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.8 (August 2017): 1290-1294.
PMID
28411174
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
8
Publish Date
2017
Start Page
1290
End Page
1294
DOI
10.1016/j.bbmt.2017.04.007

Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization.

Delayed hematopoietic recovery contributes to increased infection risk following umbilical cord blood (UCB) transplantation. In a Phase 1 study, adult recipients of UCB stem cells cultured ex vivo for 3 weeks with nicotinamide (NiCord) had earlier median neutrophil recovery compared with historical controls. To evaluate the impact of faster neutrophil recovery on clinically relevant early outcomes, we reviewed infection episodes and hospitalization during the first 100 days in an enlarged cohort of 18 NiCord recipients compared with 86 standard UCB recipients at our institution. The median time to neutrophil engraftment was shorter in NiCord recipients compared with standard UCB recipients (12.5 days versus 26 days; P < .001). Compared with standard UCB recipients, NiCord recipients had a significantly reduced risk for total infection (RR, 0.69; P = .01), grade 2-3 (moderate to severe) infection (RR, 0.36; P < .001), bacterial infection (RR, 0.39; P = .003), and grade 2-3 bacterial infection (RR, 0.21; P = .003) by Poisson regression analysis; this effect persisted after adjustment for age, disease stage, and grade II-IV acute GVHD. NiCord recipients also had significantly more time out of the hospital in the first 100 days post-transplantation after adjustment for age and Karnofsky Performance Status (69.9 days versus 49.7 days; P = .005). Overall, transplantation of NiCord was associated with faster neutrophil engraftment, fewer total and bacterial infections, and shorter hospitalization in the first 100 days compared with standard UCB transplantation. In conclusion, rapid hematopoietic recovery from an ex vivo expanded UCB transplantation approach is associated with early clinical benefit.

Authors
Anand, S; Thomas, S; Hyslop, T; Adcock, J; Corbet, K; Gasparetto, C; Lopez, R; Long, GD; Morris, AK; Rizzieri, DA; Sullivan, KM; Sung, AD; Sarantopoulos, S; Chao, NJ; Horwitz, ME
MLA Citation
Anand, S, Thomas, S, Hyslop, T, Adcock, J, Corbet, K, Gasparetto, C, Lopez, R, Long, GD, Morris, AK, Rizzieri, DA, Sullivan, KM, Sung, AD, Sarantopoulos, S, Chao, NJ, and Horwitz, ME. "Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.7 (July 2017): 1151-1157.
PMID
28392378
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
7
Publish Date
2017
Start Page
1151
End Page
1157
DOI
10.1016/j.bbmt.2017.04.001

Optimal Practices in Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies.

Unrelated donor cord blood transplantation (CBT) results in disease-free survival comparable to that of unrelated adult donor transplantation in patients with hematologic malignancies. Extension of allograft access to racial and ethnic minorities, rapid graft availability, flexibility of transplantation date, and low risks of disabling chronic graft-versus-host disease (GVHD) and relapse are significant advantages of CBT, and multiple series have reported a low risk of late transplantation-related mortality (TRM) post-transplantation. Nonetheless, early post-transplantation morbidity and TRM and the requirement for intensive early post-transplantation management have slowed the adoption of CBT. Targeted care strategies in CBT recipients can mitigate early transplantation complications and reduce transplantation costs. Herein we provide a practical "how to" guide to CBT for hematologic malignancies on behalf of the National Marrow Donor Program and the American Society of Blood and Marrow Transplantation's Cord Blood Special Interest Group. It shares the best practices of 6 experienced US transplantation centers with a special interest in the use of cord blood as a hematopoietic stem cell source. We address donor search and unit selection, unit thaw and infusion, conditioning regimens, immune suppression, management of GVHD, opportunistic infections, and other factors in supportive care appropriate for CBT. Meticulous attention to such details has improved CBT outcomes and will facilitate the success of CBT as a platform for future graft manipulations.

Authors
Barker, JN; Kurtzberg, J; Ballen, K; Boo, M; Brunstein, C; Cutler, C; Horwitz, M; Milano, F; Olson, A; Spellman, S; Wagner, JE; Delaney, C; Shpall, E
MLA Citation
Barker, JN, Kurtzberg, J, Ballen, K, Boo, M, Brunstein, C, Cutler, C, Horwitz, M, Milano, F, Olson, A, Spellman, S, Wagner, JE, Delaney, C, and Shpall, E. "Optimal Practices in Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.6 (June 2017): 882-896. (Review)
PMID
28279825
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
6
Publish Date
2017
Start Page
882
End Page
896
DOI
10.1016/j.bbmt.2017.03.006

Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

Authors
Scott, BL; Pasquini, MC; Logan, BR; Wu, J; Devine, SM; Porter, DL; Maziarz, RT; Warlick, ED; Fernandez, HF; Alyea, EP; Hamadani, M; Bashey, A; Giralt, S; Geller, NL; Leifer, E; Le-Rademacher, J; Mendizabal, AM; Horowitz, MM; Deeg, HJ; Horwitz, ME
MLA Citation
Scott, BL, Pasquini, MC, Logan, BR, Wu, J, Devine, SM, Porter, DL, Maziarz, RT, Warlick, ED, Fernandez, HF, Alyea, EP, Hamadani, M, Bashey, A, Giralt, S, Geller, NL, Leifer, E, Le-Rademacher, J, Mendizabal, AM, Horowitz, MM, Deeg, HJ, and Horwitz, ME. "Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35.11 (April 2017): 1154-1161.
PMID
28380315
Source
epmc
Published In
Journal of Clinical Oncology
Volume
35
Issue
11
Publish Date
2017
Start Page
1154
End Page
1161
DOI
10.1200/jco.2016.70.7091

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.

Authors
Sivaraj, D; Green, MM; Li, Z; Sung, AD; Sarantopoulos, S; Kang, Y; Long, GD; Horwitz, ME; Lopez, RD; Sullivan, KM; Rizzieri, DA; Chao, NJ; Gasparetto, C
MLA Citation
Sivaraj, D, Green, MM, Li, Z, Sung, AD, Sarantopoulos, S, Kang, Y, Long, GD, Horwitz, ME, Lopez, RD, Sullivan, KM, Rizzieri, DA, Chao, NJ, and Gasparetto, C. "Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.2 (February 2017): 262-268.
PMID
27856369
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
2
Publish Date
2017
Start Page
262
End Page
268
DOI
10.1016/j.bbmt.2016.11.010

Efficacy and safety of high-dose chemotherapy with autologous stem cell transplantation in senior versus younger adults with newly diagnosed multiple myeloma.

We retrospectively studied 340 fit patients with multiple myeloma (MM) who underwent autologous stem cell transplantation (ASCT). We hypothesized that progression-free survival (PFS) of older patients was non-inferior to that of younger patients after ASCT. Our null hypothesis was that the PFS hazard ratio (HR) for a 5-year increase in age was ≥1.05; the alternative (non-inferiority) hypothesis was that the HR was ≤1. The observed HR was 0.94 (95% confidence interval [CI] 0.86-1.03); since the CI upper bound was <1.05, we reject the null hypothesis and conclude that PFS in older patients was at least as good as in younger patients. We cannot reject an analogous null hypothesis for overall survival (HR 1.06 [95% CI 0.94-1.19]), since the CI upper bound >1.05. Toxicity was similar across ages and transplant-related mortality was minimal. 28% of subjects <65 versus 45% of those ≥65 received maintenance therapy. In summary, ASCT prolongs PFS equally well in older vs. younger adults. Although we cannot exclude maintenance as a confounder, these data support ASCT for fit seniors with MM.

Authors
Huang, L-W; Bacon, W; Cirrincione, C; Peterson, B; Long, G; Rizzieri, D; Sullivan, KM; Corbet, K; Horwitz, M; Chao, N; Gasparetto, C; Tuchman, SA
MLA Citation
Huang, L-W, Bacon, W, Cirrincione, C, Peterson, B, Long, G, Rizzieri, D, Sullivan, KM, Corbet, K, Horwitz, M, Chao, N, Gasparetto, C, and Tuchman, SA. "Efficacy and safety of high-dose chemotherapy with autologous stem cell transplantation in senior versus younger adults with newly diagnosed multiple myeloma." Hematological oncology (January 19, 2017).
PMID
28105753
Source
epmc
Published In
Hematological Oncology
Publish Date
2017
DOI
10.1002/hon.2379

Reply to Strahilevitz and Shapira.

Authors
Sung, A; Horwitz, M
MLA Citation
Sung, A, and Horwitz, M. "Reply to Strahilevitz and Shapira." Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (December 12, 2016).
PMID
27956457
Source
epmc
Published In
Clinical Infectious Diseases
Publish Date
2016

Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial.

Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread.In this prospective single-center study, we instituted a universal surgical mask policy requiring all individuals with direct contact with HSCT patients to wear a surgical mask, regardless of symptoms or season. The primary endpoint was the incidence of RVIs in the mask period (2010-2014) compared with the premask period (2003-2009).RVIs decreased from 10.3% (95/920 patients) in the premask period to 4.4% (40/911) in the mask period (P < .001). Significant decreases occurred after both allogeneic (64/378 [16.9%] to 24/289 [8.3%], P = .001) and autologous (31/542 [5.7%] to 16/622 [2.6%], P = .007) transplants. After adjusting for multiple covariates including season and year in a segmented longitudinal analysis, the decrease in RVIs remained significant, with risk of RVI of 0.4 in patients in the mask group compared with the premask group (0.19-0.85, P = .02). In contrast, no decrease was observed during this same period in an adjacent hematologic malignancy unit, which followed the same infection control practices except for the mask policy. The majority of this decrease was in parainfluenza virus 3 (PIV3) (8.3% to 2.2%, P < .001).Requiring all individuals with direct patient contact to wear a surgical mask is associated with a reduction in RVIs, particularly PIV3, during the most vulnerable period following HSCT.

Authors
Sung, AD; Sung, JAM; Thomas, S; Hyslop, T; Gasparetto, C; Long, G; Rizzieri, D; Sullivan, KM; Corbet, K; Broadwater, G; Chao, NJ; Horwitz, ME
MLA Citation
Sung, AD, Sung, JAM, Thomas, S, Hyslop, T, Gasparetto, C, Long, G, Rizzieri, D, Sullivan, KM, Corbet, K, Broadwater, G, Chao, NJ, and Horwitz, ME. "Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial." Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 63.8 (October 2016): 999-1006.
PMID
27481873
Source
epmc
Published In
Clinical Infectious Diseases
Volume
63
Issue
8
Publish Date
2016
Start Page
999
End Page
1006
DOI
10.1093/cid/ciw451

Myeloablative conditioning with total body irradiation for AML: Balancing survival and pulmonary toxicity.

The purpose of this study was to compare leukemia-free survival (LFS) and other clinical outcomes in patients with acute myelogenous leukemia who underwent a myeloablative allogeneic stem cell transplant with and without total body irradiation (TBI).Adult patients with acute myelogenous leukemia undergoing myeloablative allogeneic stem cell transplant at Duke University Medical Center between 1995 and 2012 were included. The primary endpoint was LFS. Secondary outcomes included overall survival (OS), nonrelapse mortality, and the risk of pulmonary toxicity. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed.A total of 206 patients were evaluated: 90 received TBI-based conditioning regimens and 116 received chemotherapy alone. Median follow-up was 36 months. For all patients, 2-year LFS and OS were 36% (95% confidence interval [CI], 29-43) and 39% (95% CI, 32-46), respectively. After adjusting for known prognostic factors using a multivariate analysis, TBI was associated with improved LFS (hazard ratio: 0.63; 95% CI: 0.44-0.91) and OS (hazard ratio: 0.63; 95% CI, 0.43-0.91). There was no difference in nonrelapse mortality between cohorts, but pulmonary toxicity was significantly more common with TBI (2-year incidence 42% vs 12%, P < .001). High-grade pulmonary toxicity predominated with both conditioning strategies (70% and 93% of cases were grade 3-5 with TBI and chemotherapy alone, respectively).TBI-based regimens were associated with superior LFS and OS but at the cost of increased pulmonary toxicity.

Authors
Stephens, SJ; Thomas, S; Rizzieri, DA; Horwitz, ME; Chao, NJ; Engemann, AM; Lassiter, M; Kelsey, CR
MLA Citation
Stephens, SJ, Thomas, S, Rizzieri, DA, Horwitz, ME, Chao, NJ, Engemann, AM, Lassiter, M, and Kelsey, CR. "Myeloablative conditioning with total body irradiation for AML: Balancing survival and pulmonary toxicity." October 2016.
PMID
28740897
Source
epmc
Published In
Advances in Radiation Oncology
Volume
1
Issue
4
Publish Date
2016
Start Page
272
End Page
280
DOI
10.1016/j.adro.2016.07.001

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.ClinicalTrials.gov NCT01280955.

Authors
Green, MMB; Chao, N; Chhabra, S; Corbet, K; Gasparetto, C; Horwitz, A; Li, Z; Venkata, JK; Long, G; Mims, A; Rizzieri, D; Sarantopoulos, S; Stuart, R; Sung, AD; Sullivan, KM; Costa, L; Horwitz, M; Kang, Y
MLA Citation
Green, MMB, Chao, N, Chhabra, S, Corbet, K, Gasparetto, C, Horwitz, A, Li, Z, Venkata, JK, Long, G, Mims, A, Rizzieri, D, Sarantopoulos, S, Stuart, R, Sung, AD, Sullivan, KM, Costa, L, Horwitz, M, and Kang, Y. "Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery." Journal of hematology & oncology 9.1 (August 17, 2016): 71-.
PMID
27535663
Source
epmc
Published In
Journal of Hematology and Oncology
Volume
9
Issue
1
Publish Date
2016
Start Page
71
DOI
10.1186/s13045-016-0301-2

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

Authors
Flowers, CR; Costa, LJ; Pasquini, MC; Le-Rademacher, J; Lill, M; Shore, TB; Vaughan, W; Craig, M; Freytes, CO; Shea, TC; Horwitz, ME; Fay, JW; Mineishi, S; Rondelli, D; Mason, J; Braunschweig, I; Ai, W; Yeh, RF; Rodriguez, TE; Flinn, I; Comeau, T; Yeager, AM; Pulsipher, MA; Bence-Bruckler, I; Laneuville, P; Bierman, P; Chen, AI; Kato, K; Wang, Y; Xu, C; Smith, AJ; Waller, EK
MLA Citation
Flowers, CR, Costa, LJ, Pasquini, MC, Le-Rademacher, J, Lill, M, Shore, TB, Vaughan, W, Craig, M, Freytes, CO, Shea, TC, Horwitz, ME, Fay, JW, Mineishi, S, Rondelli, D, Mason, J, Braunschweig, I, Ai, W, Yeh, RF, Rodriguez, TE, Flinn, I, Comeau, T, Yeager, AM, Pulsipher, MA, Bence-Bruckler, I, Laneuville, P, Bierman, P, Chen, AI, Kato, K, Wang, Y, Xu, C, Smith, AJ, and Waller, EK. "Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22.7 (July 2016): 1197-1205.
Website
http://hdl.handle.net/10161/11967
PMID
27040394
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
22
Issue
7
Publish Date
2016
Start Page
1197
End Page
1205
DOI
10.1016/j.bbmt.2016.03.018

Efficacy of Autologous Stem Cell Transplantation in Older Multiple Myeloma Patients

Authors
Huang, L-W; Bacon, W; Cirrincione, C; Peterson, B; Long, GD; Rizzieri, DA; Horwitz, ME; Sullivan, K; Corbet, K; Chao, NJ; Gasparetto, C; Tuchman, S
MLA Citation
Huang, L-W, Bacon, W, Cirrincione, C, Peterson, B, Long, GD, Rizzieri, DA, Horwitz, ME, Sullivan, K, Corbet, K, Chao, NJ, Gasparetto, C, and Tuchman, S. "Efficacy of Autologous Stem Cell Transplantation in Older Multiple Myeloma Patients." March 2016.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
22
Issue
3
Publish Date
2016
Start Page
S223
End Page
S223

Ex Vivo Expansion or Manipulation of Stem Cells to Improve Outcome of Umbilical Cord Blood Transplantation.

The outcome of umbilical cord blood transplantation for adult patients with hematologic malignancies now rivals that of matched unrelated donor transplantation. However, delayed hematopoietic and immunologic recovery remains a source of significant morbidity and mortality. Multiple strategies are now being studied to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit prior to transplantation. A second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Such a strategy may also address the problem of slow hematopoietic recovery as well as the increased risk of graft failure. Many of these strategies are now being tested in late phase multi-center clinical trials. If proven cost-effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.

