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Gasparetto, Cristina

Overview:

Dr. Gasparetto performs both laboratory and clinical research in the field of multiple myeloma. Her primary research interests are in developing immunotherapy approaches to treating multiple myeloma particularly in conjunction with hematopoietic stem cell transplantation. Ongoing laboratory research projects include the development of dendritic cell vaccines and antibody therapies. Clinical studies include a recently approved trial involving vaccination with autologous dendritic cells pulsed with idiotypic protein following high dose chemotherapy and autologous peripheral blood stem cells transplant. Upcoming trials include novel antibody therapies for multiple myeloma. Dr. Gasparetto is also an investigator on several other clinical trials for myeloma including non-myeloablative allogeneic transplantation, high dose sequential chemotherapy and autologous peripheral blood stem cell transplantation and transplantation of partially HLA matched unrelated cord blood.

Positions:

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1986

M.D. — Sapienza University of Rome (Italy)

Medical Resident, Medicine

Duke University

Fellow In Hematology/Oncology, Medicine

Duke University

Grants:

NEOD001

Administered By
Duke Cancer Institute
AwardedBy
Prothena Therapeutics Limited
Role
Principal Investigator
Start Date
October 13, 2017
End Date
October 31, 2022

Protocol 54767414MMY2004 Phase 2

Administered By
Duke Cancer Institute
AwardedBy
Janssen Research & Development, LLC
Role
Principal Investigator
Start Date
October 11, 2017
End Date
June 30, 2022

Study to evaluate the safety of SAR650984 (isatuximab) in R/R MM pts

Administered By
Duke Cancer Institute
AwardedBy
Sanofi US
Role
Principal Investigator
Start Date
January 10, 2017
End Date
December 30, 2021

Phase III double blind study of Bortezomib and Dex in combination with Venetoclax or Placebo in R/R MM

Administered By
Duke Cancer Institute
AwardedBy
AbbVie Inc.
Role
Principal Investigator
Start Date
October 01, 2016
End Date
September 30, 2021

A Feasibility Phase II study of BEAM followed by MLN 9708 Maintenance therapy in high risk MM patients

Administered By
Duke Cancer Institute
AwardedBy
Oregon Health & Science University
Role
Principal Investigator
Start Date
September 08, 2016
End Date
September 07, 2021

Ph 3 Trial of Combinations of Nivolumab, Elotuzumab, Pomalidomide and Dexamethasone

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2021

Phase Ib/2 Study of Selinexor (KPT330) for R/R MM

Administered By
Duke Cancer Institute
AwardedBy
Karyopharm Therapeutics
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 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 1/2 Open label study of SL-401 with Pom/Dex in R/R MM

Administered By
Duke Cancer Institute
AwardedBy
Stemline Therapeutics, Inc
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

Phase III study of Pomalidomide and low dose Dex with or without Pembrolizumab (MK3475) in MM

Administered By
Duke Cancer Institute
AwardedBy
Merck Sharp & Dohme
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

A Phase I Study of ABT-199 Monotherapy in R/R Multiple Myeloma

Administered By
Duke Cancer Institute
AwardedBy
AbbVie Inc.
Role
Principal Investigator
Start Date
February 01, 2015
End Date
January 31, 2020

A Phase II study of Filanesib (ARRY-520) with patients with Advanced Multiple Myeloma

Administered By
Duke Cancer Institute
AwardedBy
Array BioPharma Inc
Role
Principal Investigator
Start Date
December 01, 2014
End Date
November 30, 2019

An Observational Study on Newly Diagnosed MM to assess the realtionship between patient outcomes, treatment regimens

Administered By
Duke Cancer Institute
AwardedBy
Multiple Myeloma Research Foundation
Role
Principal Investigator
Start Date
November 02, 2013
End Date
November 01, 2018

Phase 1/2b study of Ibrutinib with Carlfizomib with R/R Myeloma

Administered By
Duke Cancer Institute
AwardedBy
Pharmacyclics, Inc.
Role
Principal Investigator
Start Date
January 20, 2013
End Date
January 19, 2018

CELGENE MULTIPLE MYELOMA TUMOR PRACTICUM

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
Celgene Corporation
Role
Principal Investigator
Start Date
November 01, 2017
End Date
November 08, 2017

Randomized Phase II trial study of lenalidomide, bortezomib and dexamethsone (RVD) in new MM pts

Administered By
Duke Cancer Institute
AwardedBy
Novartis Pharmaceuticals Corporation
Role
Principal Investigator
Start Date
September 01, 2016
End Date
October 24, 2017

Phase II, study of Selinexor KPT-330 Carlf, and Dexa, in R/R MM pts

Administered By
Duke Cancer Institute
AwardedBy
Karyopharm Therapeutics
Role
Principal Investigator
Start Date
March 15, 2016
End Date
October 14, 2017

KPT-330 (KCP-330-011) SLAM in R/R MM

Administered By
Duke Cancer Institute
AwardedBy
Karyopharm Therapeutics
Role
Principal Investigator
Start Date
July 15, 2015
End Date
September 13, 2017

Dendritic Cell Based Vaccination for Multiple Myeloma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2002
End Date
July 31, 2007
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Publications:

Recognition of early mortality in multiple myeloma by a prediction matrix.

Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%-14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r-ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma-specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow-up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ-5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient-specific treatment strategies to improve outcomes.

Authors
Terebelo, H; Srinivasan, S; Narang, M; Abonour, R; Gasparetto, C; Toomey, K; Hardin, JW; Larkins, G; Kitali, A; Rifkin, RM; Shah, JJ
MLA Citation
Terebelo, H, Srinivasan, S, Narang, M, Abonour, R, Gasparetto, C, Toomey, K, Hardin, JW, Larkins, G, Kitali, A, Rifkin, RM, and Shah, JJ. "Recognition of early mortality in multiple myeloma by a prediction matrix." American journal of hematology 92.9 (September 2017): 915-923.
PMID
28543165
Source
epmc
Published In
American Journal of Hematology
Volume
92
Issue
9
Publish Date
2017
Start Page
915
End Page
923
DOI
10.1002/ajh.24796

Analysis of Common Eligibility Criteria of Randomized Controlled Trials in Newly Diagnosed Multiple Myeloma Patients and Extrapolating Outcomes.

The performance of multiple myeloma (MM) therapies in a general patient population and specific eligibility criteria that might limit enrollment into randomized controlled trials (RCTs) have not been evaluated in depth. This study aimed to determine if improvements seen with MM therapies in RCTs are reflected in the general patient population and to identify eligibility criteria that can be modified to increase enrollment.The Connect MM Registry is a prospective observational cohort study of patients with newly diagnosed MM (NDMM) in the United States. Using common RCT exclusion criteria collected from 16 published studies, patients in the registry were categorized according to their eligibility for inclusion in RCTs.On the basis of common criteria, 563 of 1406 of registry patients (40.0%) are ineligible for RCTs. Criteria leading to exclusion included M-protein ≤ 1.0 g/dL (25.2%), creatinine > 2.5 mg/dL (13.9%), low absolute neutrophil count (10.0%), and low hemoglobin (9.6%). Significantly more RCT-ineligible versus RCT-eligible patients had hypercalcemia (11.0% vs. 5.5%), elevated creatinine levels (38.9% vs. 6.2%), low hemoglobin levels (59.5% vs. 39.5%), or International Staging System stage III disease (40.1% vs. 22.1%; P < .001 for all comparisons). RCT-ineligible patients had a lower 3-year survival rate than RCT-eligible patients (63% vs. 70%). The incidence of serious adverse events was similar between groups.Of patients with NDMM enrolled in the Connect MM Registry, 40% are ineligible for RCTs. This study provides insight into potential modifications of standard eligibility criteria that can lead to improved RCT design and accelerated enrollment.

Authors
Shah, JJ; Abonour, R; Gasparetto, C; Hardin, JW; Toomey, K; Narang, M; Srinivasan, S; Kitali, A; Zafar, F; Flick, ED; Rifkin, RM
MLA Citation
Shah, JJ, Abonour, R, Gasparetto, C, Hardin, JW, Toomey, K, Narang, M, Srinivasan, S, Kitali, A, Zafar, F, Flick, ED, and Rifkin, RM. "Analysis of Common Eligibility Criteria of Randomized Controlled Trials in Newly Diagnosed Multiple Myeloma Patients and Extrapolating Outcomes." Clinical lymphoma, myeloma & leukemia 17.9 (September 2017): 575-583.e2.
PMID
28886839
Source
epmc
Published In
Clinical Lymphoma, Myeloma and Leukemia
Volume
17
Issue
9
Publish Date
2017
Start Page
575
End Page
583.e2
DOI
10.1016/j.clml.2017.06.013

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

Authors
Vogl, DT; Martin, TG; Vij, R; Hari, P; Mikhael, JR; Siegel, D; Wu, KL; Delforge, M; Gasparetto, C
MLA Citation
Vogl, DT, Martin, TG, Vij, R, Hari, P, Mikhael, JR, Siegel, D, Wu, KL, Delforge, M, and Gasparetto, C. "Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma." Leukemia & lymphoma 58.8 (August 2017): 1872-1879.
PMID
28140719
Source
epmc
Published In
Leukemia & Lymphoma (Informa)
Volume
58
Issue
8
Publish Date
2017
Start Page
1872
End Page
1879
DOI
10.1080/10428194.2016.1263842

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

Panobinostat for the management of multiple myeloma.