Authors
Horwitz, ME
MLA Citation
Horwitz, ME. "Ex Vivo Expansion or Manipulation of Stem Cells to Improve Outcome of Umbilical Cord Blood Transplantation." Current hematologic malignancy reports 11.1 (February 2016): 12-18.
PMID
26677145
Source
epmc
Published In
Current Hematologic Malignancy Reports
Volume
11
Issue
1
Publish Date
2016
Start Page
12
End Page
18
DOI
10.1007/s11899-015-0297-7

A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Recipients with Hematological Malignancies

Authors
Chen, Y-B; Le-Rademacher, J; Kiefer, DM; Hamadani, M; DiPersio, JF; Litzow, MR; Craig, M; Horwitz, ME; Artz, A; McClune, B; Waller, EK; Fernandez, HF; Duong, HK; Kobusingye, H; Proue, M; Drexler, RJ; Horowitz, MM; Miller, JP; Devine, SM
MLA Citation
Chen, Y-B, Le-Rademacher, J, Kiefer, DM, Hamadani, M, DiPersio, JF, Litzow, MR, Craig, M, Horwitz, ME, Artz, A, McClune, B, Waller, EK, Fernandez, HF, Duong, HK, Kobusingye, H, Proue, M, Drexler, RJ, Horowitz, MM, Miller, JP, and Devine, SM. "A Phase II Study Evaluating the Safety and Efficacy of Subcutaneous Plerixafor for the Mobilization and Transplantation of HLA-Matched Sibling Donor Hematopoietic Stem Cells in Recipients with Hematological Malignancies." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901

Authors
Scott, BL; Pasquini, MC; Logan, B; Wu, J; Devine, S; Porter, DL; Maziarz, RT; Warlick, E; Fernandez, HF; Alyea, EP; Hamadani, M; Bashey, A; Giralt, SA; Leifer, E; Geller, N; Le-Rademacher, J; Mendizabal, AM; Horowitz, MM; Deeg, HJ; Horwitz, ME
MLA Citation
Scott, BL, Pasquini, MC, Logan, B, Wu, J, Devine, S, Porter, DL, Maziarz, RT, Warlick, E, Fernandez, HF, Alyea, EP, Hamadani, M, Bashey, A, Giralt, SA, Leifer, E, Geller, N, Le-Rademacher, J, Mendizabal, AM, Horowitz, MM, Deeg, HJ, and Horwitz, ME. "Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.

The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts.In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417.96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively.Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies.US National Heart, Lung, and Blood Institute and National Cancer Institute.

Authors
Anderlini, P; Wu, J; Gersten, I; Ewell, M; Tolar, J; Antin, JH; Adams, R; Arai, S; Eames, G; Horwitz, ME; McCarty, J; Nakamura, R; Pulsipher, MA; Rowley, S; Leifer, E; Carter, SL; DiFronzo, NL; Horowitz, MM; Confer, D; Deeg, HJ; Eapen, M
MLA Citation
Anderlini, P, Wu, J, Gersten, I, Ewell, M, Tolar, J, Antin, JH, Adams, R, Arai, S, Eames, G, Horwitz, ME, McCarty, J, Nakamura, R, Pulsipher, MA, Rowley, S, Leifer, E, Carter, SL, DiFronzo, NL, Horowitz, MM, Confer, D, Deeg, HJ, and Eapen, M. "Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study." The Lancet. Haematology 2.9 (September 2, 2015): e367-e375.
PMID
26685770
Source
epmc
Published In
The Lancet. Haematology
Volume
2
Issue
9
Publish Date
2015
Start Page
e367
End Page
e375
DOI
10.1016/s2352-3026(15)00147-7

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma.

High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 10(6) CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.

Authors
Tuchman, SA; Bacon, WA; Huang, L-W; Long, G; Rizzieri, D; Horwitz, M; Chute, JP; Sullivan, K; Morris Engemann, A; Yopp, A; Li, Z; Corbet, K; Chao, N; Gasparetto, C
MLA Citation
Tuchman, SA, Bacon, WA, Huang, L-W, Long, G, Rizzieri, D, Horwitz, M, Chute, JP, Sullivan, K, Morris Engemann, A, Yopp, A, Li, Z, Corbet, K, Chao, N, and Gasparetto, C. "Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma." Journal of clinical apheresis 30.3 (June 2015): 176-182.
PMID
25293363
Source
epmc
Published In
Journal of Clinical Apheresis
Volume
30
Issue
3
Publish Date
2015
Start Page
176
End Page
182
DOI
10.1002/jca.21360

Improving the outcome of umbilical cord blood transplantation through ex vivo expansion or graft manipulation.

The outcome of umbilical cord blood transplantation for adult patients with hematologic malignancies now rivals that of matched unrelated donor transplantation. However, relatively low lymphocyte and hematopoietic stem and progenitor cell dose is a source of significant morbidity and mortality. Multiple strategies are now being studied to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit before transplantation. Ex vivo expansion has the potential to increase the number of lymphocytes, committed progenitors and long-term repopulating hematopoietic stem cells. Increasing the numbers of lymphocytes and committed progenitor cells will address the issue of delayed hematopoietic recovery after umbilical cord blood transplantation. Increasing the hematopoietic stem cell content will improve the availability of adequately sized and matched cord blood units for transplantation. It may also eliminate the need for dual umbilical cord blood transplantation for those without an adequately sized single umbilical cord blood graft. The second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Such a strategy may also address the problem of slow hematopoietic recovery as well as the increased risk of graft failure. Many of these strategies are now being tested in late-phase multi-center clinical trials. If proven cost-effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.

Authors
Horwitz, ME; Frassoni, F
MLA Citation
Horwitz, ME, and Frassoni, F. "Improving the outcome of umbilical cord blood transplantation through ex vivo expansion or graft manipulation." Cytotherapy 17.6 (June 2015): 730-738. (Review)
PMID
25778757
Source
epmc
Published In
Cytotherapy (Informa)
Volume
17
Issue
6
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1016/j.jcyt.2015.02.004

Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia.

Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 10(7) /kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80-96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51-76) and 36% (95%CI: 24-49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26-52), and the 3-year relapse incidence was 11% (95%CI: 4-21). With a median 37-month (range 23-71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37-63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

Authors
Barker, JN; Fei, M; Karanes, C; Horwitz, M; Devine, S; Kindwall-Keller, TL; Holter, J; Adams, A; Logan, B; Navarro, WH; Riches, M; RCI BMT 05-DCB Protocol Team,
MLA Citation
Barker, JN, Fei, M, Karanes, C, Horwitz, M, Devine, S, Kindwall-Keller, TL, Holter, J, Adams, A, Logan, B, Navarro, WH, Riches, M, and RCI BMT 05-DCB Protocol Team, . "Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia." British journal of haematology 168.3 (February 2015): 405-412.
PMID
25272241
Source
epmc
Published In
British Journal of Haematology
Volume
168
Issue
3
Publish Date
2015
Start Page
405
End Page
412
DOI
10.1111/bjh.13136

Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial

Authors
Green, MMB; Horwitz, ME; Kang, Y; Chao, NJ; Long, GD; Rizzieri, D; Gasparetto, C; Sung, AD; Sarantopoulos, S; Li, Z; Corbet, K; Riggan-Stuelke, E; Sullivan, K; Wilson, B; Chhabra, S; Costa, LV; Mims, A; Stuart, R
MLA Citation
Green, MMB, Horwitz, ME, Kang, Y, Chao, NJ, Long, GD, Rizzieri, D, Gasparetto, C, Sung, AD, Sarantopoulos, S, Li, Z, Corbet, K, Riggan-Stuelke, E, Sullivan, K, Wilson, B, Chhabra, S, Costa, LV, Mims, A, and Stuart, R. "Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial." February 2015.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
S31
End Page
S32

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma

© 2014 Wiley Periodicals, Inc. High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 10 < sup > 6 < /sup > CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54] ). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.

Authors
Tuchman, SA; Bacon, WA; Huang, LW; Long, G; Rizzieri, D; Horwitz, M; Chute, JP; Sullivan, K; Engemann, AM; Yopp, A; Li, Z; Corbet, K; Chao, N; Gasparetto, C
MLA Citation
Tuchman, SA, Bacon, WA, Huang, LW, Long, G, Rizzieri, D, Horwitz, M, Chute, JP, Sullivan, K, Engemann, AM, Yopp, A, Li, Z, Corbet, K, Chao, N, and Gasparetto, C. "Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma." Journal of Clinical Apheresis 30.3 (January 1, 2015): 176-182.
Source
scopus
Published In
Journal of Clinical Apheresis
Volume
30
Issue
3
Publish Date
2015
Start Page
176
End Page
182
DOI
10.1002/jca.21360

Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia

© 2014 John Wiley & Sons Ltd.Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 107/kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80-96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51-76) and 36% (95%CI: 24-49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26-52), and the 3-year relapse incidence was 11% (95%CI: 4-21). With a median 37-month (range 23-71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37-63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

Authors
Barker, JN; Fei, M; Karanes, C; Horwitz, M; Devine, S; Kindwall-Keller, TL; Holter, J; Adams, A; Logan, B; Navarro, WH; Riches, M
MLA Citation
Barker, JN, Fei, M, Karanes, C, Horwitz, M, Devine, S, Kindwall-Keller, TL, Holter, J, Adams, A, Logan, B, Navarro, WH, and Riches, M. "Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia." British Journal of Haematology 168.3 (2015): 405-412.
Source
scival
Published In
British Journal of Haematology
Volume
168
Issue
3
Publish Date
2015
Start Page
405
End Page
412
DOI
10.1111/bjh.13136

Cardiopulmonary exercise testing prior to myeloablative allo-SCT: a feasibility study.

The feasibility of symptom-limited cardiopulmonary exercise testing (CPET) prior to allo-SCT was assessed in addition to the prognostic value of CPET-derived measures. CPET was performed prospectively on 21 patients with hematologic malignancies, with assessments of peak (for example, peak oxygen consumption, VO2peak) and submaximal (for example, ventilatory threshold (VT)) measures of cardiopulmonary function. No serious adverse events were observed during CPET procedures, with 95% of patients achieving criteria for a peak test. Mean VO2peak was 24.7±6.4 mL kg(-1 )min(-1) (range: 10.9-35.5), equivalent to 29%±17% below that of age-matched healthy controls. All patients proceeded with the conditioning regimen followed by allo-SCT. Median follow-up was 25 months. During this period, 11 (52.4%) patients died (n=6, relapsed disease; n=5, non-relapse mortality (NRM)); 9 patients (43%) developed pulmonary toxicity. In univariate analyses, both peak and submaximal markers of cardiopulmonary function were predictors of OS, pulmonary toxicity and NRM. For OS, the HR for VO2peak and VT were 0.89 (95% CI, 0.8-0.99, P=0.04) and 0.84 (95% CI, 0.71-0.98, P=0.03), respectively. In conclusion, CPET is safe and feasible prior to allo-SCT. Patients have marked impairments in cardiopulmonary function prior to allo-SCT. CPET-derived metrics may complement conventional measures to improve risk stratification.

Authors
Kelsey, CR; Scott, JM; Lane, A; Schwitzer, E; West, MJ; Thomas, S; Herndon, JE; Michalski, MG; Horwitz, ME; Hennig, T; Jones, LW
MLA Citation
Kelsey, CR, Scott, JM, Lane, A, Schwitzer, E, West, MJ, Thomas, S, Herndon, JE, Michalski, MG, Horwitz, ME, Hennig, T, and Jones, LW. "Cardiopulmonary exercise testing prior to myeloablative allo-SCT: a feasibility study." Bone marrow transplantation 49.10 (October 2014): 1330-1336.
PMID
25068429
Source
epmc
Published In
Bone Marrow Transplantation
Volume
49
Issue
10
Publish Date
2014
Start Page
1330
End Page
1336
DOI
10.1038/bmt.2014.159

Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.Clinicaltrials.gov NCT01221857.Gamida Cell Ltd.

Authors
Horwitz, ME; Chao, NJ; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; McDonald, C; Waters-Pick, B; Stiff, P; Wease, S; Peled, A; Snyder, D; Cohen, EG; Shoham, H; Landau, E; Friend, E; Peleg, I; Aschengrau, D; Yackoubov, D; Kurtzberg, J; Peled, T
MLA Citation
Horwitz, ME, Chao, NJ, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, McDonald, C, Waters-Pick, B, Stiff, P, Wease, S, Peled, A, Snyder, D, Cohen, EG, Shoham, H, Landau, E, Friend, E, Peleg, I, Aschengrau, D, Yackoubov, D, Kurtzberg, J, and Peled, T. "Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment." The Journal of clinical investigation 124.7 (July 2014): 3121-3128.
PMID
24911148
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
7
Publish Date
2014
Start Page
3121
End Page
3128
DOI
10.1172/jci74556

Increased BCR responsiveness in B cells from patients with chronic GVHD.

Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.

Authors
Allen, JL; Tata, PV; Fore, MS; Wooten, J; Rudra, S; Deal, AM; Sharf, A; Hoffert, T; Roehrs, PA; Shea, TC; Serody, JS; Richards, KL; Jagasia, M; Lee, SJ; Rizzieri, D; Horwitz, ME; Chao, NJ; Sarantopoulos, S
MLA Citation
Allen, JL, Tata, PV, Fore, MS, Wooten, J, Rudra, S, Deal, AM, Sharf, A, Hoffert, T, Roehrs, PA, Shea, TC, Serody, JS, Richards, KL, Jagasia, M, Lee, SJ, Rizzieri, D, Horwitz, ME, Chao, NJ, and Sarantopoulos, S. "Increased BCR responsiveness in B cells from patients with chronic GVHD." Blood 123.13 (March 2014): 2108-2115.
PMID
24532806
Source
epmc
Published In
Blood
Volume
123
Issue
13
Publish Date
2014
Start Page
2108
End Page
2115
DOI
10.1182/blood-2013-10-533562

Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies.

We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.

Authors
Kanda, J; Long, GD; Gasparetto, C; Horwitz, ME; Sullivan, KM; Chute, JP; Morris, A; Shafique, M; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Long, GD, Gasparetto, C, Horwitz, ME, Sullivan, KM, Chute, JP, Morris, A, Shafique, M, Li, Z, Chao, NJ, and Rizzieri, DA. "Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies." Biol Blood Marrow Transplant 20.2 (February 2014): 257-263.
PMID
24269380
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
2
Publish Date
2014
Start Page
257
End Page
263
DOI
10.1016/j.bbmt.2013.11.010

Matched Pair Comparison of Busulfan/Cyclophosphamide/Etoposide (BuCyE) to Carmustine/Etoposide/Cytarabine/Melphalan (BEAM) Conditioning Regimen Prior to Autologous Hematopoietic Cell Transplantation (autoHCT) for Lymphoma

Authors
Pasquini, MC; Le Rademacher, J; Flowers, C; Lill, M; Costa, LJ; Shore, TB; Vaughan, W; Craig, M; Freytes, CO; Shea, TC; Horwitz, ME; Fay, JW; Mineishi, S; Rondelli, D; Mason, J; Reddy, V; Braunschweig, I; Ai, W; Armstrong, E; Smith, A; Zhao, C; Elekes, A; Carreras, J; Kato, K; Waller, EK
MLA Citation
Pasquini, MC, Le Rademacher, J, Flowers, C, Lill, M, Costa, LJ, Shore, TB, Vaughan, W, Craig, M, Freytes, CO, Shea, TC, Horwitz, ME, Fay, JW, Mineishi, S, Rondelli, D, Mason, J, Reddy, V, Braunschweig, I, Ai, W, Armstrong, E, Smith, A, Zhao, C, Elekes, A, Carreras, J, Kato, K, and Waller, EK. "Matched Pair Comparison of Busulfan/Cyclophosphamide/Etoposide (BuCyE) to Carmustine/Etoposide/Cytarabine/Melphalan (BEAM) Conditioning Regimen Prior to Autologous Hematopoietic Cell Transplantation (autoHCT) for Lymphoma." February 2014.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
2
Publish Date
2014
Start Page
S162
End Page
S162

Cardiopulmonary exercise testing prior to myeloablative allo-SCT: A feasibility study

© 2014 Macmillan Publishers Limited All rights reserved. The feasibility of symptom-limited cardiopulmonary exercise testing (CPET) prior to allo-SCT was assessed in addition to the prognostic value of CPET-derived measures. CPET was performed prospectively on 21 patients with hematologic malignancies, with assessments of peak (for example, peak oxygen consumption, VO 2peak ) and submaximal (for example, ventilatory threshold (VT)) measures of cardiopulmonary function. No serious adverse events were observed during CPET procedures, with 95% of patients achieving criteria for a peak test. Mean VO 2peak was 24.7 ± 6.4 mL kg -1 min -1 (range: 10.9-35.5), equivalent to 29% ± 17% below that of age-matched healthy controls. All patients proceeded with the conditioning regimen followed by allo-SCT. Median follow-up was 25 months. During this period, 11 (52.4%) patients died (n = 6, relapsed disease; n = 5, non-relapse mortality (NRM)); 9 patients (43%) developed pulmonary toxicity. In univariate analyses, both peak and submaximal markers of cardiopulmonary function were predictors of OS, pulmonary toxicity and NRM. For OS, the HR for VO 2peak and VT were 0.89 (95% CI, 0.8-0.99, P = 0.04) and 0.84 (95% CI, 0.71-0.98, P = 0.03), respectively. In conclusion, CPET is safe and feasible prior to allo-SCT. Patients have marked impairments in cardiopulmonary function prior to allo-SCT. CPET-derived metrics may complement conventional measures to improve risk stratification.

Authors
Kelsey, CR; Scott, JM; Lane, A; Schwitzer, E; West, MJ; Thomas, S; Herndon, JE; Michalski, MG; Horwitz, ME; Hennig, T; Jones, LW
MLA Citation
Kelsey, CR, Scott, JM, Lane, A, Schwitzer, E, West, MJ, Thomas, S, Herndon, JE, Michalski, MG, Horwitz, ME, Hennig, T, and Jones, LW. "Cardiopulmonary exercise testing prior to myeloablative allo-SCT: A feasibility study." Bone Marrow Transplantation 49.10 (January 1, 2014): 1330-1336.
Source
scopus
Published In
Bone Marrow Transplantation
Volume
49
Issue
10
Publish Date
2014
Start Page
1330
End Page
1336
DOI
10.1038/bmt.2014.159

Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34 + cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34 + cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10 6 cells/kg on day 1 vs 2.92 × 10 6 cells/kg, P=0.0231; myeloma: 4.16 × 10 6 vs 3.69 × 10 6 cells/kg, P < 0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10 6 cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P < 0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10 300 vs $7300, P < 0.0001; myeloma: $8800 vs $5600, P < 0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.

Authors
Sung, AD; Grima, DT; Bernard, LM; Brown, S; Carrum, G; Holmberg, L; Horwitz, ME; Liesveld, JL; Kanda, J; McClune, B; Shaughnessy, P; Tricot, GJ; Chao, NJ
MLA Citation
Sung, AD, Grima, DT, Bernard, LM, Brown, S, Carrum, G, Holmberg, L, Horwitz, ME, Liesveld, JL, Kanda, J, McClune, B, Shaughnessy, P, Tricot, GJ, and Chao, NJ. "Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone." Bone Marrow Transplantation 48.11 (November 1, 2013): 1444-1449.
Source
scopus
Published In
Bone Marrow Transplantation
Volume
48
Issue
11
Publish Date
2013
Start Page
1444
End Page
1449
DOI
10.1038/bmt.2013.80

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment.

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥ 12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥ 13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥ 38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.

Authors
Kanda, J; Kaynar, L; Kanda, Y; Prasad, VK; Parikh, SH; Lan, L; Shen, T; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; Winkel, S; McPherson, J; Kurtzberg, J; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Kaynar, L, Kanda, Y, Prasad, VK, Parikh, SH, Lan, L, Shen, T, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, Winkel, S, McPherson, J, Kurtzberg, J, Chao, NJ, and Horwitz, ME. "Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment." Bone Marrow Transplant 48.7 (July 2013): 926-931.
PMID
23334274
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
48
Issue
7
Publish Date
2013
Start Page
926
End Page
931
DOI
10.1038/bmt.2012.279

A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma.

PURPOSE: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma. EXPERIMENTAL DESIGN: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m(2) or 1.3 mg/m(2) IV bolus on days 1 and 8 of a 21-day cycle). RESULTS: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. CONCLUSION: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.

Authors
Held, LA; Rizzieri, D; Long, GD; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Horwitz, ME; Chao, NJ; Gasparetto, C
MLA Citation
Held, LA, Rizzieri, D, Long, GD, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Horwitz, ME, Chao, NJ, and Gasparetto, C. "A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma." Cancer Invest 31.3 (March 2013): 172-176.
PMID
23406188
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
31
Issue
3
Publish Date
2013
Start Page
172
End Page
176
DOI
10.3109/07357907.2012.756109

Surgical Mask Usage Reduces the Incidence of Parainfleunza Virus 3 in Recipients of Stem Cell Transplantation

Authors
Sung, AD; Sung, JAM; Corbet, K; Hars, V; Lan, L; Broadwater, G; Zanter, A; Chute, J; Gasparetto, C; Long, G; Rizzieri, D; Sullivan, K; Chao, NJ; Horwitz, ME
MLA Citation
Sung, AD, Sung, JAM, Corbet, K, Hars, V, Lan, L, Broadwater, G, Zanter, A, Chute, J, Gasparetto, C, Long, G, Rizzieri, D, Sullivan, K, Chao, NJ, and Horwitz, ME. "Surgical Mask Usage Reduces the Incidence of Parainfleunza Virus 3 in Recipients of Stem Cell Transplantation." February 2013.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
19
Issue
2
Publish Date
2013
Start Page
S271
End Page
S272

Nicord (R) Expanded Hematopoietic Progenitor Cells (HPC) Are Capable of Outcompeting the Unmanipulated (UM) Cord Blood Unit and of Prolonged Myeloid and Lymphoid Engraftment Following Myeloablative Dual Umbilical Cord Blood (UCB) Transplantation

Authors
Horwitz, ME; Stiff, PJ; Chao, NJ; Rizzieri, D; Long, G; Sullivan, K; Gasparetto, C; Chute, J; Morris, A; McDonald, C; Wease, S; Snyder, D; Galamidi-Cohen, E; Shoham, H; Landau, E; Friend, E; Kurtzberg, J; Peled, T
MLA Citation
Horwitz, ME, Stiff, PJ, Chao, NJ, Rizzieri, D, Long, G, Sullivan, K, Gasparetto, C, Chute, J, Morris, A, McDonald, C, Wease, S, Snyder, D, Galamidi-Cohen, E, Shoham, H, Landau, E, Friend, E, Kurtzberg, J, and Peled, T. "Nicord (R) Expanded Hematopoietic Progenitor Cells (HPC) Are Capable of Outcompeting the Unmanipulated (UM) Cord Blood Unit and of Prolonged Myeloid and Lymphoid Engraftment Following Myeloablative Dual Umbilical Cord Blood (UCB) Transplantation." February 2013.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
19
Issue
2
Publish Date
2013
Start Page
S118
End Page
S118

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation. © 2013 Macmillan Publishers Limited All rights reserved.

Authors
Kanda, J; Kaynar, L; Kanda, Y; Prasad, VK; Parikh, SH; Lan, L; Shen, T; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; Winkel, S; McPherson, J; Kurtzberg, J; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Kaynar, L, Kanda, Y, Prasad, VK, Parikh, SH, Lan, L, Shen, T, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, Winkel, S, McPherson, J, Kurtzberg, J, Chao, NJ, and Horwitz, ME. "Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment." Bone Marrow Transplantation 48.7 (2013): 926-931.
Source
scival
Published In
Bone Marrow Transplantation
Volume
48
Issue
7
Publish Date
2013
Start Page
926
End Page
931
DOI
10.1038/bmt.2012.279

Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34+ cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34+ cells/day than those with G-CSF alone (lymphoma: average 5.51 × 106 cells/kg on day 1 vs 2.92 × 106 cells/kg, P=0.0231; myeloma: 4.16 × 106 vs 3.69 × 106 cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 106 cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10 300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.Bone Marrow Transplantation advance online publication, 10 June 2013; doi:10.1038/bmt.2013.80.

Authors
Sung, AD; Grima, DT; Bernard, LM; Brown, S; Carrum, G; Holmberg, L; Horwitz, ME; Liesveld, JL; Kanda, J; McClune, B; al, E
MLA Citation
Sung, AD, Grima, DT, Bernard, LM, Brown, S, Carrum, G, Holmberg, L, Horwitz, ME, Liesveld, JL, Kanda, J, McClune, B, and al, E. "Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone." Bone Marrow Transplantation (2013).
PMID
23749109
Source
scival
Published In
Bone Marrow Transplantation
Publish Date
2013
DOI
10.1038/bmt.2013.80

Surgical Mask Usage Reduces the Incidence of Parainfluenza Virus 3 in Recipients of Stem Cell Transplantation

Authors
Sung, AD; Sung, JAM; Corbet, K; Broadwater, G; Hars, V; Zanter, A; Chao, NJ; Horwitz, ME
MLA Citation
Sung, AD, Sung, JAM, Corbet, K, Broadwater, G, Hars, V, Zanter, A, Chao, NJ, and Horwitz, ME. "Surgical Mask Usage Reduces the Incidence of Parainfluenza Virus 3 in Recipients of Stem Cell Transplantation." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Surgical Mask Usage Reduces the Incidence of Parainfluenza Virus 3 in Recipients of Stem Cell Transplantation

Authors
Sung, AD; Sung, JAM; Corbet, K; Broadwater, G; Hars, V; Zanter, A; Chao, NJ; Horwitz, ME
MLA Citation
Sung, AD, Sung, JAM, Corbet, K, Broadwater, G, Hars, V, Zanter, A, Chao, NJ, and Horwitz, ME. "Surgical Mask Usage Reduces the Incidence of Parainfluenza Virus 3 in Recipients of Stem Cell Transplantation." November 16, 2012.
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation.

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.

Authors
Kanda, J; Chiou, L-W; Szabolcs, P; Sempowski, GD; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; McPherson, J; Hale, J; Livingston, JA; Broadwater, G; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Chiou, L-W, Szabolcs, P, Sempowski, GD, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, McPherson, J, Hale, J, Livingston, JA, Broadwater, G, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation." Biol Blood Marrow Transplant 18.11 (November 2012): 1664-1676.e1.
PMID
22698485
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
11
Publish Date
2012
Start Page
1664
End Page
1676.e1
DOI
10.1016/j.bbmt.2012.06.005

Mini test dose of intravenous busulfan (busulfex(®)) in allogeneic non-myeloablative stem cell transplantation, followed by liquid chromatography tandem-mass spectrometry.

Authors
Spasojevic, I; da Costa, LRS; Horwitz, ME; Long, GD; Sullivan, KM; Chute, JP; Gasparetto, C; Morris, A; Chao, NJ; Rizzieri, DA
MLA Citation
Spasojevic, I, da Costa, LRS, Horwitz, ME, Long, GD, Sullivan, KM, Chute, JP, Gasparetto, C, Morris, A, Chao, NJ, and Rizzieri, DA. "Mini test dose of intravenous busulfan (busulfex(®)) in allogeneic non-myeloablative stem cell transplantation, followed by liquid chromatography tandem-mass spectrometry." Cancer Invest 30.9 (November 2012): 679-682.
PMID
23020519
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
30
Issue
9
Publish Date
2012
Start Page
679
End Page
682
DOI
10.3109/07357907.2012.726386

Efficacy and safety of hematopoietic stem cell remobilization with plerixafor+G-CSF in adult patients with germ cell tumors.

Autologous hematopoietic SCT (auto-HSCT) can be curative for patients with germ cell tumors. Poor stem cell mobilization jeopardizes the ability to deliver this therapy. Herein, we describe a retrospective study examining safety and efficacy of plerixafor in combination with G-CSF for patients with germ cell tumors who had previously failed stem cell collection. Overall, 21 patients with germ cell tumors and previous mobilization failure were remobilized with G-CSF (10 μg/kg SC) and plerixafor (0.24 mg/kg SC) beginning the evening of day 4 of G-CSF treatment. Dosing of G-CSF and plerixafor was repeated until collection of ≥ 2 × 10(6) CD34+ cells/kg. Remobilization resulted in a median yield of 3.2 × 10(6) CD34+ cells/kg. A total of 17 (81%) patients collected ≥ 2 × 10(6) and 9 (43%) patients collected ≥ 4 × 10(6) CD34+ cells/kg in a median of 2 (range 1-3) and 3 (range 1-4) days, respectively. In all, 16 (76%) patients proceeded to transplant; 8 (38%) received tandem transplants. There were no serious adverse events. In summary, the majority of patients with germ cell tumors who failed prior mobilization with growth factors ± chemotherapy were remobilized with plerixafor plus G-CSF facilitating at least one auto-HSCT. Use of plerixafor plus G-CSF can increase access of this potentially life-saving procedure to patients with high-risk germ cell tumors.

Authors
Horwitz, ME; Long, G; Holman, P; Libby, E; Calandra, GC; Schriber, JR
MLA Citation
Horwitz, ME, Long, G, Holman, P, Libby, E, Calandra, GC, and Schriber, JR. "Efficacy and safety of hematopoietic stem cell remobilization with plerixafor+G-CSF in adult patients with germ cell tumors." Bone Marrow Transplant 47.10 (October 2012): 1283-1286.
PMID
22343676
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
10
Publish Date
2012
Start Page
1283
End Page
1286
DOI
10.1038/bmt.2012.21

Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism.

It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD), and inborn errors of metabolism (IEM) return to rates observed in the general population, matched for age, sex, and nationality. We studied patients with SCID (n = 201), non-SCID PIDD (n = 405), and IEM (n = 348) who survived for at least 2 years after transplantation with normal T cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rate was significantly higher in these patients compared with the general population for several years after transplantation. The rate decreased toward the normal rate in patients with SCID and non-SCID PIDD beyond 6 years after transplantation, but not in patients with IEM. Active chronic graft-versus-host disease at 2 years was associated with increased risk of late mortality for all diseases (hazard ratio [HR], 1.87; P = .05). In addition, late mortality was higher in patients with non-SCID PIDD who received T cell-depleted grafts (HR 4.16; P = .007) and in patients with IEM who received unrelated donor grafts (HR, 2.72; P = .03) or mismatched related donor grafts (HR, 3.76; P = .01). The finding of higher mortality rates in these long-term survivors for many years after transplantation confirms the need for long-term surveillance.

Authors
Eapen, M; Ahn, KW; Orchard, PJ; Cowan, MJ; Davies, SM; Fasth, A; Hassebroek, A; Ayas, M; Bonfim, C; O'Brien, TA; Gross, TG; Horwitz, M; Horwitz, E; Kapoor, N; Kurtzberg, J; Majhail, N; Ringden, O; Szabolcs, P; Veys, P; Baker, KS
MLA Citation
Eapen, M, Ahn, KW, Orchard, PJ, Cowan, MJ, Davies, SM, Fasth, A, Hassebroek, A, Ayas, M, Bonfim, C, O'Brien, TA, Gross, TG, Horwitz, M, Horwitz, E, Kapoor, N, Kurtzberg, J, Majhail, N, Ringden, O, Szabolcs, P, Veys, P, and Baker, KS. "Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism." Biol Blood Marrow Transplant 18.9 (September 2012): 1438-1445.
PMID
22430083
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
9
Publish Date
2012
Start Page
1438
End Page
1445
DOI
10.1016/j.bbmt.2012.03.003

Preemptive dosing of plerixafor given to poor stem cell mobilizers on day 5 of G-CSF administration.

Plerixafor, given on day 4 of G-CSF treatment is more effective than G-CSF alone in mobilizing hematopoietic progenitor cells. We tested a strategy of preemptive plerixafor use following assessment of the peak mobilization response to 5 days of G-CSF. Patients were eligible for plerixafor if, on day 5 of G-CSF, there were <7 circulating CD34+ cells/μL or if <1.3 × 10(6) CD34+ cells/kg were collected on the first day of apheresis. Plerixafor (0.24 mg/kg s.c.) was given on day 5 of G-CSF followed by apheresis on day 6. This was repeated for up to two additional doses of plerixafor. The primary end point of the study was the percentage of patients who collected at least 2 × 10(6) CD34+ cells/kg. Twenty candidates for auto-SCT enrolled on the trial. The circulating CD34+ cell level increased a median of 3.1 fold (range 1-8 fold) after the first dose of plerixafor and a median of 1.2 fold (range 0.3-6.5 fold) after the second dose of plerixafor. In all, 15 out of 20 (75%) patients achieved the primary end point. In conclusion, the decision to administer plerixafor can be delayed until after the peak mobilization response to G-CSF has been fully assessed.

Authors
Horwitz, ME; Chute, JP; Gasparetto, C; Long, GD; McDonald, C; Morris, A; Rizzieri, DA; Sullivan, KM; Chao, NJ
MLA Citation
Horwitz, ME, Chute, JP, Gasparetto, C, Long, GD, McDonald, C, Morris, A, Rizzieri, DA, Sullivan, KM, and Chao, NJ. "Preemptive dosing of plerixafor given to poor stem cell mobilizers on day 5 of G-CSF administration." Bone Marrow Transplant 47.8 (August 2012): 1051-1055.
PMID
22080963
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
8
Publish Date
2012
Start Page
1051
End Page
1055
DOI
10.1038/bmt.2011.217

Differential impact of inhibitory and activating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors.

The impact of activating KIR (aKIR) and inhibitory KIR (iKIR) on OS, relapse-related mortality (RRM) and acute GVHD (aGVHD) was prospectively studied in 84 adults with high-risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic SCT (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM is dependent on GVL effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both GVH and rejection directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (P=0.009) and RRM was lower (P=0.036) in patients missing HLA-C group2 ligand to donor iKIR. OS was higher if patients had >1 missing ligand (P=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was better with donor aKIR 2DS2 (P=0.028). There was a trend towards shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes were too small to provide inferential statistics. Findings in lymphoid malignancy patients should be further studied. These results suggest that the absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.

Authors
Chen, D-F; Prasad, VK; Broadwater, G; Reinsmoen, NL; DeOliveira, A; Clark, A; Sullivan, KM; Chute, JP; Horwitz, ME; Gasparetto, C; Long, GD; Yang, Y; Chao, NJ; Rizzieri, DA
MLA Citation
Chen, D-F, Prasad, VK, Broadwater, G, Reinsmoen, NL, DeOliveira, A, Clark, A, Sullivan, KM, Chute, JP, Horwitz, ME, Gasparetto, C, Long, GD, Yang, Y, Chao, NJ, and Rizzieri, DA. "Differential impact of inhibitory and activating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors." Bone Marrow Transplant 47.6 (June 2012): 817-823.
PMID
22139069
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
6
Publish Date
2012
Start Page
817
End Page
823
DOI
10.1038/bmt.2011.181

Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation.