Multiple myeloma (MM) is the second most common blood cancer following non-Hodgkin's lymphoma. While the treatments for MM have improved over the past decade, for the most part, it remains an incurable disease. For this reason newer therapeutic agents are needed to combat this malignancy. Panobinostat is a pan-deacetylase inhibitor that impedes protein destruction by disturbing the enzymatic activity of deacetylases. It was US FDA approved in February 2015 for the management of relapsed/refractory MM in combination with bortezomib and dexamethasone. Several trials are ongoing, exploring the utility of panobinostat in various other settings for the management of MM. This review will detail the biology, clinical efficacy and potential future applications of panobinostat in the treatment of MM.

Authors
Sivaraj, D; Green, MM; Gasparetto, C
MLA Citation
Sivaraj, D, Green, MM, and Gasparetto, C. "Panobinostat for the management of multiple myeloma." Future oncology (London, England) 13.6 (March 2017): 477-488. (Review)
PMID
27776419
Source
epmc
Published In
Future oncology (London, England)
Volume
13
Issue
6
Publish Date
2017
Start Page
477
End Page
488
DOI
10.2217/fon-2016-0329

Clinical practice guidelines in oncology

©copy;JNCCN-Journal of the National Comprehensive Cancer Network. Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

Authors
Kumar, SK; Callander, NS; Alsina, M; Atanackovic, D; Biermann, JS; Chandler, JC; Costello, C; Faiman, M; Fung, HC; Gasparetto, C; Godby, K; Hofmeister, C; Holmberg, L; Holstein, S; Huff, CA; Kassim, A; Liedtke, M; Martin, T; Omel, J; Raje, N; Reu, FJ; Singhal, S; Somlo, G; Stockerl-Goldstein, K; Treon, SP; Weber, D; Yahalom, J; Shead, DA; Kumar, R
MLA Citation
Kumar, SK, Callander, NS, Alsina, M, Atanackovic, D, Biermann, JS, Chandler, JC, Costello, C, Faiman, M, Fung, HC, Gasparetto, C, Godby, K, Hofmeister, C, Holmberg, L, Holstein, S, Huff, CA, Kassim, A, Liedtke, M, Martin, T, Omel, J, Raje, N, Reu, FJ, Singhal, S, Somlo, G, Stockerl-Goldstein, K, Treon, SP, Weber, D, Yahalom, J, Shead, DA, and Kumar, R. "Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 15.2 (February 1, 2017): 230-269.
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
15
Issue
2
Publish Date
2017
Start Page
230
End Page
269

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

Risk stratification, treatment selection, and transplant eligibility in multiple myeloma: a qualitative study of the perspectives and self-reported practices of oncologists.

Since the early 2000s, treatment options for multiple myeloma have rapidly expanded, adding significant complexity to the management of this disease. To our knowledge, no systematic qualitative research on clinical decision-making in multiple myeloma has been published. We sought to characterize how physicians view and implement guidelines and incorporate novel approaches into patient care.We designed a semi-structured qualitative interview guide informed by literature review and an expert advisory panel. We conducted 60-minute interviews with a diverse sample of oncology physicians in the southeast United States. We used a constant comparative method to code and analyze interview transcripts. The research team and advisory panel discussed and validated emergent themes.Participants were 13 oncologists representing 5 academic and 4 community practices. Academic physicians reported using formal risk-stratification schemas; community physicians typically did not. Physicians also described differences in eligibility criteria for transplantation; community physicians emphasized distance, social support, and psychosocial capacity in making decisions about transplantation referral; the academic physicians reported using more specific clinical criteria. All physicians reported using a maintenance strategy both for post-transplant and for transplant-ineligible patients; however, determining the timing of maintenance therapy initiation and the response were reported as challenging, as was recognition or definition of relapse, especially in terms of when treatment re-initiation is indicated.Practices reported by both academic and community physicians suggest opportunities for interventions to improve patient care and outcomes through optimal multiple myeloma management and therapy selection. Community physicians in particular might benefit from targeted education interventions about risk stratification, transplant eligibility, and novel therapies.