Primary graft failure after allogeneic hematopoietic cell transplantation is a life-threatening complication. A shortened conditioning regimen may reduce the risk of infection and increase the chance of survival. Here, we report the outcome of 11 patients with hematologic diseases (median age, 44; range, 25-67 years, seven males) who received a 1-day reduced-intensity preparative regimen given as a re-transplantation for primary graft failure. The salvage regimen consisted of fludarabine, cyclophosphamide, alemtuzumab and TBI, all administered 1 day before re-transplantation. All patients received T-cell replete PBSCs from the same or a different haploidentical donor (n=10) or from the same matched sibling donor (n=1). Neutrophil counts promptly increased to >500/μL for 10 of the 11 patients at a median of 13 days. Of these, none developed grade III/IV acute GVHD. At present, 8 of the 11 patients are alive with a median follow-up of 11.2 months from re-transplantation and 5 of the 8 are in remission. In conclusion, this series suggests that our 1-day preparative regimen is feasible, leads to successful engraftment in a high proportion of patients, and is appropriate for patients requiring immediate re-transplantation after primary graft failure following reduced-intensity transplantation.

Authors
Kanda, J; Horwitz, ME; Long, GD; Gasparetto, C; Sullivan, KM; Chute, JP; Morris, A; Hennig, T; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Horwitz, ME, Long, GD, Gasparetto, C, Sullivan, KM, Chute, JP, Morris, A, Hennig, T, Li, Z, Chao, NJ, and Rizzieri, DA. "Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation." Bone Marrow Transplant 47.5 (May 2012): 700-705.
PMID
21804612
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
5
Publish Date
2012
Start Page
700
End Page
705
DOI
10.1038/bmt.2011.158

USE OF CYCLOSPORINE IS ASSOCIATED WITH THE INCREASE IN PRE-ENGRAFTMENT SYNDROME AFTER MYELOABLATIVE DUAL CORD BLOOD TRANSPLANTATION

Authors
Kanda, J; Kaynar, L; Kanda, Y; Prasad, VK; Parikh, SH; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; Winkel, S; McPherson, J; Kurtzberg, J; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Kaynar, L, Kanda, Y, Prasad, VK, Parikh, SH, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, Winkel, S, McPherson, J, Kurtzberg, J, Chao, NJ, and Horwitz, ME. "USE OF CYCLOSPORINE IS ASSOCIATED WITH THE INCREASE IN PRE-ENGRAFTMENT SYNDROME AFTER MYELOABLATIVE DUAL CORD BLOOD TRANSPLANTATION." February 2012.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
2
Publish Date
2012
Start Page
S332
End Page
S332

DOSE PRECISION USING A PRETRANSPLANT TEST PK OF INTRAVENOUS BUSULFAN PRIOR TO BuCyVP-16 PREPARATIVE REGIMEN IN LYMPHOMA

Authors
Lill, M; Lim, S; Yeh, RF; Waller, E; Costa, LJ; Shore, T; Craig, M; Freytes, CO; Shea, TC; Mineishi, S; Rondelli, D; Horwitz, ME; Braunschweig, I; Fay, JW; Mason, JR; Yu, LH; Patil, S; Sun, Y; Armstrong, E; Elekes, A; Kato, K; Vaughan, WP
MLA Citation
Lill, M, Lim, S, Yeh, RF, Waller, E, Costa, LJ, Shore, T, Craig, M, Freytes, CO, Shea, TC, Mineishi, S, Rondelli, D, Horwitz, ME, Braunschweig, I, Fay, JW, Mason, JR, Yu, LH, Patil, S, Sun, Y, Armstrong, E, Elekes, A, Kato, K, and Vaughan, WP. "DOSE PRECISION USING A PRETRANSPLANT TEST PK OF INTRAVENOUS BUSULFAN PRIOR TO BuCyVP-16 PREPARATIVE REGIMEN IN LYMPHOMA." February 2012.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
2
Publish Date
2012
Start Page
S246
End Page
S246

Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels

Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m2), and antithymocyte globulin was associated with excessive organ toxicity. © 2012 American Society for Blood and Marrow Transplantation.

Authors
Tolar, J; Deeg, HJ; Arai, S; Horwitz, M; Antin, JH; McCarty, JM; Adams, RH; Ewell, M; Leifer, ES; Gersten, ID; Carter, SL; Horowitz, MM; Nakamura, R; Pulsipher, MA; DiFronzo, NL; Confer, DL; Eapen, M; Anderlini, P
MLA Citation
Tolar, J, Deeg, HJ, Arai, S, Horwitz, M, Antin, JH, McCarty, JM, Adams, RH, Ewell, M, Leifer, ES, Gersten, ID, Carter, SL, Horowitz, MM, Nakamura, R, Pulsipher, MA, DiFronzo, NL, Confer, DL, Eapen, M, and Anderlini, P. "Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels." Biology of Blood and Marrow Transplantation 18.7 (2012): 1007-1011.
PMID
22546497
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
7
Publish Date
2012
Start Page
1007
End Page
1011
DOI
10.1016/j.bbmt.2012.04.014

Impact of High Dose Cyclophosphamide on the Outcome of Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma

Authors
Bacon, WA; Long, GD; Rizzieri, DA; Horwitz, ME; Chute, JP; Sullivan, KM; Yopp, A; Johns, A; Chao, NJ; Gasparetto, C
MLA Citation
Bacon, WA, Long, GD, Rizzieri, DA, Horwitz, ME, Chute, JP, Sullivan, KM, Yopp, A, Johns, A, Chao, NJ, and Gasparetto, C. "Impact of High Dose Cyclophosphamide on the Outcome of Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
1765
End Page
1765

The Impact of Lymphocyte Subset Recovery At 3 Months on Progression-Free Survival After Myeloablative Allogeneic Stem Cell Transplantation

Authors
Kanda, J; Rizzieri, DA; Long, GD; Gasparetto, C; Chute, JP; Sullivan, KM; Morris, A; McPherson, J; Livingston, JA; Broadwater, G; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Long, GD, Gasparetto, C, Chute, JP, Sullivan, KM, Morris, A, McPherson, J, Livingston, JA, Broadwater, G, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "The Impact of Lymphocyte Subset Recovery At 3 Months on Progression-Free Survival After Myeloablative Allogeneic Stem Cell Transplantation." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
1736
End Page
1736

High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation

Authors
Gasparetto, C; Bacon, WA; Doan, P; Rizzieri, DA; Horwitz, ME; Chute, JP; Sullivan, KM; Yopp, A; Li, Z; Chao, NJ; Long, GD
MLA Citation
Gasparetto, C, Bacon, WA, Doan, P, Rizzieri, DA, Horwitz, ME, Chute, JP, Sullivan, KM, Yopp, A, Li, Z, Chao, NJ, and Long, GD. "High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
879
End Page
879

Chemo-Mobilization Provides Superior Mobilization and Collection in Autologous Stem Cell Transplants but with Less Predictability and At a Higher Cost

Authors
Chao, NJ; Grima, DT; Carrum, G; Holmberg, L; Fung, HC; Brown, S; Horwitz, ME; Bernard, LM; Kanda, J; Liesveld, JL; McClune, B; Shaughnessy, P; Tricot, GJ
MLA Citation
Chao, NJ, Grima, DT, Carrum, G, Holmberg, L, Fung, HC, Brown, S, Horwitz, ME, Bernard, LM, Kanda, J, Liesveld, JL, McClune, B, Shaughnessy, P, and Tricot, GJ. "Chemo-Mobilization Provides Superior Mobilization and Collection in Autologous Stem Cell Transplants but with Less Predictability and At a Higher Cost." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
1729
End Page
1729

Differences in Stem Cell Collection Practices and Related Outcomes Between Centers That Conduct and Do Not Conduct Aphaeresis on Weekends

Authors
Chao, NJ; Bernard, LM; Carrum, G; Fung, HC; Grima, DT; Holmberg, L; Brown, S; Horwitz, ME; Kanda, J; Liesveld, JL; McClune, B; Shaughnessy, P; Tricot, GJ
MLA Citation
Chao, NJ, Bernard, LM, Carrum, G, Fung, HC, Grima, DT, Holmberg, L, Brown, S, Horwitz, ME, Kanda, J, Liesveld, JL, McClune, B, Shaughnessy, P, and Tricot, GJ. "Differences in Stem Cell Collection Practices and Related Outcomes Between Centers That Conduct and Do Not Conduct Aphaeresis on Weekends." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
839
End Page
840

Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.

PURPOSE: To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation. METHODS AND MATERIALS: A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity. RESULTS: The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen). CONCLUSIONS: Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.

Authors
Kelsey, CR; Horwitz, ME; Chino, JP; Craciunescu, O; Steffey, B; Folz, RJ; Chao, NJ; Rizzieri, DA; Marks, LB
MLA Citation
Kelsey, CR, Horwitz, ME, Chino, JP, Craciunescu, O, Steffey, B, Folz, RJ, Chao, NJ, Rizzieri, DA, and Marks, LB. "Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors." Int J Radiat Oncol Biol Phys 81.3 (November 1, 2011): 812-818.
PMID
20932682
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
81
Issue
3
Publish Date
2011
Start Page
812
End Page
818
DOI
10.1016/j.ijrobp.2010.06.058

Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning.

High treatment-related mortality (TRM) and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total-body irradiation (TBI; 1350 cGy) and fludarabine (Flu) (160 mg/m(2)). Twenty-seven patients (median age, 33 years; range: 20-58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 10(7)/kg (range: 3.2-7.7 × 10(7)/kg). The cumulative incidences of neutrophil (≥500/μL) and platelet (≥50,000/μL) engraftment were 80% (95% confidence interval [CI], 58%-91%) and 68% (95% CI, 46%-83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days posttransplantation. A higher cryopreserved and infused TNC dose and infused CD3(+) cell dose were significant factors associated with the predominant UCB unit (P = .032, .020, and .042, respectively). TRM and relapse rates at 2 years were 28% (95% CI, 12%-47%) and 20% (95% CI, 7%-37%), respectively. Cumulative incidences of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) were 37% (95% CI, 20%-55%) and 11% (95% CI, 3%-26%), respectively, and that of chronic GVHD was 31% (95% CI, 15%-49%). With a median follow-up of 23 months, overall survival and disease-free survival rates at 2 years were 58% (95% CI, 34%-75%) and 52% (95% CI, 29%-70%), respectively. This study supports the use of TBI 1350 cGy/Flu as an alternative to conventional myeloablative conditioning for dual UCB transplantation.

Authors
Kanda, J; Rizzieri, DA; Gasparetto, C; Long, GD; Chute, JP; Sullivan, KM; Morris, A; Smith, CA; Hogge, DE; Nitta, J; Song, K; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Gasparetto, C, Long, GD, Chute, JP, Sullivan, KM, Morris, A, Smith, CA, Hogge, DE, Nitta, J, Song, K, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning." Biol Blood Marrow Transplant 17.6 (June 2011): 867-874.
PMID
20868761
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
6
Publish Date
2011
Start Page
867
End Page
874
DOI
10.1016/j.bbmt.2010.09.009

Donor cell-derived leukemias/myelodysplastic neoplasms in allogeneic hematopoietic stem cell transplant recipients: a clinicopathologic study of 10 cases and a comprehensive review of the literature.

We report 10 cases of donor cell leukemia (DCL). All cases except the case of chronic lymphocytic leukemia had anemia, neutropenia, and/or thrombocytopenia when DCL was diagnosed. Eight cases with sex-mismatched hematopoietic stem cell transplant (HCT) showed donor gonosomal complements, suggesting DCL. Clonal cytogenetic abnormalities were detected in 8 cases: 6 were monosomy 7/del(7q). In all 10 cases, engraftment studies confirmed donor cell origin. Retrospective fluorescence in situ hybridization in archived donor cells in 4 cases showed a low level of abnormalities in 2. Of 7 patients with clinical follow-up of 5 months or more, 1 (with acute myeloid leukemia) died of disease; 6 are alive, including 1 with myelodysplastic syndrome with spontaneous remission. Similar to reported cases, we found disproportional sex-mismatched HCTs, suggesting probable underdetection of DCL in sex-matched HCTs. The latency between HCT and DCL ranged from 1 to 193 months (median, 24 months), in keeping with the literature. Analyzing our cases, pooled with reported cases, with survival models showed much shorter latency for malignancy as primary disease, for T-cell large granular lymphocyte leukemia as type of DCL, and for umbilical cord blood as stem cell source.

Authors
Wang, E; Hutchinson, CB; Huang, Q; Lu, CM; Crow, J; Wang, FF; Sebastian, S; Rehder, C; Lagoo, A; Horwitz, M; Rizzieri, D; Yu, J; Goodman, B; Datto, M; Buckley, P
MLA Citation
Wang, E, Hutchinson, CB, Huang, Q, Lu, CM, Crow, J, Wang, FF, Sebastian, S, Rehder, C, Lagoo, A, Horwitz, M, Rizzieri, D, Yu, J, Goodman, B, Datto, M, and Buckley, P. "Donor cell-derived leukemias/myelodysplastic neoplasms in allogeneic hematopoietic stem cell transplant recipients: a clinicopathologic study of 10 cases and a comprehensive review of the literature." Am J Clin Pathol 135.4 (April 2011): 525-540. (Review)
PMID
21411775
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
135
Issue
4
Publish Date
2011
Start Page
525
End Page
540
DOI
10.1309/AJCPPJUQ9DNR1GHP

Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial.

PURPOSE: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol. METHODS AND MATERIALS: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34(+) selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered. RESULTS: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 ± 18.1 cGy, with an average dkB of 5.0 ± 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 ± 5.1 cGy. CONCLUSIONS: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.

Authors
Craciunescu, OI; Steffey, BA; Kelsey, CR; Larrier, NA; Paarz-Largay, CJ; Prosnitz, RG; Chao, N; Chute, J; Gasparetto, C; Horwitz, M; Long, G; Rizzieri, D; Sullivan, KM
MLA Citation
Craciunescu, OI, Steffey, BA, Kelsey, CR, Larrier, NA, Paarz-Largay, CJ, Prosnitz, RG, Chao, N, Chute, J, Gasparetto, C, Horwitz, M, Long, G, Rizzieri, D, and Sullivan, KM. "Renal shielding and dosimetry for patients with severe systemic sclerosis receiving immunoablation with total body irradiation in the scleroderma: cyclophosphamide or transplantation trial." Int J Radiat Oncol Biol Phys 79.4 (March 15, 2011): 1248-1255.
PMID
20800376
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
79
Issue
4
Publish Date
2011
Start Page
1248
End Page
1255
DOI
10.1016/j.ijrobp.2010.05.036

Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia.

PURPOSE OF REVIEW: Use of a reduced intensity conditioning (RIC) regimen has now become standard practice among older or more infirmed stem cell transplantation candidates. Encouraging outcome in this population has led to the question of whether RIC should replace standard myeloablative conditioning (MAC) regimens. This review will summarize the available outcomes data comparing RIC and MAC approaches to stem cell transplantation in adult patients with acute myeloid leukemia, myelodysplastic syndrome (MDS) and acute lymphoid leukemia. RECENT FINDINGS: There are currently no completed prospective randomized controlled studies comparing outcomes of RIC to MAC. The best insight into differences in outcome comes from large registry-based retrospective studies. These studies demonstrate that the use of RIC is associated with a reduction in transplant-related mortality but an increased risk of disease relapse. As a result, for patients undergoing stem cell transplantation in remission, disease free and overall survival are similar. SUMMARY: The current retrospective data provide justification for the use of RIC regimens in all adult stem cell transplant candidates with acute leukemia in remission and MDS. More definitive conclusions regarding differences between the MAC and RIC approach to stem cell transplantation await results of ongoing prospective randomized trials.

Authors
Horwitz, ME
MLA Citation
Horwitz, ME. "Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia." Curr Opin Oncol 23.2 (March 2011): 197-202. (Review)
PMID
21252669
Source
pubmed
Published In
Current Opinion in Oncology
Volume
23
Issue
2
Publish Date
2011
Start Page
197
End Page
202
DOI
10.1097/CCO.0b013e328342b82a

OUTCOMES OF A 1-DAY NONMYELOABLATIVE PREPARATIVE REGIMEN FOR PRIMARY GRAFT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION

Authors
Kanda, J; Horwitz, ME; Long, GD; Gasparetto, C; Sullivan, KM; Chute, JP; Morris, A; Hennig, T; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Horwitz, ME, Long, GD, Gasparetto, C, Sullivan, KM, Chute, JP, Morris, A, Hennig, T, Chao, NJ, and Rizzieri, DA. "OUTCOMES OF A 1-DAY NONMYELOABLATIVE PREPARATIVE REGIMEN FOR PRIMARY GRAFT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION." February 2011.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
2
Publish Date
2011
Start Page
S308
End Page
S308
DOI
10.1016/j.bbmt.2010.12.460

Feasibility of low-dose interleukin-2 therapy following T-cell-depleted nonmyeloablative allogeneic hematopoietic stem cell transplantation from HLA-matched or -mismatched family member donors.