Authors
LeBlanc, TW; Howson, A; Turell, W; Sheldon, P; Locke, SC; Tuchman, SA; Gasparetto, C; Kaura, S; Khan, ZM; Abernethy, AP
MLA Citation
LeBlanc, TW, Howson, A, Turell, W, Sheldon, P, Locke, SC, Tuchman, SA, Gasparetto, C, Kaura, S, Khan, ZM, and Abernethy, AP. "Risk stratification, treatment selection, and transplant eligibility in multiple myeloma: a qualitative study of the perspectives and self-reported practices of oncologists." Current oncology (Toronto, Ont.) 23.6 (December 21, 2016): e598-e604.
PMID
28050150
Source
epmc
Published In
Current oncology (Toronto, Ont.)
Volume
23
Issue
6
Publish Date
2016
Start Page
e598
End Page
e604
DOI
10.3747/co.23.3298

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Authors
Scott, EC; Hari, P; Sharma, M; Le-Rademacher, J; Huang, J; Vogl, D; Abidi, M; Beitinjaneh, A; Fung, H; Ganguly, S; Hildebrandt, G; Holmberg, L; Kalaycio, M; Kumar, S; Kyle, R; Lazarus, H; Lee, C; Maziarz, RT; Meehan, K; Mikhael, J; Nishihori, T; Ramanathan, M; Usmani, S; Tay, J; Vesole, D; Wirk, B; Yared, J; Savani, BN; Gasparetto, C; Krishnan, A; Mark, T; Nieto, Y; D'Souza, A
MLA Citation
Scott, EC, Hari, P, Sharma, M, Le-Rademacher, J, Huang, J, Vogl, D, Abidi, M, Beitinjaneh, A, Fung, H, Ganguly, S, Hildebrandt, G, Holmberg, L, Kalaycio, M, Kumar, S, Kyle, R, Lazarus, H, Lee, C, Maziarz, RT, Meehan, K, Mikhael, J, Nishihori, T, Ramanathan, M, Usmani, S, Tay, J, Vesole, D, Wirk, B, Yared, J, Savani, BN, Gasparetto, C, Krishnan, A, Mark, T, Nieto, Y, and D'Souza, A. "Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22.10 (October 2016): 1893-1899.
PMID
27496215
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
22
Issue
10
Publish Date
2016
Start Page
1893
End Page
1899
DOI
10.1016/j.bbmt.2016.07.007

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

Connect MM® - the Multiple Myeloma Disease Registry: incidence of second primary malignancies in patients treated with lenalidomide.

Authors
Rifkin, RM; Abonour, R; Shah, JJ; Mehta, J; Narang, M; Terebelo, H; Gasparetto, C; Toomey, K; Hardin, JW; Lu, JJ; Kenvin, L; Srinivasan, S; Knight, R; Nagarwala, Y; Durie, BGM
MLA Citation
Rifkin, RM, Abonour, R, Shah, JJ, Mehta, J, Narang, M, Terebelo, H, Gasparetto, C, Toomey, K, Hardin, JW, Lu, JJ, Kenvin, L, Srinivasan, S, Knight, R, Nagarwala, Y, and Durie, BGM. "Connect MM® - the Multiple Myeloma Disease Registry: incidence of second primary malignancies in patients treated with lenalidomide." Leukemia & lymphoma 57.9 (September 2016): 2228-2231.
PMID
26766599
Source
epmc
Published In
Leukemia & Lymphoma (Informa)
Volume
57
Issue
9
Publish Date
2016
Start Page
2228
End Page
2231
DOI
10.3109/10428194.2015.1132419

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

Can We Cure Light Chain Deposition Disease of the Kidneys?-A Review and Case Report of a Patient Treated With a Triple Transplant Approach.

Authors
Sivaraj, D; Green, MM; Ciftci, AM; Zahid, MF; Johns, AA; Ross, M; Gasparetto, C
MLA Citation
Sivaraj, D, Green, MM, Ciftci, AM, Zahid, MF, Johns, AA, Ross, M, and Gasparetto, C. "Can We Cure Light Chain Deposition Disease of the Kidneys?-A Review and Case Report of a Patient Treated With a Triple Transplant Approach." Clinical lymphoma, myeloma & leukemia 16.6 (June 2016): e95-e100. (Review)
PMID
27101986
Source
epmc
Published In
Clinical Lymphoma, Myeloma and Leukemia
Volume
16
Issue
6
Publish Date
2016
Start Page
e95
End Page
e100
DOI
10.1016/j.clml.2016.03.002

NCCN guidelines®insights multiple myeloma, version 3.2016 featured updates to the NCCN guidelines

© 2016 JNCCN-Journal of the National Comprehensive Cancer Network. These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

Authors
Anderson, KC; Alsina, M; Atanackovic, D; Biermann, JS; Chandler, JC; Costello, C; Djulbegovic, B; Fung, HC; Gasparetto, C; Godby, K; Hofmeister, C; Holmberg, L; Holstein, S; Huff, CA; Kassim, A; Krishnan, AY; Kumar, SK; Liedtke, M; Lunning, M; Raje, N; Reu, FJ; Singhal, S; Somlo, G; Stockerl-Goldstein, K; Treon, SP; Weber, D; Yahalom, J; Shead, DA; Kumar, R
MLA Citation
Anderson, KC, Alsina, M, Atanackovic, D, Biermann, JS, Chandler, JC, Costello, C, Djulbegovic, B, Fung, HC, Gasparetto, C, Godby, K, Hofmeister, C, Holmberg, L, Holstein, S, Huff, CA, Kassim, A, Krishnan, AY, Kumar, SK, Liedtke, M, Lunning, M, Raje, N, Reu, FJ, Singhal, S, Somlo, G, Stockerl-Goldstein, K, Treon, SP, Weber, D, Yahalom, J, Shead, DA, and Kumar, R. "NCCN guidelines®insights multiple myeloma, version 3.2016 featured updates to the NCCN guidelines." JNCCN Journal of the National Comprehensive Cancer Network 14.4 (April 1, 2016): 389-400.
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
14
Issue
4
Publish Date
2016
Start Page
389
End Page
400

Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma.

Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone (CPD) in an open-label, multicenter, phase 1, dose-escalation study. Patients who relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib IV on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m(2)), pomalidomide once daily on days 1 to 21 (4 mg as the initial dose level), and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m(2), pomalidomide 4 mg, dexamethasone 40 mg). Hematologic adverse events (AEs) occurred in ≥60% of all patients, including 11 patients with grade ≥3 anemia. Dyspnea was limited to grade 1/2 in 10 patients. Peripheral neuropathy was uncommon and limited to grade 1/2. Eight patients had dose reductions during therapy, and 7 patients discontinued treatment due to AEs. Two deaths were noted on study due to pneumonia and pulmonary embolism (n = 1 each). The combination of CPD is well-tolerated and highly active in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT01464034.

Authors
Shah, JJ; Stadtmauer, EA; Abonour, R; Cohen, AD; Bensinger, WI; Gasparetto, C; Kaufman, JL; Lentzsch, S; Vogl, DT; Gomes, CL; Pascucci, N; Smith, DD; Orlowski, RZ; Durie, BGM
MLA Citation
Shah, JJ, Stadtmauer, EA, Abonour, R, Cohen, AD, Bensinger, WI, Gasparetto, C, Kaufman, JL, Lentzsch, S, Vogl, DT, Gomes, CL, Pascucci, N, Smith, DD, Orlowski, RZ, and Durie, BGM. "Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma." Blood 126.20 (November 2015): 2284-2290.
PMID
26384354
Source
epmc
Published In
Blood
Volume
126
Issue
20
Publish Date
2015
Start Page
2284
End Page
2290
DOI
10.1182/blood-2015-05-643320

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

Connect MM Registry: The Importance of Establishing Baseline Disease Characteristics.