INTRODUCTION: High relapse rates and infections remain primary causes of failure in nonmyeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T-cell-depleted nonmyeloablative hematopoietic stem cell transplant. METHODS: Patients received T-cell-depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment,

Authors
Rizzieri, DA; Crout, C; Storms, R; Golob, J; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Lagoo, AS; Morris, A; Beaven, A; Yang, Y; Peterson, B; Li, Z; Chao, NJ
MLA Citation
Rizzieri, DA, Crout, C, Storms, R, Golob, J, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Lagoo, AS, Morris, A, Beaven, A, Yang, Y, Peterson, B, Li, Z, and Chao, NJ. "Feasibility of low-dose interleukin-2 therapy following T-cell-depleted nonmyeloablative allogeneic hematopoietic stem cell transplantation from HLA-matched or -mismatched family member donors." Cancer Invest 29.1 (January 2011): 56-61.
PMID
21166499
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
29
Issue
1
Publish Date
2011
Start Page
56
End Page
61
DOI
10.3109/07357907.2010.535055

Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma

Positron emission tomography (PET) in conjunction with computed tomography is a frequently used modality for staging patients with lymphoma. Utility of PET-computed tomography before or early following auto-SCT has not been as rigorously evaluated. We retrospectively analyzed patients who received auto-SCT for treatment of relapsed or refractory non-Hodgkins lymphoma or Hodgkins disease between the years of 1996 and 2007. Patients who had either a PET scan following salvage chemotherapy within 14 weeks of transplantation (pre-PET), and/or a PET scan 6-14 weeks following transplantation (post-PET) were included. A total of 90 patients were identified for analysis. The median follow-up time is 3.3 years, with a range of 0.13-12.0 years. The median PFS was 4.6 years, and median OS was 5.1 years. At the time of this analysis, 34 patients (37%) experienced disease relapse, and 25 (27%) of the patients died from disease progression. In multivariate Cox proportional hazards analysis, post-PET did not predict for outcome, pre-PET positivity predicted for decrease in PFS. In conclusion, post-PET scan did not predict for PFS or OS in multivariate analysis. Positive pre-PET scan did predict for PFS as seen in previous studies, and may help identify patients who would benefit from innovative post transplant therapies. © 2011 Macmillan Publishers Limited All rights reserved.

Authors
Palmer, J; Goggins, T; Broadwater, G; Chao, N; Horwitz, M; Beaven, A; Sullivan, K; Coleman, RE; Rizzieri, D
MLA Citation
Palmer, J, Goggins, T, Broadwater, G, Chao, N, Horwitz, M, Beaven, A, Sullivan, K, Coleman, RE, and Rizzieri, D. "Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma." Bone Marrow Transplantation 46.6 (2011): 847-851.
PMID
20856212
Source
scival
Published In
Bone Marrow Transplantation
Volume
46
Issue
6
Publish Date
2011
Start Page
847
End Page
851
DOI
10.1038/bmt.2010.203

Clinical outcomes following hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy Syndrome) is one of approximately 50 known lysosomal storage disorders. MPS VI is characterized by an absence or deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B) resulting in accumulation of dermatan sulfate. Prior to the availability of enzyme replacement therapy (ERT), the clinical management of MPS VI was limited to supportive care and allogeneic hematopoietic stem cell transplantation (HSCT); however, due to the rarity of this disease, little is known about the long-term outcomes of HSCT for MPS VI. The following retrospective study was performed using aggregate data gathered by the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1982 and 2007 to determine survival probability for patients with MPS VI following allogeneic HSCT. This analysis identified 45 MPS VI patients with a median age of 5. years (range, 1-22. years) at the time they received an allogeneic HSCT. Cumulative incidence (95% CI) of acute graft-vs.-host disease at 100. days was 36% (21-53%). Probability of survival was 78% (65-89%) at 100. days and 66% (52-79%) at 1 and 3. years. While these data are based upon small numbers of recipients, they represent the largest series to date and may help clinicians assess the relative risks and benefits of currently available therapies. © 2010 Elsevier Inc.

Authors
Turbeville, S; Nicely, H; Rizzo, JD; Pedersen, TL; Orchard, PJ; Horwitz, ME; Horwitz, EM; Veys, P; Bonfim, C; Al-Seraihy, A
MLA Citation
Turbeville, S, Nicely, H, Rizzo, JD, Pedersen, TL, Orchard, PJ, Horwitz, ME, Horwitz, EM, Veys, P, Bonfim, C, and Al-Seraihy, A. "Clinical outcomes following hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis VI." Molecular Genetics and Metabolism 102.2 (2011): 111-115.
PMID
20980181
Source
scival
Published In
Molecular Genetics and Metabolism
Volume
102
Issue
2
Publish Date
2011
Start Page
111
End Page
115
DOI
10.1016/j.ymgme.2010.09.010

Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning

Authors
Kanda, J; Rizzieri, DA; Gasparetto, C; Long, GD; Chute, JP; Sullivan, KM; Morris, A; Smith, CA; Hogge, DE; Nitta, J; Song, K; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Gasparetto, C, Long, GD, Chute, JP, Sullivan, KM, Morris, A, Smith, CA, Hogge, DE, Nitta, J, Song, K, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning." November 19, 2010.
PMID
28729147
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1448
End Page
1448

Prospective, Biological Randomized Study of T-Cell Depleted Nonmyeloablative Allogeneic Transplantation From HLA-Matched Related, Unrelated or Haploidentical Donors for Patients with Hematologic Malignancies.

Authors
Kanda, J; Long, GD; Gasparetto, C; Horwitz, ME; Sullivan, KM; Chute, JP; Morris, A; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Long, GD, Gasparetto, C, Horwitz, ME, Sullivan, KM, Chute, JP, Morris, A, Li, Z, Chao, NJ, and Rizzieri, DA. "Prospective, Biological Randomized Study of T-Cell Depleted Nonmyeloablative Allogeneic Transplantation From HLA-Matched Related, Unrelated or Haploidentical Donors for Patients with Hematologic Malignancies." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1456
End Page
1457

Donor Cell Leukemia: A Clinicopathological Study of 9 Cases and a Comprehensive Review of Literature

Authors
Hutchinson, CB; Crow, JH; Huang, Q; Lu, CM; Sebastain, S; Rehder, C; Lagoo, AS; Goodman, B; Horwitz, ME; Rizzieri, DA; Datto, M; Buckley, P; Wang, E
MLA Citation
Hutchinson, CB, Crow, JH, Huang, Q, Lu, CM, Sebastain, S, Rehder, C, Lagoo, AS, Goodman, B, Horwitz, ME, Rizzieri, DA, Datto, M, Buckley, P, and Wang, E. "Donor Cell Leukemia: A Clinicopathological Study of 9 Cases and a Comprehensive Review of Literature." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1423
End Page
1424

Efficacy and Safety of Hematopoietic Stem Cell Remobilization with Plerixafor (Mozobil (R)) plus G-CSF In Adult Patients with Non-Hematologic Malignancies.

Authors
Horwitz, ME; Gorak, E; Holman, P; Libby, E; Huebner, D; Mody, PD; Schriber, JR
MLA Citation
Horwitz, ME, Gorak, E, Holman, P, Libby, E, Huebner, D, Mody, PD, and Schriber, JR. "Efficacy and Safety of Hematopoietic Stem Cell Remobilization with Plerixafor (Mozobil (R)) plus G-CSF In Adult Patients with Non-Hematologic Malignancies." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
925
End Page
925

A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation

Authors
Chiou, L-W; Kanda, J; Szabolcs, P; Sempowski, GE; Hale, J; Niedzwiecki, D; Broadwater, G; Chao, NJ; Horwitz, ME
MLA Citation
Chiou, L-W, Kanda, J, Szabolcs, P, Sempowski, GE, Hale, J, Niedzwiecki, D, Broadwater, G, Chao, NJ, and Horwitz, ME. "A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
954
End Page
955

Long-Term Follow-up of Adults with Severe Sickle Cell Disease After Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning

Authors
Biernacki, MA; Okam, M; Shenoy, S; Krishnamurti, L; Horwitz, ME; Neuberg, D; Antin, JH; Wu, CJ
MLA Citation
Biernacki, MA, Okam, M, Shenoy, S, Krishnamurti, L, Horwitz, ME, Neuberg, D, Antin, JH, and Wu, CJ. "Long-Term Follow-up of Adults with Severe Sickle Cell Disease After Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
120
End Page
120

Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation.

Infusing natural killer (NK) cells following transplantation may allow less infections and relapse with little risk of acute graft-versus-host disease (aGVHD). We delivered 51 total NK cell-enriched donor lymphocyte infusions (DLIs) to 30 patients following a 3-6/6 HLA matched T cell-depleted nonmyeloablative allogeneic transplant. The primary endpoint of this study was feasibility and safety. Eight weeks following transplantation, donor NK cell-enriched DLIs were processed using a CD56(+) selecting column with up to 3 fresh infusions allowed. Toxicity, relapse, and survival were monitored. T cell phenotype, NK cell functional recovery, and KIR typing were assessed for association with outcomes. Fourteen matched and 16 mismatched transplanted patients received a total of 51 NK cell-enriched DLIs. Selection resulted in 96% (standard deviation [SD] 8%) purity and 83% (SD 21%) yield in the matched setting and 97% (SD 3%) purity and 77% (SD 24%) yield in the mismatched setting. The median number of CD3(-) CD56(+) NK cells infused was 10.6 (SD 7.91) x 10(6) cells/kg and 9.21 (SD 5.6) x 10(6) cells/kg, respectively. The median number of contaminating CD3(+)CD56(-) T cells infused was .53 (1.1) x 10(6) and .27 (.78) x 10(6) in the matched and mismatched setting, respectively. Only 1 patient each in the matched (n = 14) or mismatched (n = 16) setting experienced severe aGVHD with little other toxicity attributable to the infusions. Long-term responders with multiple NK cell-enriched infusions and improved T cell phenotypic recovery had improved duration of responses (p = .0045) and overall survival (OS) (P = .0058). A 1-step, high-yield process is feasible, and results in high doses of NK cells infused with little toxicity. NK cell-enriched DLIs result in improved immune recovery and outcomes for some. Future studies must assess whether the improved outcomes are the direct result of the high doses and improved NK cell function or other aspects of immune recovery.

Authors
Rizzieri, DA; Storms, R; Chen, D-F; Long, G; Yang, Y; Nikcevich, DA; Gasparetto, C; Horwitz, M; Chute, J; Sullivan, K; Hennig, T; Misra, D; Apple, C; Baker, M; Morris, A; Green, PG; Hasselblad, V; Chao, NJ
MLA Citation
Rizzieri, DA, Storms, R, Chen, D-F, Long, G, Yang, Y, Nikcevich, DA, Gasparetto, C, Horwitz, M, Chute, J, Sullivan, K, Hennig, T, Misra, D, Apple, C, Baker, M, Morris, A, Green, PG, Hasselblad, V, and Chao, NJ. "Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation." Biol Blood Marrow Transplant 16.8 (August 2010): 1107-1114.
PMID
20188202
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
16
Issue
8
Publish Date
2010
Start Page
1107
End Page
1114
DOI
10.1016/j.bbmt.2010.02.018

Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.

Authors
Crout, CA; Koh, L-P; Gockerman, JP; Moore, JO; Decastro, C; Long, GD; Diehl, L; Gasparetto, C; Niedzwiecki, D; Edwards, J; Prosnitz, L; Horwitz, M; Chute, J; Morris, A; Davis, P; Beaven, A; Chao, NJ; Ali-Osman, F; Rizzieri, DA
MLA Citation
Crout, CA, Koh, L-P, Gockerman, JP, Moore, JO, Decastro, C, Long, GD, Diehl, L, Gasparetto, C, Niedzwiecki, D, Edwards, J, Prosnitz, L, Horwitz, M, Chute, J, Morris, A, Davis, P, Beaven, A, Chao, NJ, Ali-Osman, F, and Rizzieri, DA. "Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy." Cancer Invest 28.6 (July 2010): 654-660.
PMID
20521909
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
28
Issue
6
Publish Date
2010
Start Page
654
End Page
660
DOI
10.3109/07357901003631015

Non-myeloablative umbilical cord blood transplantation.

Allogeneic umbilical cord blood (UCB) transplantation is an established alternative to unrelated bone marrow or peripheral blood transplantation for treatment of high-risk hematologic disorders. There is growing evidence that non-myeloablative bone marrow conditioning can be used to facilitate engraftment of UCB-derived stem cells. Use of non-myeloablative conditioning reduces the risk of treatment-related mortality but increases the risk for relapse of the underlying hematologic condition. Disease status at the time of transplantation and potency of the graft versus tumor effect are important predictors of a successful outcome. It is for these reasons that non-myeloablative conditioning is best suited for patients felt to be at increased risk for treatment-related complications, and whose underlying disease is under good control. The optimal non-myeloablative conditioning regimen has yet to be determined. Further studies are needed to determine if non-myeloablative UCB transplantation can be successfully applied to pediatric patients and patients without prior exposure to cytotoxic chemotherapy.

Authors
Horwitz, ME; Chao, N
MLA Citation
Horwitz, ME, and Chao, N. "Non-myeloablative umbilical cord blood transplantation." Best Pract Res Clin Haematol 23.2 (June 2010): 231-236. (Review)
PMID
20837335
Source
pubmed
Published In
Best Practice and Research: Clinical Haematology
Volume
23
Issue
2
Publish Date
2010
Start Page
231
End Page
236
DOI
10.1016/j.beha.2010.06.001

"Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma.

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11, plus melphalan 6 mg/m(2) and prednisone 60 mg/m(2), days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% >or=CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6 x 10(6) CD34(+) cells/kg. Posttransplant response rates were 30% >or=CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations.

Authors
Gasparetto, C; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Long, GD; Horwitz, ME; Keogh, G; Chute, JP; Sullivan, KM; Neuwirth, R; Davis, PH; Sutton, LM; Anderson, RD; Chao, NJ; Rizzieri, D
MLA Citation
Gasparetto, C, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Long, GD, Horwitz, ME, Keogh, G, Chute, JP, Sullivan, KM, Neuwirth, R, Davis, PH, Sutton, LM, Anderson, RD, Chao, NJ, and Rizzieri, D. ""Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma." Biol Blood Marrow Transplant 16.1 (January 2010): 70-77.
PMID
19733251
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
16
Issue
1
Publish Date
2010
Start Page
70
End Page
77
DOI
10.1016/j.bbmt.2009.08.017

Umbilical cord blood transplantation for treatment of non-malignant disorders

As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies. © The Authors.

Authors
Horwitz, ME; Chao, N
MLA Citation
Horwitz, ME, and Chao, N. "Umbilical cord blood transplantation for treatment of non-malignant disorders." Cellular Therapy and Transplantation 2.7 (2010).
Source
scival
Published In
Cellular Therapy and Transplantation
Volume
2
Issue
7
Publish Date
2010
DOI
10.3205/ctt-2010-en-000069.01

Response and toxicity of donor lymphocyte infusions following T-cell depleted non-myeloablative allogeneic hematopoietic SCT from 3-6/6 HLA matched donors.

We report the outcome of early donor lymphocyte infusions (DLIs) after T-cell depleted non-myeloablative transplantation using stem cells from HLA-matched or mismatched donors. Sixty-nine patients with high-risk hematologic malignancies received DLI following fludarabine, CY and alemtuzumab with infusion of stem cells from a matched sibling (52) or partially matched family member donor (17). Patients received the first infusion at a median of 50 days after transplant, and doses ranged from 1 x 10(4) CD3+ cells/kg to 3.27 x 10(8) CD3+ cells/kg, depending on clinical status and the physician's discretion. A median cell dose of 1 x 10(5) CD3+ cells/kg in the mismatched setting and 1 x 10(6) CD3+ cells/kg in the matched sibling setting appears safe with only 1 of 7 (14%) and 4 of 31 patients (13%), respectively, experiencing severe acute GVHD at these doses. Importantly, 38% of patients with persistent disease before DLI attained a remission after infusion. Nine of the 69 patients remain alive and disease-free 32-71 months after the first DLI. In conclusion, low doses of DLI can be safely provided soon after T-cell depleted non-myeloablative therapy and provide a chance of remission. However, long-term survival still remains poor, primarily because of relapse in these patients.

Authors
Rizzieri, DA; Dev, P; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Chao, NJ
MLA Citation
Rizzieri, DA, Dev, P, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, and Chao, NJ. "Response and toxicity of donor lymphocyte infusions following T-cell depleted non-myeloablative allogeneic hematopoietic SCT from 3-6/6 HLA matched donors." Bone Marrow Transplant 43.4 (February 2009): 327-333.
PMID
18850014
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
43
Issue
4
Publish Date
2009
Start Page
327
End Page
333
DOI
10.1038/bmt.2008.321

SURVIVAL FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION FOR CONGENITAL IMMUNODEFICIENCY AND METABOLIC DISORDERS

Authors
Horwitz, ME; da Silva, TG; Eapen, M; Horwitz, EM
MLA Citation
Horwitz, ME, da Silva, TG, Eapen, M, and Horwitz, EM. "SURVIVAL FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION FOR CONGENITAL IMMUNODEFICIENCY AND METABOLIC DISORDERS." BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 15.2 (February 2009): 78-78.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
15
Issue
2
Publish Date
2009
Start Page
78
End Page
78

P134 A phase II pilot study of sorafenib in patients with myelodysplastic syndromes

Authors
Castro, CD; Adams, D; Rizzieri, D; Moore, J; Gockerman, J; Diehl, L; Horwitz, M; Edmonds, E; Warzecho, J
MLA Citation
Castro, CD, Adams, D, Rizzieri, D, Moore, J, Gockerman, J, Diehl, L, Horwitz, M, Edmonds, E, and Warzecho, J. "P134 A phase II pilot study of sorafenib in patients with myelodysplastic syndromes." Leukemia Research 33.SUPPL. 1 (2009): S137-.
Source
scival
Published In
Leukemia Research
Volume
33
Issue
SUPPL. 1
Publish Date
2009
Start Page
S137
DOI
10.1016/S0145-2126(09)70215-2

P129 A pilot study of decitabine in combination with arsenic trioxide for patients with myelodysplastic syndromes

Authors
Castro, CD; Adams, D; Rizzieri, D; Moore, J; Gockerman, J; Diehl, L; Horwitz, M; Edmonds, E; Warzecho, J
MLA Citation
Castro, CD, Adams, D, Rizzieri, D, Moore, J, Gockerman, J, Diehl, L, Horwitz, M, Edmonds, E, and Warzecho, J. "P129 A pilot study of decitabine in combination with arsenic trioxide for patients with myelodysplastic syndromes." Leukemia Research 33.SUPPL. 1 (2009): S134-.
Source
scival
Published In
Leukemia Research
Volume
33
Issue
SUPPL. 1
Publish Date
2009
Start Page
S134
DOI
10.1016/S0145-2126(09)70210-3

Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma

This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 μg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 x 106 CD34+ cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 106 CD34+ cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34+ cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www. clinicaltrials.gov as #NCT00103662. © 2009 by The American Society of Hematology.

Authors
DiPersio, JF; Stadtmauer, EA; Nademanee, A; Micallef, INM; Stiff, PJ; Kaufman, JL; Maziarz, RT; Hosing, C; Früehauf, S; Horwitz, M; Cooper, D; Bridger, G; Calandra, G
MLA Citation
DiPersio, JF, Stadtmauer, EA, Nademanee, A, Micallef, INM, Stiff, PJ, Kaufman, JL, Maziarz, RT, Hosing, C, Früehauf, S, Horwitz, M, Cooper, D, Bridger, G, and Calandra, G. "Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma." Blood 113.23 (2009): 5720-5726.
PMID
19363221
Source
scival
Published In
Blood
Volume
113
Issue
23
Publish Date
2009
Start Page
5720
End Page
5726
DOI
10.1182/blood-2008-08-174946

Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

OBJECTIVES. Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 β-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed wound healing. Allogeneic hematopoietic stem-cell transplantation offers the possibility of curative therapy, and with patient numbers at any individual center being limited, we surveyed the transplant experience at 14 centers worldwide. METHODS. The course of 36 children with a confirmed diagnosis of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/ European Group for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research. RESULTS. At a median follow-up of 62 months (extending to 14 years), the overall survival rate was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced-intensity conditioning in 8 patients, with no deaths in this subgroup. Survival rates after matched family donor and unrelated donor transplants were similar, with 11 of 14 matched family donor and 12 of 14 unrelated donor recipients alive; mortality was greatest after haploidentical transplants, after which 4 of 8 children did not survive. Twenty-seven transplant recipients were alive, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS. Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early therapeutic option if a suitable HLA-matched stem-cell donation is available. Reduced-intensity conditioning was particularly safe, and mixed-donor chimerism seems sufficient to prevent significant symptoms, although careful long-term monitoring will be required for these patients. Copyright © 2009 by the American Academy of Pediatrics. Waseem Qasim.

Authors
Qasim, W; Cavazzana-Calvo, M; Davies, EG; Davis, J; Duval, M; Eames, G; Farinha, N; Filopovich, A; Fischer, A; Friedrich, W; Gennery, A; Heilmann, C; Landais, P; Horwitz, M; Porta, F; Sedlacek, P; Seger, R; Slatten, M; Teague, L; Eapen, M; Veys, P
MLA Citation
Qasim, W, Cavazzana-Calvo, M, Davies, EG, Davis, J, Duval, M, Eames, G, Farinha, N, Filopovich, A, Fischer, A, Friedrich, W, Gennery, A, Heilmann, C, Landais, P, Horwitz, M, Porta, F, Sedlacek, P, Seger, R, Slatten, M, Teague, L, Eapen, M, and Veys, P. "Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency." Pediatrics 123.3 (2009): 836-840.
PMID
19255011
Source
scival
Published In
Pediatrics
Volume
123
Issue
3
Publish Date
2009
Start Page
836
End Page
840
DOI
10.1542/peds.2008-1191

Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients.

The efficacy of once-daily intravenous busulfan with fludarabine as a preparative regimen for partially matched umbilical cord blood transplantation has not been formally studied. We randomized 10 adult patients with myeloid malignancies to receive either concurrent or sequential administration of intravenous busulfan 130 mg/m(2) once daily x 4 days and fludarabine 40 mg/m(2) daily x 4 days, followed by dual umbilical cord blood transplantation. The median combined cryopreserved total nucleated cell dose was 3.6 x 10(7)/kg recipient body weight (range: 2.8-4.5 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was provided by tacrolimus and mycophenolate mofetil (MMF). Donor-derived neutrophil recovery was observed in only 2 of 10 patients, resulting in premature closure of the study as per graft failure stopping rules. We conclude that the myeloablative conditioning regimen of once-daily intravenous busulfan with fludarabine provides insufficient immunosuppression to allow for engraftment of partially matched, dual umbilical cord blood grafts.

Authors
Horwitz, ME; Morris, A; Gasparetto, C; Sullivan, K; Long, G; Chute, J; Rizzieri, D; McPherson, J; Chao, N
MLA Citation
Horwitz, ME, Morris, A, Gasparetto, C, Sullivan, K, Long, G, Chute, J, Rizzieri, D, McPherson, J, and Chao, N. "Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients." Biol Blood Marrow Transplant 14.5 (May 2008): 591-594.
PMID
18410902
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
14
Issue
5
Publish Date
2008
Start Page
591
End Page
594
DOI
10.1016/j.bbmt.2008.02.016

Outcomes of a second non-myeloablative allogeneic stem cell transplantation following graft rejection.

Following initial graft rejection, a second attempt at allogeneic immunotherapy is often contemplated, but data on the success is limited. We therefore report on 11 patients with hematologic malignancies, renal cell cancer or marrow failure who underwent a second reduced-intensity regimen for primary or secondary graft failure. Nine of the 11 patients initially engrafted with the second attempt including two of four who used the same donor. One of the patients engrafted after the third attempt using a different donor and conditioning regimen. There were two treatment-related deaths. Four patients died from progressive disease 1-9 months after the second transplant. Two patients are still in recovery phase less than 1 year from the second transplant. Long-term remission is possible and three patients are alive in complete remission.

Authors
Byrne, BJ; Horwitz, M; Long, GD; Gasparetto, C; Sullivan, KM; Chute, J; Chao, NJ; Rizzieri, DA
MLA Citation
Byrne, BJ, Horwitz, M, Long, GD, Gasparetto, C, Sullivan, KM, Chute, J, Chao, NJ, and Rizzieri, DA. "Outcomes of a second non-myeloablative allogeneic stem cell transplantation following graft rejection." Bone Marrow Transplant 41.1 (January 2008): 39-43.
PMID
17982503
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
41
Issue
1
Publish Date
2008
Start Page
39
End Page
43
DOI
10.1038/sj.bmt.1705882

Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1)

Leukocyte adhesion deficiency type-1 (LAD-1) is an autosomal recessive immunodeficiency caused by mutations in the β2 integrin, CD18, that impair CD11/CD18 heterodimer surface expression and/or function. Absence of functional CD11/CD18 integrins on leukocytes, particularly neutrophils, leads to their incapacity to adhere to the endothelium and migrate to sites of infection. We studied 3 LAD-1 patients with markedly diminished neutrophil CD18 expression, each of whom had a small population of lymphocytes with normal CD18 expression (CD18+). These CD18+ lymphocytes were predominantly cytotoxic T cells, with a memory/effector phenotype. Microsatellite analyses proved patient origin of these cells. Sequencing of T-cell subsets showed that in each patient one CD18 allele had undergone further mutation. Interestingly, all 3 patients were young adults with inflammatory bowel disease. Somatic reversions of inherited mutations in primary T-cell immunodeficiencies are typically associated with milder clinical phenotypes. We hypothesize that these somatic revertant CD18+ cytotoxic T lymphocytes (CTLs) may have altered immune regulation. The discovery of 3 cases of reversion mutations in LAD-1 at one center suggests that this may be a relatively common event in this rare disease. © 2008 by The American Society of Hematology.

Authors
Uzel, G; Tng, E; Rosenzweig, SD; Hsu, AP; Shaw, JM; Horwitz, ME; Linton, GF; Anderson, SM; Kirby, MR; Oliveira, JB; Brown, MR; Fleisher, TA; Law, SKA; Holland, SM
MLA Citation
Uzel, G, Tng, E, Rosenzweig, SD, Hsu, AP, Shaw, JM, Horwitz, ME, Linton, GF, Anderson, SM, Kirby, MR, Oliveira, JB, Brown, MR, Fleisher, TA, Law, SKA, and Holland, SM. "Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1)." Blood 111.1 (2008): 209-218.
PMID
17875809
Source
scival
Published In
Blood
Volume
111
Issue
1
Publish Date
2008
Start Page
209
End Page
218
DOI
10.1182/blood-2007-04-082552

Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics.

End-organ damage is common in patients with sickle cell disease (SCD) thereby limiting the use of allogeneic stem cell transplantation (SCT). We report the outcome of 2 adult SCD patients, 1 with end-stage renal disease (ESRD), who underwent fludarabine-based nonmyeloablative SCT from HLA-identical matched siblings. To prevent fludarabine toxicity, the patient with ESRD underwent aggressive dialysis following adjusted fludarabine dosing. Pharmacokinetics of the fludarabine metabolite F-Ara-A was studied on the patient with ESRD and 2 additional patients with normal renal function. Both patients with SCD achieved full donor erythroid chimerism, have normal blood counts, and are on no immunosuppressive medications. With a 20% dose reduction followed by daily dialysis, we achieved fludarabine drug exposure that is nearly identical to that achieved in patients with normal renal function. We conclude that fludarabine-based nonmyeloablative allogeneic SCT for adult patients with SCD is feasible, even in the setting of ESRD.

Authors
Horwitz, ME; Spasojevic, I; Morris, A; Telen, M; Essell, J; Gasparetto, C; Sullivan, K; Long, G; Chute, J; Chao, N; Rizzieri, D
MLA Citation
Horwitz, ME, Spasojevic, I, Morris, A, Telen, M, Essell, J, Gasparetto, C, Sullivan, K, Long, G, Chute, J, Chao, N, and Rizzieri, D. "Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics." Biol Blood Marrow Transplant 13.12 (December 2007): 1422-1426.
PMID
18022571
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
13
Issue
12
Publish Date
2007
Start Page
1422
End Page
1426
DOI
10.1016/j.bbmt.2007.08.050

Sources of human and murine hematopoietic stem cells.

This unit describes various sites from which human and murine hematopoietic stem cells (HSC) can be collected, including bone marrow, peripheral blood, and, in the case of human HSC, umbilical cord blood. Guidelines related to each of the cell harvesting procedures are described, and a discussion of the expected populations of cells harvested from these various sites is included. Cell products can be composed of a combination of true HSC, lineage-committed hematopoietic progenitor cells, and terminally differentiated fully mature cells. While use of steady-state peripheral blood as a source of HSC is the most convenient approach, yields of these cells are very low. However, mobilization methods that stimulate movement of stem cells out of the bone marrow into peripheral blood significantly increase HSC yields. Use of G-CSF has been accepted as the standard method for stem cell mobilization. The unit describes a variety of investigational cytokines and chemokines that have been shown to mobilize human stem including interleukin 3, 11, and 8, flt-3 ligand, and stem cell factor.

Authors
Horwitz, ME
MLA Citation
Horwitz, ME. "Sources of human and murine hematopoietic stem cells." Curr Protoc Immunol Chapter 22 (November 2007): Unit-22A.2.
PMID
18432991
Source
pubmed
Published In
Current Protocols in Immunology
Volume
Chapter 22
Publish Date
2007
Start Page
Unit
End Page
22A.2
DOI
10.1002/0471142735.im22a02s79

Comparison of the Digene Hybrid Capture System Cytomegalovirus (CMV) DNA (version 2.0), Roche CMV UL54 analyte-specific reagent, and QIAGEN RealArt CMV LightCycler PCR reagent tests using AcroMetrix OptiQuant CMV DNA quantification panels and specimens from allogeneic-stem-cell transplant recipients.

The Digene Hybrid Capture system cytomegalovirus (CMV) DNA (version 2.0), Roche CMV UL54 analyte-specific reagent, and QIAGEN RealArt CMV LightCycler PCR reagent tests were compared using whole-virus standards and plasma specimens collected from allogeneic-stem-cell transplant recipients. PCR assays showed better speed, sensitivity, and specificity.

Authors
Hanson, KE; Reller, LB; Kurtzberg, J; Horwitz, M; Long, G; Alexander, BD
MLA Citation
Hanson, KE, Reller, LB, Kurtzberg, J, Horwitz, M, Long, G, and Alexander, BD. "Comparison of the Digene Hybrid Capture System Cytomegalovirus (CMV) DNA (version 2.0), Roche CMV UL54 analyte-specific reagent, and QIAGEN RealArt CMV LightCycler PCR reagent tests using AcroMetrix OptiQuant CMV DNA quantification panels and specimens from allogeneic-stem-cell transplant recipients." J Clin Microbiol 45.6 (June 2007): 1972-1973.
PMID
17314226
Source
pubmed
Published In
Journal of clinical microbiology
Volume
45
Issue
6
Publish Date
2007
Start Page
1972
End Page
1973
DOI
10.1128/JCM.02515-06

Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution.

PURPOSE: Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype. PATIENTS AND METHODS: Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported. RESULTS: Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months). CONCLUSION: Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Smith, C; Gong, JZ; Lagoo, A; Niedzwiecki, D; Dowell, JM; Waters-Pick, B; Liu, C; Marshall, D; Vredenburgh, JJ; Gockerman, J; Decastro, C; Moore, J; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Smith, C, Gong, JZ, Lagoo, A, Niedzwiecki, D, Dowell, JM, Waters-Pick, B, Liu, C, Marshall, D, Vredenburgh, JJ, Gockerman, J, Decastro, C, Moore, J, and Chao, NJ. "Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution." J Clin Oncol 25.6 (February 20, 2007): 690-697.
PMID
17228020
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
6
Publish Date
2007
Start Page
690
End Page
697
DOI
10.1200/JCO.2006.07.0953

Chronic graft-versus-host disease.

Chronic graft versus host disease (GVHD) remains today one of the most vexing late complications of allogeneic stem cell transplantation. Occurring a minimum of 100 days following stem cell transplantation, approximately 50% of patients will experience some degree of chronic GVHD. Host-reactive lymphocytes of donor origin are the cells responsible for the "alloimmune" attack. The increased use of hematopoietic stem cells collected from the peripheral blood instead of bone marrow and the increasing age of stem cell transplant recipients has led to a higher incidence of chronic GVHD. Chronic GVHD most commonly affects the skin, liver, eyes or the mouth, however multiple other sites may also be affected. Chronic GVHD and the medications used to treat it result in a profoundly immunocompromised state. Death due to severe chronic GVHD is usually a consequence of infectious complications. Standard treatment for severe chronic GVHD is a combination of cyclosporine and prednisone. An alternating day regimen of these two agents prolongs survival and reduces drug-related adverse events. Topical therapy to affected areas is preferred for patients with mild disease. The 10-year survival of patients with mild chronic GVHD is approximately 80%, but is less than 5% for patients affected by severe chronic GVHD.

Authors
Horwitz, ME; Sullivan, KM
MLA Citation
Horwitz, ME, and Sullivan, KM. "Chronic graft-versus-host disease." Blood Rev 20.1 (January 2006): 15-27. (Review)
PMID
16426941
Source
pubmed
Published In
Blood Reviews
Volume
20
Issue
1
Publish Date
2006
Start Page
15
End Page
27
DOI
10.1016/j.blre.2005.01.007

Patients with chronic granulomatous disease have a reduced peripheral blood memory B cell compartment

In this study, we have identified an altered B cell compartment in patients with chronic granulomatous disease (CGD), a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH activity. This is characterized by an expansion of CD5-expressing B cells, and profound reduction in B cells expressing the memory B cell marker, CD27. Both findings were independent of the age, genotype, and clinical status of the patients, and were not accompanied by altered CD5 and CD27 expression on T cells. Focusing on CD27-positive B cells, considered to be memory cells based on somatically mutated Ig genes, we found that the reduction was not caused by CD27 shedding or abnormal retention of CD27 protein inside the cell. Rather, it was determined that CD27-negative B cells were, appropriately, CD27 mRNA negative, consistent with a naive phenotype, whereas CD27-positive B cells contained abundant CD27 mRNA and displayed somatic mutations, consistent with a memory B cell phenotype. Thus, it appears that CGD is associated with a significant reduction in the peripheral blood memory B cell compartment, but that the basic processes of somatic mutation and expression of CD27 are intact. X-linked carriers of CGD revealed a significant correlation between the percentage of CD27-positive B cells and the percentage of neutrophils with normal NADPH activity, reflective of the degree of X chromosome lyonization. These results suggest a role for NADPH in the process of memory B cell formation, inviting further exploration of secondary Ab responses in CGD patients. Copyright © 2006 by The American Association of Immunologists, Inc.