Connect MM is the first and largest observational, noninterventional, prospective registry of patients newly diagnosed with multiple myeloma (NDMM) in the United States. It collects longitudinal data on patients within clinical practice including patients in clinical trials.Of the 1513 patients enrolled, 1493 were protocol-eligible.Median age was 67 years, 81.9% (1223/1493) were Caucasian, and 57.2% (854/1493) were male. Of these patients, 26.5% (232/877) were International Staging System stage I, 34.9% (306/877) stage II, and 38.7% (339/877) stage III. Eastern Cooperative Oncology Group performance status of 0/1/2 were reported in 96.6% (1017/1053). Clonal plasma cells > 10% were found in 91.6% (1282/1399) of patients and M-component in 98.8% (1343/1359). Hypercalcemia was present in 7.3% (108/1481) of patients, serum creatinine > 2 mg/dL in 18.3% (271/1484), anemia in 45.1% (673/1493), and bone involvement in 76.7% (1143/1490). Of the 15 National Comprehensive Cancer Network (NCCN) recommended diagnostic tests, a median of 12 were performed. Lactate dehydrogenase assessment, serum free light chain ratio, and immunofixation were reported in 38.4% (574/1493), 62.1% (927/1493), and 66% (985/1493) of patients, respectively. Quantitative immunoglobulin, β-2 microglobulin, and protein electrophoresis (serum or urine) were reported in 72.3% (1080/1493), 74.1% (1107/1493), and 78.0% (1164/1493) of patients, respectively. Bone marrow biopsy was reported in 92.2% (1376/1493), but conventional cytogenetic and fluorescence in situ hybridization analysis were reported in only 63.2% (944/1493) and 59.8% (893/1493) of patients, respectively. A high-risk cytogenetic profile (according to International Myeloma Working Group [IMWG] criteria) was found in 16.9% (253/1493).This analysis provides insight into the demographic and disease characteristics of NDMM patients in a range of clinical practices. Creating solid records of baseline patient disease characteristics using suggested NCCN diagnostic work-up and IMWG criteria provides a foundation for monitoring disease progression and response to treatment.

Authors
Rifkin, RM; Abonour, R; Terebelo, H; Shah, JJ; Gasparetto, C; Hardin, J; Srinivasan, S; Ricafort, R; Nagarwala, Y; Durie, BGM
MLA Citation
Rifkin, RM, Abonour, R, Terebelo, H, Shah, JJ, Gasparetto, C, Hardin, J, Srinivasan, S, Ricafort, R, Nagarwala, Y, and Durie, BGM. "Connect MM Registry: The Importance of Establishing Baseline Disease Characteristics." Clinical lymphoma, myeloma & leukemia 15.6 (June 2015): 368-376.
PMID
25617035
Source
epmc
Published In
Clinical Lymphoma, Myeloma and Leukemia
Volume
15
Issue
6
Publish Date
2015
Start Page
368
End Page
376
DOI
10.1016/j.clml.2014.12.002

Quantitative measures of physical functioning after autologous hematopoietic stem cell transplantation in multiple myeloma: a feasibility study.

BACKGROUND: The safety and feasibility of the symptom-limited cardiopulmonary exercise test (CPET) and the 6-minute walk test (6MWT) has not been rigorously tested in patients with multiple myeloma (MM) after high-dose chemotherapy with autologous stem cell transplantation (ASCT), nor have correlations with patient-reported outcomes (PROs) been explored. PATIENTS AND METHODS: We undertook CPET, 6MWT, and PRO assessments using standardized measurements and questionnaires in patients with MM in remission after ASCT. RESULTS: A total of 22 patients who were a median of 17 months after ASCT underwent assessment. No severe adverse events were observed. Exercise capacity, measured during CPET as the peak oxygen consumption, was 17.5 ± 5.9 mL/kg/min, the equivalent of 38% ± 18% less than that for age- and sex-predicted sedentary normative values. During the 6MWT, the mean 6-minute walk distance was 500 m, or 25% ± 13% less than the predicted values. Additional analysis using Pearson's correlation revealed no significant univariate associations between exercise or functional capacity and any PROs. CONCLUSION: Patients with MM have marked and significant reductions in quantitative measures of physical function for years after the initial therapy, although that did not correlate with PROs in the present pilot study. Larger prospective studies are required to determine the clinical ramifications of these findings and to mechanistically dissect them, as well to test interventions aimed at mitigating them.

Authors
Tuchman, SA; Lane, A; Hornsby, WE; Bishop, C; Thomas, S; Herndon, JE; Long, G; Gasparetto, C; Jones, LW
MLA Citation
Tuchman, SA, Lane, A, Hornsby, WE, Bishop, C, Thomas, S, Herndon, JE, Long, G, Gasparetto, C, and Jones, LW. "Quantitative measures of physical functioning after autologous hematopoietic stem cell transplantation in multiple myeloma: a feasibility study." Clinical lymphoma, myeloma & leukemia 15.2 (February 2015): 103-109.
PMID
25445473
Source
epmc
Published In
Clinical Lymphoma, Myeloma and Leukemia
Volume
15
Issue
2
Publish Date
2015
Start Page
103
End Page
109
DOI
10.1016/j.clml.2014.09.002

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

Connect MM registry: The importance of establishing baseline disease characteristics