Authors
Bleesing, JJ; Souto-Carneiro, MM; Savage, WJ; Brown, MR; Martinez, C; Yavuz, S; Brenner, S; Siegel, RM; Horwitz, ME; Lipsky, PE; Malech, HL; Fleisher, TA
MLA Citation
Bleesing, JJ, Souto-Carneiro, MM, Savage, WJ, Brown, MR, Martinez, C, Yavuz, S, Brenner, S, Siegel, RM, Horwitz, ME, Lipsky, PE, Malech, HL, and Fleisher, TA. "Patients with chronic granulomatous disease have a reduced peripheral blood memory B cell compartment." Journal of Immunology 176.11 (2006): 7096-7103.
PMID
16709872
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
176
Issue
11
Publish Date
2006
Start Page
7096
End Page
7103

Polyclonal Long-Term MFGS-gp91phox Marking in Rhesus Macaques after Nonmyeloablative Transplantation with Transduced Autologous Peripheral Blood Progenitor Cells

We have recently reported that the RD114-pseudotyped MFGS-gp91phox vector achieves unprecedented levels of correction of the NADPH-oxidase gp91phox (approved gene symbol CYBB) defect in CD34+ cells from patients with X-linked chronic granulomatous disease in the NOD/SCID mouse model. Considering clinical use of this vector, we transplanted autologous mobilized peripheral blood CD34+ progenitor cells, transduced with the RD114-MFGS-gp91phox vector, into two healthy rhesus macaques following nonmyeloablative conditioning. The moderately high levels of in vivo marking seen in the first months following transduction decreased and stabilized at about 8 months posttransplant. Marking for both healthy animals after 15 months was 0.3 to 1.3 vector copies per 100 cells in lymphocytes, neutrophils, and monocytes. Vector insertion analyses performed by linear amplification-mediated PCR and sequencing identified 32 and 45 separate insertion sites in the animals. Identical insertion sites were found in myeloid cells and lymphocytes, demonstrating the successful transduction of lymphomyeloid progenitors. Some inserts landed in the vicinity of genes controlling cell cycle and proliferation. Statistical analyses of insertion sites 1 year posttransplant suggest a high diversity of insertion sites despite low marking.

Authors
Brenner, S; Ryser, MF; Choi, U; Whiting-Theobald, N; Kuhlisch, E; Linton, G; Kang, E; Lehmann, R; Rosen-Wolff, A; Rudikoff, AG; Farese, AM; MacVittie, TJ; Roesler, J; Horwitz, ME; Malech, HL
MLA Citation
Brenner, S, Ryser, MF, Choi, U, Whiting-Theobald, N, Kuhlisch, E, Linton, G, Kang, E, Lehmann, R, Rosen-Wolff, A, Rudikoff, AG, Farese, AM, MacVittie, TJ, Roesler, J, Horwitz, ME, and Malech, HL. "Polyclonal Long-Term MFGS-gp91phox Marking in Rhesus Macaques after Nonmyeloablative Transplantation with Transduced Autologous Peripheral Blood Progenitor Cells." Molecular Therapy 14.2 (2006): 202-211.
PMID
16600688
Source
scival
Published In
Molecular Therapy
Volume
14
Issue
2
Publish Date
2006
Start Page
202
End Page
211
DOI
10.1016/j.ymthe.2006.01.015

Unique abnormalities of CD4+ and CD8+ central memory cells associated with chronic graft-versus-host disease improve after extracorporeal photopheresis

Chronic graft-versus-host disease (cGVHD) remains a problematic complication of allogeneic hematopoietic stem cell transplantation. Laboratory parameters correlated with cGVHD have not been fully defined, although changes in CD4/CD8 ratios occur and a decrease in CD4+ central memory T cells has been noted. Extracorporeal photopheresis (ECP) is an effective therapy for steroid-refractory cGVHD. We have noted changes in lymphocyte subsets after ECP. CD4+ and CD8+ T-cell central and effector memory populations were enumerated by flow cytometry in a cohort of 37 patients postallogeneic transplantation with symptomatic cGVHD. Of the patients with symptomatic cGVHD, 7 were treated with ECP over 6 months and prospectively assessed for changes in lymphocyte subsets. There was a highly significant correlation of an increase in CD8+ central memory cells and a concomitant decrease in CD4+ central memory cells in patients with symptomatic cGVHD. These changes were not detected in patients without cGVHD posttransplantation. In all, 7 patients with cGVHD followed up prospectively during ECP treatment showed a statistically significant normalization of the pattern of CD4+ and a trend toward normalization of CD8+ central memory T cells coincident with improvement of cGVHD. These data indicate a high correlation between disturbances in the balance of central and effector memory populations and cGVHD suggesting use in following up responses to therapy. The normalization of central and effector memory populations in response to ECP coincident with clinical improvement of cGVHD support a correlation between these laboratory parameters and cGVHD. Further studies are needed to demonstrate whether laboratory measurements of the magnitude of changes in central and effector memory populations are useful prognostically or can be used to guide response to therapy. The contrasting change in central memory cells (CD8+ increased versus CD4+ decreased) in cGVHD provide support for recent reports suggesting unique differences in the differentiation pathways for CD8+ versus CD4+ T cells. © 2006 American Society for Blood and Marrow Transplantation.

Authors
Yamashita, K; Horwitz, ME; Kwatemaa, A; Nomicos, E; Castro, K; Sokolic, R; Foster, SF; Garofalo, M; Choi, U; Ryherd, M; Brown, MR; Leitman, SF; Wayne, AS; Fowler, DH; Bishop, MR; Childs, RW; Barrett, AJ; Pavletic, SZ; Malech, HL
MLA Citation
Yamashita, K, Horwitz, ME, Kwatemaa, A, Nomicos, E, Castro, K, Sokolic, R, Foster, SF, Garofalo, M, Choi, U, Ryherd, M, Brown, MR, Leitman, SF, Wayne, AS, Fowler, DH, Bishop, MR, Childs, RW, Barrett, AJ, Pavletic, SZ, and Malech, HL. "Unique abnormalities of CD4+ and CD8+ central memory cells associated with chronic graft-versus-host disease improve after extracorporeal photopheresis." Biology of Blood and Marrow Transplantation 12.SUPPL. 2 (2006): 22-30.
PMID
16399598
Source
scival
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
SUPPL. 2
Publish Date
2006
Start Page
22
End Page
30
DOI
10.1016/j.bbmt.2005.11.004

Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey.

OBJECTIVES: To evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in a series of patients with inherited complete IFN-gamma receptor 1 (IFNgammaR1) deficiency. STUDY DESIGN: We report 8 patients who received altogether 11 HSCT from family donors, including 10 HLA-identical (5 siblings and 5 relatives) and 1 HLA-haplo-identical donors. Five grafts were T-cell depleted, and conditioning regimens varied in intensity. RESULTS: Four patients died within 8 months after HSCT. Two of these deaths were due to specific complications related to mycobacterial infection. There was no or very low (2%) donor cell engraftment in 2 survivors. Only 2 patients are in full remission of mycobacterial disease 5 years after HSCT. These are the only patients who received non-T-cell-depleted grafts from an HLA-identical sibling after a fully myeloablative conditioning regimen. CONCLUSIONS: HSCT can lead to prolonged remission of mycobacterial disease in children with complete IFNgammaR1 deficiency. However, optimal control of mycobacterial infection before HSCT and the use of a non-T-cell-depleted transplant from an HLA-identical sibling after a fully myeloablative conditioning regimen are recommended.

Authors
Roesler, J; Horwitz, ME; Picard, C; Bordigoni, P; Davies, G; Koscielniak, E; Levin, M; Veys, P; Reuter, U; Schulz, A; Thiede, C; Klingebiel, T; Fischer, A; Holland, SM; Casanova, J-L; Friedrich, W
MLA Citation
Roesler, J, Horwitz, ME, Picard, C, Bordigoni, P, Davies, G, Koscielniak, E, Levin, M, Veys, P, Reuter, U, Schulz, A, Thiede, C, Klingebiel, T, Fischer, A, Holland, SM, Casanova, J-L, and Friedrich, W. "Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey." J Pediatr 145.6 (December 2004): 806-812.
PMID
15580206
Source
pubmed
Published In
The Journal of Pediatrics
Volume
145
Issue
6
Publish Date
2004
Start Page
806
End Page
812
DOI
10.1016/j.jpeds.2004.08.021

Campath-1H may have activity in the treatment of multiple myeloma.

Authors
Gasparetto, C; Horwitz, ME; Gockerman, JP; de Castro, CM; Moore, JO; Smith, CA; Davis, P; Lassiter, M; Houser, L; Chao, NJ; Rizzieri, D
MLA Citation
Gasparetto, C, Horwitz, ME, Gockerman, JP, de Castro, CM, Moore, JO, Smith, CA, Davis, P, Lassiter, M, Houser, L, Chao, NJ, and Rizzieri, D. "Campath-1H may have activity in the treatment of multiple myeloma." November 16, 2004.
Source
wos-lite
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
314B
End Page
314B

Adult recipients of umbilical cord blood transplants after nonmyeloablative preparative regimens.

We report the outcome of 13 patients with advanced malignancies who underwent nonmyeloablative conditioning therapy followed by infusion of partially matched unrelated cord blood cells. The median age of these patients was 49 years, and their median weight was 65.7 kg. The median nucleated cell dose infused was 2.07 x 10(7)/kg. Eight of the 13 patients demonstrated donor chimerism between 4 weeks and 6 months, and subsequent conversion to full donor chimerism was achieved in 5 patients. Three patients were alive and free of disease at 158 to 1054 days, with a median survival of 288 days after transplantation. The 100-day event-free survival is 69%, and overall survival is 77%. At 1 year, the event-free and overall survival was 43%. Treatment-related mortality observed within the first 100 days after transplantation was low: 1 previously extensively pretreated patient died of multiorgan failure. This result provides a basis for further exploring this potentially curative approach to selected patients who lack matched related or unrelated hematopoietic stem cell donors.

Authors
Chao, NJ; Koh, L-P; Long, GD; Gasparetto, C; Horwitz, M; Morris, A; Lassiter, M; Sullivan, KM; Rizzieri, DA
MLA Citation
Chao, NJ, Koh, L-P, Long, GD, Gasparetto, C, Horwitz, M, Morris, A, Lassiter, M, Sullivan, KM, and Rizzieri, DA. "Adult recipients of umbilical cord blood transplants after nonmyeloablative preparative regimens." Biol Blood Marrow Transplant 10.8 (August 2004): 569-575.
PMID
15282535
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
10
Issue
8
Publish Date
2004
Start Page
569
End Page
575
DOI
10.1016/j.bbmt.2004.05.001

Severe chronic graft-versus-host disease is characterized by a preponderance of CD4(+) effector memory cells relative to central memory cells.

Donor alloreactive CD4(+) T cells are important to the pathogenesis of chronic graft-versus-host disease (cGVHD), but specific subsets of CD4(+) T cells responsible for GVHD have not been defined. We hypothesized that cGVHD might be associated with a preponderance of CD4(+) effector memory cells (CCR7(-)/CD62L(low), CD4(EM)). We analyzed CCR7 and CD62L expression on CD4(+) T cells from stem cell transplantation patients, who did or did not develop cGVHD, and healthy donors. Patients with cGVHD had a higher percentage of CD4(EM) cells (35.5% +/- 2.9%) than healthy donors (13.8% +/- 0.7%; P <.0001) or patients without cGVHD that received a transplant (21.7% +/- 2.1%; P <.01). Using corticosteroid dose as a surrogate marker for cGVHD severity, severe cGVHD was associated with a higher percentage of CD4(EM) cells. The proportion of CD4(EM) cells in corticosteroid-dependent patients with systemic lupus erythematosis or Wegener granulomatosis did not differ from patients without cGVHD that received a transplant. This finding implies that overrepresentation of CD4(EM) cells is a unique feature of cGVHD.

Authors
Yamashita, K; Choi, U; Woltz, PC; Foster, SF; Sneller, MC; Hakim, FT; Fowler, DH; Bishop, MR; Pavletic, SZ; Tamari, M; Castro, K; Barrett, AJ; Childs, RW; Illei, GG; Leitman, SF; Malech, HL; Horwitz, ME
MLA Citation
Yamashita, K, Choi, U, Woltz, PC, Foster, SF, Sneller, MC, Hakim, FT, Fowler, DH, Bishop, MR, Pavletic, SZ, Tamari, M, Castro, K, Barrett, AJ, Childs, RW, Illei, GG, Leitman, SF, Malech, HL, and Horwitz, ME. "Severe chronic graft-versus-host disease is characterized by a preponderance of CD4(+) effector memory cells relative to central memory cells." Blood 103.10 (May 15, 2004): 3986-3988.
PMID
14764530
Source
pubmed
Published In
Blood
Volume
103
Issue
10
Publish Date
2004
Start Page
3986
End Page
3988
DOI
10.1182/blood-2003-09-3286

Insertional analyses in rhesus monkey blood cells after non-myeloablative hematopoietic stem cell marking with a therapeutic onco-retroviral vector for X-linked chronic granulomatous disease

Authors
Ryser, MF; Brenner, S; Whiting-Theobald, N; Lehmann, R; Choi, U; Linton, GF; Kang, E; Rudikoff, AG; Farese, AM; MacVittie, TJ; Horwitz, ME; Malech, HL
MLA Citation
Ryser, MF, Brenner, S, Whiting-Theobald, N, Lehmann, R, Choi, U, Linton, GF, Kang, E, Rudikoff, AG, Farese, AM, MacVittie, TJ, Horwitz, ME, and Malech, HL. "Insertional analyses in rhesus monkey blood cells after non-myeloablative hematopoietic stem cell marking with a therapeutic onco-retroviral vector for X-linked chronic granulomatous disease." May 2004.
Source
wos-lite
Published In
Molecular Therapy
Volume
9
Publish Date
2004
Start Page
S350
End Page
S350

Pediatric large-volume leukapheresis: A single institution experience with heparin versus citrate-based anticoagulant regimens

BACKGROUND: Anticoagulant-associated toxicity may exert significant effects on the safety and efficacy of large-volume leukapheresis (LVL) in children, however, few studies specifically address management of this issue. STUDY DESIGN AND METHODS: Seventy-four consecutive LVL procedures (mean, 4 blood volumes processed) in children weighing less than or equal to 30 kg (minimum, 10.9 kg) were analyzed. The first 21 procedures were evaluated retrospectively; 11 used heparin alone (Group I) and 10 used heparin plus reduced-dose ACD-A (whole blood to anticoagulant ratio ≥20:1) (Group II). The next 53 procedures were evaluated prospectively and used full-dose ACD-A (whole blood to anticoagulant ratio ≤513:1), intravenous divalent cation prophylaxis and no heparin; 11 used calcium alone (Group III) followed by 42 with calcium plus magnesium (Group IV). RESULTS: Seventy-four LVL (56 PBPC and 18 MNC) collections were performed in 38 subjects. One donor in Group I experienced a significant groin hematoma at the site of line placement. One donor each in Groups III and IV had mild paresthesias. Despite a mean citrate infusion rate of 2.6 mg per kg per minute, mean postapheresis serum potassium and ionized magnesium and calcium concentrations in Group IV declined by only 9, 8, and 4 percent, respectively, and stable levels of these variables were maintained 24 hours later. Postapheresis PLT counts declined significantly from baseline preapheresis levels in all groups (mean, 52% decrease). CONCLUSIONS: Use of full-dose citrate anticoagulant with prophylactic intravenous divalent cation infusion offers an effective and safe approach to management of anticoagulant-related toxicity in children undergoing LVL.

Authors
Bolan, CD; Yau, YY; Cullis, HC; Horwitz, ME; Mackall, CL; Barrett, AJ; Malech, HL; Rehak, NN; Wayne, AS; Leitman, SF
MLA Citation
Bolan, CD, Yau, YY, Cullis, HC, Horwitz, ME, Mackall, CL, Barrett, AJ, Malech, HL, Rehak, NN, Wayne, AS, and Leitman, SF. "Pediatric large-volume leukapheresis: A single institution experience with heparin versus citrate-based anticoagulant regimens." Transfusion 44.2 (2004): 229-238.
PMID
14962314
Source
scival
Published In
Transfusion
Volume
44
Issue
2
Publish Date
2004
Start Page
229
End Page
238
DOI
10.1111/j.1537-2995.2004.00668.x

Clinical outcome and immune reconstitution following alemtuzumab T cell depleted nonmyeloablative allogeneic immunotherapy from HLA matched siblings.

Authors
Rizzieri, DA; Koh, LP; Long, GD; Lagoo, AS; Gasparatto, C; Vredenburgh, JJ; Buckley, PJ; Gong, G; Loftis, J; Rowe, K; Rooney, B; Niedzweicki, D; Waters-Pick, B; Eren, P; Vujevich, D; Catlin, C; Folz, RJ; Sullivan, K; Horwitz, ME; Morris, A; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Lagoo, AS, Gasparatto, C, Vredenburgh, JJ, Buckley, PJ, Gong, G, Loftis, J, Rowe, K, Rooney, B, Niedzweicki, D, Waters-Pick, B, Eren, P, Vujevich, D, Catlin, C, Folz, RJ, Sullivan, K, Horwitz, ME, Morris, A, and Chao, NJ. "Clinical outcome and immune reconstitution following alemtuzumab T cell depleted nonmyeloablative allogeneic immunotherapy from HLA matched siblings." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
238A
End Page
239A

One day preparative regimen for allogeneic non-myeloablative stem cell transplantation (NMSCT) using 3-5/6 HLA matched related donors.