© 2015 Elsevier Inc. All rights reserved. Background Connect MM is the first and largest observational, noninterventional, prospective registry of patients newly diagnosed with multiple myeloma (NDMM) in the United States. It collects longitudinal data on patients within clinical practice including patients in clinical trials. Patients and Methods Of the 1513 patients enrolled, 1493 were protocol-eligible. Results Median age was 67 years, 81.9% (1223/1493) were Caucasian, and 57.2% (854/1493) were male. Of these patients, 26.5% (232/877) were International Staging System stage I, 34.9% (306/877) stage II, and 38.7% (339/877) stage III. Eastern Cooperative Oncology Group performance status of 0/1/2 were reported in 96.6% (1017/1053). Clonal plasma cells > 10% were found in 91.6% (1282/1399) of patients and M-component in 98.8% (1343/1359). Hypercalcemia was present in 7.3% (108/1481) of patients, serum creatinine > 2 mg/dL in 18.3% (271/1484), anemia in 45.1% (673/1493), and bone involvement in 76.7% (1143/1490). Of the 15 National Comprehensive Cancer Network (NCCN) recommended diagnostic tests, a median of 12 were performed. Lactate dehydrogenase assessment, serum free light chain ratio, and immunofixation were reported in 38.4% (574/1493), 62.1% (927/1493), and 66% (985/1493) of patients, respectively. Quantitative immunoglobulin, β-2 microglobulin, and protein electrophoresis (serum or urine) were reported in 72.3% (1080/1493), 74.1% (1107/1493), and 78.0% (1164/1493) of patients, respectively. Bone marrow biopsy was reported in 92.2% (1376/1493), but conventional cytogenetic and fluorescence in situ hybridization analysis were reported in only 63.2% (944/1493) and 59.8% (893/1493) of patients, respectively. A high-risk cytogenetic profile (according to International Myeloma Working Group [IMWG] criteria) was found in 16.9% (253/1493). Conclusion This analysis provides insight into the demographic and disease characteristics of NDMM patients in a range of clinical practices. Creating solid records of baseline patient disease characteristics using suggested NCCN diagnostic work-up and IMWG criteria provides a foundation for monitoring disease progression and response to treatment.

Authors
Rifkin, RM; Abonour, R; Terebelo, H; Shah, JJ; Gasparetto, C; Hardin, J; Srinivasan, S; Ricafort, R; Nagarwala, Y; Durie, BGM
MLA Citation
Rifkin, RM, Abonour, R, Terebelo, H, Shah, JJ, Gasparetto, C, Hardin, J, Srinivasan, S, Ricafort, R, Nagarwala, Y, and Durie, BGM. "Connect MM registry: The importance of establishing baseline disease characteristics." Clinical Lymphoma, Myeloma and Leukemia 15.6 (January 1, 2015): 368-376.
Source
scopus
Published In
Clinical Lymphoma, Myeloma and Leukemia
Volume
15
Issue
6
Publish Date
2015
Start Page
368
End Page
376
DOI
10.1016/j.clml.2014.12.002

Older patients with myeloma derive similar benefit from autologous transplantation.

Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n = 5818), 60 to 69 years (n = 4666), and >70 years (n = 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P = .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P = not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P = not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P = not significant). Postrelapse survival was significantly worse for the older cohort (P = .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS.

Authors
Sharma, M; Zhang, M-J; Zhong, X; Abidi, MH; Akpek, G; Bacher, U; Callander, NS; Dispenzieri, A; Freytes, CO; Fung, HC; Gale, RP; Gasparetto, C; Gibson, J; Holmberg, LA; Kindwall-Keller, TL; Klumpp, TR; Krishnan, AY; Landau, HJ; Lazarus, HM; Lonial, S; Maiolino, A; Marks, DI; Mehta, P; Mikhael Med, JR; Nishihori, T; Olsson, R; Ramanathan, M; Roy, V; Savani, BN; Schouten, HC; Scott, E; Tay, J; To, LB; Vesole, DH; Vogl, DT; Hari, P
MLA Citation
Sharma, M, Zhang, M-J, Zhong, X, Abidi, MH, Akpek, G, Bacher, U, Callander, NS, Dispenzieri, A, Freytes, CO, Fung, HC, Gale, RP, Gasparetto, C, Gibson, J, Holmberg, LA, Kindwall-Keller, TL, Klumpp, TR, Krishnan, AY, Landau, HJ, Lazarus, HM, Lonial, S, Maiolino, A, Marks, DI, Mehta, P, Mikhael Med, JR, Nishihori, T, Olsson, R, Ramanathan, M, Roy, V, Savani, BN, Schouten, HC, Scott, E, Tay, J, To, LB, Vesole, DH, Vogl, DT, and Hari, P. "Older patients with myeloma derive similar benefit from autologous transplantation." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20.11 (November 2014): 1796-1803.
PMID
25046833
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
11
Publish Date
2014
Start Page
1796
End Page
1803
DOI
10.1016/j.bbmt.2014.07.013