Authors
Goggins, TF; Rizzieri, DA; Prosnitz, R; Gasparetto, C; Long, G; Horwitz, ME; Sullivan, K; Morris, A; Thompson, M; Lassiter, M; Rowe, K; Chao, NJ
MLA Citation
Goggins, TF, Rizzieri, DA, Prosnitz, R, Gasparetto, C, Long, G, Horwitz, ME, Sullivan, K, Morris, A, Thompson, M, Lassiter, M, Rowe, K, and Chao, NJ. "One day preparative regimen for allogeneic non-myeloablative stem cell transplantation (NMSCT) using 3-5/6 HLA matched related donors." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
476B
End Page
477B

Pharmacokinetics of subcutaneous alemtuzumab in a patient with myeloma.

Authors
Gasparetto, C; Chao, NJ; Horwitz, ME; Moore, JO; DeCastro, C; Gockerman, J; Sullivan, K; Rooney, B; Houser, L; Anderson, E; Hale, G; Toaso, B; Rizzieri, DA
MLA Citation
Gasparetto, C, Chao, NJ, Horwitz, ME, Moore, JO, DeCastro, C, Gockerman, J, Sullivan, K, Rooney, B, Houser, L, Anderson, E, Hale, G, Toaso, B, and Rizzieri, DA. "Pharmacokinetics of subcutaneous alemtuzumab in a patient with myeloma." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
385B
End Page
385B

Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency.

Interferon-gamma receptor-1 (IFNgammaR1) deficiency is a rare inherited immunodeficiency. We performed a nonmyeloablative allogeneic stem cell transplantation on a boy with complete IFNgammaR1 deficiency and refractory disseminated Myco- bacterium avium infection. Despite the patient's profound immune defect, early donor stem cell engraftment was low. Full donor engraftment was accomplished only following multiple donor lymphocyte infusions. Detection of IFNgammaR1 expression on peripheral blood monocytes and neutrophils corresponded with establishment of stable, complete donor hematopoietic chimerism. However, expression of, and signaling through IFNgammaR1 disappeared shortly thereafter. Disseminated Mycobacterium avium infection persisted and the patient died. Coculture of Myco- bacterium avium with normal myeloid cells resulted in an IFNgamma signaling defect similar to that observed in vivo. Active disseminated Mycobacterium avium infection may significantly compromise normal immune reconstitution following allogeneic stem cell transplantation. Patients with IFNgammaR1 deficiency should receive transplants before developing refractory mycobacterial infections.

Authors
Horwitz, ME; Uzel, G; Linton, GF; Miller, JA; Brown, MR; Malech, HL; Holland, SM
MLA Citation
Horwitz, ME, Uzel, G, Linton, GF, Miller, JA, Brown, MR, Malech, HL, and Holland, SM. "Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency." Blood 102.7 (October 1, 2003): 2692-2694.
PMID
12805054
Source
pubmed
Published In
Blood
Volume
102
Issue
7
Publish Date
2003
Start Page
2692
End Page
2694
DOI
10.1182/blood-2003-04-1268

Concentrated RD114-pseudotyped MFGS-gp91phox vector achieves high levels of functional correction of the chronic granulomatous disease oxidase defect in NOD/SCID/β2-microglobulin-/- repopulating mobilized human peripheral blood CD34+ cells

In previous studies amphotropic MFGS-gp91phox (murine onco-retrovirus vector) was used in a clinical trial of X-linked chronic granulomatous disease (X-CGD) gene therapy to achieve transient correction of oxidase activity in 0.1% of neutrophils. We later showed that transduced CD34+ peripheral blood stem cells (CD34+ PBSCs) from this trial transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice resulted in correction of only 2.5% of human neutrophils. However, higher rates of transduction into stem cells are required. In the current study we demonstrate that the same vector (MFGS-gp91phox) pseudotyped with RD114 envelope in a 4-day culture/transduction regimen results in a 7-fold increase in correction of NOD/SCID mouse repopulating X-CGD CD34+ PBSCs (14%-22% corrected human neutrophils; human cell engraftment 13%-67%). This increase may result from high expression of receptor for RD114 that we demonstrate on CD34+CD38- stem cells. Using RD114-MFGS encoding cyan fluorescent protein to allow similar studies of normal CD34+ PBSCs, we show that progressively higher levels of gene marking of human neutrophils (67%-77%) can be achieved by prolongation of culture/ transduction to 6 days, but with lower rates of human cell engraftment. Our data demonstrate the highest reported level of functional correction of any inherited metabolic disorder in human cells in vivo with the NOD/SCID mouse system using onco-retrovirus vector. © 2003 by The American Society of Hematology.

Authors
Brenner, S; Whiting-Theobald, NL; Linton, GF; Holmes, KL; Anderson-Cohen, M; Kelly, PF; Vanin, EF; Pilon, AM; Bodine, DM; Horwitz, ME; Malech, HL
MLA Citation
Brenner, S, Whiting-Theobald, NL, Linton, GF, Holmes, KL, Anderson-Cohen, M, Kelly, PF, Vanin, EF, Pilon, AM, Bodine, DM, Horwitz, ME, and Malech, HL. "Concentrated RD114-pseudotyped MFGS-gp91phox vector achieves high levels of functional correction of the chronic granulomatous disease oxidase defect in NOD/SCID/β2-microglobulin-/- repopulating mobilized human peripheral blood CD34+ cells." Blood 102.8 (2003): 2789-2797.
PMID
12829597
Source
scival
Published In
Blood
Volume
102
Issue
8
Publish Date
2003
Start Page
2789
End Page
2797
DOI
10.1182/blood-2002-05-1482

Immunomodulation in stem-cell transplantation

Acute graft-versus-host disease is a complication that affects 30-60% of patients undergoing allogeneic stem-cell transplantation. The standard for prophylaxis for graft-versus-host disease has historically been the combination of cyclosporine and methotrexate. Recently, tacrolimus has been used more frequently and current studies are exploring the potential of mycophenolate mofetil. There is little published experience with the use of sirolimus in prophylaxis or treatment but studies are ongoing. There have been significant advances recently in the treatment of steroid-refractory acute graft-versus-host disease. Historically, antithymocyte globulin was used when patients did not respond to the steroid treatment. New monoclonal antibodies such as daclizumab, and tumor necrosis factor α inhibitors such as infliximab are producing more promising results. Chronic graft-versus-host disease continues to be a major complication of stem-cell transplantation, affecting 35-50% of patients. Finding effective treatments for chronic graft-versus-host disease other than steroids continues to be a challenge.

Authors
Abo-Zena, RA; Horwitz, ME
MLA Citation
Abo-Zena, RA, and Horwitz, ME. "Immunomodulation in stem-cell transplantation." Current Opinion in Pharmacology 2.4 (2002): 452-457.
PMID
12127880
Source
scival
Published In
Current Opinion in Pharmacology
Volume
2
Issue
4
Publish Date
2002
Start Page
452
End Page
457
DOI
10.1016/S1471-4892(02)00174-1

Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism.

The effect of mixed chimerism on the pace of post-transplant immune reconstitution is unknown. Using flow cytometry, recall and neo-antigen vaccine responses, and T cell receptor recombination excision circle (TREC) quantification, we evaluated phenotypic and functional characteristics of T and B cells in nine patients following non-myeloablative, HLA-identical peripheral blood stem cell transplantation for chronic granulomatous disease. Engraftment of T cell, B cell, and myeloid lineages proceeded at similar paces within each patient, but engraftment kinetics segregated patients into two groups: adults, who became full donor T cell chimeras before 6 months (rapid engrafters) and children, who became full donor T cell chimeras after 6 months or not at all (slow engrafters). Quantitative B cell recovery was achieved by 6 weeks after transplantation in children, but was delayed until 1 year in adults. Early quantitative B cell recovery was not accompanied by an early humoral immune response to tetanus toxoid (TT). Emergence of TT-specific T cell responses coincided with naive T cell reconstitution, as measured by CD4/CD45RA T cell recovery and TREC quantification. These data suggest that immune reconstitution occurs faster in pediatric patients who have prolonged mixed hematopoietic chimerism compared to adults, who have rapid donor stem cell engraftment.

Authors
Savage, WJ; Bleesing, JJ; Douek, D; Brown, MR; Linton, GM; Malech, HL; Horwitz, ME
MLA Citation
Savage, WJ, Bleesing, JJ, Douek, D, Brown, MR, Linton, GM, Malech, HL, and Horwitz, ME. "Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism." Bone Marrow Transplant 28.5 (September 2001): 463-471.
PMID
11593319
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
28
Issue
5
Publish Date
2001
Start Page
463
End Page
471
DOI
10.1038/sj.bmt.1703176

Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft.

BACKGROUND: The treatment of chronic granulomatous disease with conventional allogeneic hematopoietic stem-cell transplantation carries a high risk of serious complications and death. We investigated the feasibility of stem-cell transplantation without ablation of the recipient's bone marrow. METHODS: Ten patients, five children and five adults, with chronic granulomatous disease underwent peripheral-blood stem-cell transplantation from an HLA-identical sibling. We used a nonmyeloablative conditioning regimen consisting of cyclophosphamide, fludarabine, and antithymocyte globulin. The allograft was depleted of T cells to reduce the risk of severe graft-versus-host disease. Donor lymphocytes were administered at intervals of 30 days or more after the transplantation to facilitate engraftment. RESULTS: After a median follow-up of 17 months (range, 8 to 26), the proportion of donor neutrophils in the circulation in 8 of the 10 patients was 33 to 100 percent, a level that can be expected to provide normal host defense; in 6 the proportion was 100 percent. In two patients, graft rejection occurred. Acute graft-versus-host disease (grade II, III, or IV) developed in three of the four adult patients with engraftment, one of whom subsequently had chronic graft-versus-host disease. None of the five children had grade II, III, or IV acute graft-versus-host disease. During the follow-up period, four serious infections occurred among the patients who had engraftment. Three of the 10 recipients died. Preexisting granulomatous lesions resolved in the patients in whom transplantation was successful. CONCLUSIONS: Nonmyeloablative conditioning followed by a T-cell-depleted hematopoietic stem-cell allograft is a feasible option for patients with chronic granulomatous disease, recurrent life-threatening infections, and an HLA-identical family donor.

Authors
Horwitz, ME; Barrett, AJ; Brown, MR; Carter, CS; Childs, R; Gallin, JI; Holland, SM; Linton, GF; Miller, JA; Leitman, SF; Read, EJ; Malech, HL
MLA Citation
Horwitz, ME, Barrett, AJ, Brown, MR, Carter, CS, Childs, R, Gallin, JI, Holland, SM, Linton, GF, Miller, JA, Leitman, SF, Read, EJ, and Malech, HL. "Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft." N Engl J Med 344.12 (March 22, 2001): 881-888.
PMID
11259721
Source
pubmed
Published In
The New England journal of medicine
Volume
344
Issue
12
Publish Date
2001
Start Page
881
End Page
888
DOI
10.1056/NEJM200103223441203

Autologous Stem Cell Transplantation for Pediatric Rheumatic Diseases

The National Institute of Allergy and Infectious Disease, National Institutes of Health, convened a workshop entitled The Next Step: Protocol Development for Autologous Stem Cell Transplantation for Pediatric Rheumatic Disease, June 2000, co-chaired by Drs. Karyl Barron and Carol Wallace. The goal of the workshop was to focus on the scientific rationale for stem cell transplantation therapy in the pediatric diseases, unique aspects of this therapy in the pediatric rheumatic diseases, transplantation issues and options, regulatory issues, and development of a DNA repository for these diseases.

Authors
Barron, KS; Wallace, C; Woolfrey, A; Laxer, RM; Hirsch, R; Horwitz, M; Siegel, J; Filipovich, L; Wulffraat, N; Passo, M; Rider, LG
MLA Citation
Barron, KS, Wallace, C, Woolfrey, A, Laxer, RM, Hirsch, R, Horwitz, M, Siegel, J, Filipovich, L, Wulffraat, N, Passo, M, and Rider, LG. "Autologous Stem Cell Transplantation for Pediatric Rheumatic Diseases." Journal of Rheumatology 28.10 (2001): 2337-2358.
PMID
11669179
Source
scival
Published In
Journal of Rheumatology
Volume
28
Issue
10
Publish Date
2001
Start Page
2337
End Page
2358

Stem-cell transplantation for inherited immunodeficiency disorders.

For patients with well-characterized, rapidly fatal, nonmalignant immunodeficiency disorders, such as SCID, the decision to proceed with allogeneic SCT is clear-cut. For patients with many other disorders, this decision can be extremely difficult. Disorders such as LAD or CGD have a variable natural history. Each patient must be considered individually, with the risk for SCT-related morbidity and mortality carefully weighed against that of the underlying disease. Significant advances during the past 10 years have made SCT a much safer procedure. Use of nonmyeloablative conditioning regimens as a means of reducing toxicity of high-dose chemotherapy and irradiation hold great promise. Highly immunosuppressive, nonchemotherapeutic agents that inhibit graft rejection or GVHD by blocking the critical costimulatory component of the T-cell receptor-antigen interaction are beginning to emerge and may be ideal for SCT of nonmalignant diseases. Therefore, the risk-benefit equation must be reassessed each year as the severity of patients' disorders is better defined and techniques of SCT improve.

Authors
Horwitz, ME
MLA Citation
Horwitz, ME. "Stem-cell transplantation for inherited immunodeficiency disorders." Pediatr Clin North Am 47.6 (December 2000): 1371-1387. (Review)
PMID
11131001
Source
pubmed
Published In
Pediatric Clinics of North America
Volume
47
Issue
6
Publish Date
2000
Start Page
1371
End Page
1387

The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators

Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation. We recently identified the gene causing FMF, designated MEFV, and found it to be expressed in mature neutrophils, suggesting that it functions as an inflammatory regulator. To facilitate our understanding of the normal function of MEFV, we extended our previous studies. MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization. CD34 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment. The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation. MEFV was also expressed in the monocytic cell lines U937 and THP-1. Among peripheral blood leukocytes, MEFV expression was detected in neutrophils, eosinophils, and to varying degrees, monocytes. Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements. In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN)γ, tumor necrosis factor, and lipopolysaccharide induced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL) 4, IL-10, and transforming growth factor β inhibited such expression. Induction by IFN-γ occurred rapidly and was resistant to cycloheximide. IFN-α also induced MEFV expression. In granulocytes, MEFV was up-regulated by IFN-γ and the combination of IFN-α and colchicine. These results refine understanding of MEFV by placing the gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an IFN-γ immediate early gene. (C) 2000 by The American Society of Hematology.

Authors
Centola, M; Wood, G; Frucht, DM; Galon, J; Aringer, M; Farrell, C; Kingma, DW; Horwitz, ME; Mansfield, E; Holland, SM; O'Shea, JJ; Rosenberg, HF; Malech, HL; Kastner, DL
MLA Citation
Centola, M, Wood, G, Frucht, DM, Galon, J, Aringer, M, Farrell, C, Kingma, DW, Horwitz, ME, Mansfield, E, Holland, SM, O'Shea, JJ, Rosenberg, HF, Malech, HL, and Kastner, DL. "The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators." Blood 95.10 (2000): 3223-3231.
PMID
10807793
Source
scival
Published In
Blood
Volume
95
Issue
10
Publish Date
2000
Start Page
3223
End Page
3231

Granulocyte colony-stimulating factor mobilized peripheral blood stem cells enter into G1 of the cell cycle and express higher levels of amphotropic retrovirus receptor mRNA.

We compared the cell cycle status and expression of mRNA for the amphotropic retroviral receptor in hematopoietic stem cells isolated from bone marrow and cytokine mobilized peripheral blood. CD34+ cells from six normal volunteers were enriched by immune selection from steady-state bone marrow and granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood (10 microg/kg/day for 5 days). Cell cycle status of the phenotypically primitive CD34+CD38- hematopoietic stem cell population was analyzed using a four-color flow cytometry technique that distinguished the G0, G1, and S/IG2/M phases of the cell cycle. Semiquantitative reverse transcriptase-polymerase chain reaction was performed to measure mRNA expression of the amphotropic retroviral receptor. Peripheral blood hematopoietic stem cells had 2.6-fold more cells in the G1 phase of the cell cycle compared to steady-state bone marrow. Furthermore, lineage CD34+CD38- cells from G-CSF mobilized peripheral blood had a fourfold higher level of amphotropic retrovirus receptor mRNA. In conclusion, we found that CD34+ CD38- hematopoietic stem cells isolated from G-CSF mobilized peripheral blood differ from those isolated from steady-state bone marrow in that a significant proportion have entered the G1 phase of the cell cycle and express higher levels of amphotropic receptor mRNA. These biologic properties are consistent with the reported rapid recovery of hematopoietic function following transplantation with peripheral blood hematopoietic stem cells and make these cells a preferred target for retroviral-based gene transfer.

Authors
Horwitz, ME; Malech, HL; Anderson, SM; Girard, LJ; Bodine, DM; Orlic, D
MLA Citation
Horwitz, ME, Malech, HL, Anderson, SM, Girard, LJ, Bodine, DM, and Orlic, D. "Granulocyte colony-stimulating factor mobilized peripheral blood stem cells enter into G1 of the cell cycle and express higher levels of amphotropic retrovirus receptor mRNA." Exp Hematol 27.7 (July 1999): 1160-1167.
PMID
10390191
Source
pubmed
Published In
Experimental Hematology
Volume
27
Issue
7
Publish Date
1999
Start Page
1160
End Page
1167
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