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

Hematopoietic Cell Transplant Comorbidity Index Is Predictive of Survival after Autologous Hematopoietic Cell Transplantation in Multiple Myeloma

Authors
Saad, A; Mahindra, A; Zhang, M-J; Zhong, X; Costa, LJ; Dispenzieri, A; Drobyski, WR; Freytes, CO; Gale, RP; Gasparetto, CJ; Holmberg, LA; Kamble, RT; Krishnan, AY; Kyle, RA; Marks, D; Nishihori, T; Pasquini, MC; Ramanathan, M; Lonial, S; Savani, BN; Saber, W; Sharma, M; Sorror, ML; Wirk, BM; Hari, PN
MLA Citation
Saad, A, Mahindra, A, Zhang, M-J, Zhong, X, Costa, LJ, Dispenzieri, A, Drobyski, WR, Freytes, CO, Gale, RP, Gasparetto, CJ, Holmberg, LA, Kamble, RT, Krishnan, AY, Kyle, RA, Marks, D, Nishihori, T, Pasquini, MC, Ramanathan, M, Lonial, S, Savani, BN, Saber, W, Sharma, M, Sorror, ML, Wirk, BM, and Hari, PN. "Hematopoietic Cell Transplant Comorbidity Index Is Predictive of Survival after Autologous Hematopoietic Cell Transplantation in Multiple Myeloma." Biology of Blood and Marrow Transplantation 20.3 (March 2014): 402-408.e1.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
3
Publish Date
2014
Start Page
402
End Page
408.e1
DOI
10.1016/j.bbmt.2013.12.557

Hematopoietic cell transplant comorbidity index is predictive of survival after autologous hematopoietic cell transplantation in multiple myeloma.

Autologous hematopoietic stem cell transplantation (AHCT) improves survival in patients with multiple myeloma (MM) but is associated with morbidity and nonrelapse mortality (NRM). Hematopoietic cell transplant comorbidity index (HCT-CI) was shown to predict risk of NRM and survival after allogeneic transplantation. We tested the utility of HCT-CI as a predictor of NRM and survival in patients with MM undergoing AHCT. We analyzed outcomes of 1156 patients of AHCT after high-dose melphalan reported to the Center for International Blood and Marrow Transplant Research. Individual comorbidities were prospectively collected at the time of AHCT. The impact of HCT-CI and other potential prognostic factors, including Karnofsky performance score (KPS), on NRM and survival were studied in multivariate Cox regression models. HCT-CI score was 0, 1, 2, 3, and >3 in 42%, 18%, 13%, 13%, and 14% of the study cohort, respectively. Subjects were stratified into 3 risk groups: HCT-CI score of 0 (42%) versus HCT-CI score of 1 to 2 (32%) versus HCT-CI score > 2 (26%). Higher HCT-CI was associated with lower KPS < 90 (33% of subjects score of 0 versus 50% in HCT-CI score > 2). HCT-CI score > 2 was associated with melphalan dose reduction (22% versus 10% in score 0 cohort). One-year NRM was low at 2% (95% confidence interval, 1% to 4%) and did not correlate with HCT-CI score (P = .9). On multivariate analysis, overall survival was inferior in groups with HCT-CI score of 1 to 2 (relative risk, 1.37, [95% confidence interval, 1.01 to 1.87], P = .04) and HCT-CI score > 2 (relative risk, 1.5 [95% confidence interval, 1.09 to 2.08], P = .01). Overall survival was also inferior with KPS < 90 (P < .001), IgA subtype (P ≤ .001), those receiving >1 pretransplant induction regimen (P = .007), and those with resistant disease at the time of AHCT (P < .001). AHCT for MM is associated with low NRM, and death is predominantly related to disease progression. Although a higher HCT-CI score did not predict NRM, it was associated with inferior survival.

Authors
Saad, A; Mahindra, A; Zhang, M-J; Zhong, X; Costa, LJ; Dispenzieri, A; Drobyski, WR; Freytes, CO; Gale, RP; Gasparetto, CJ; Holmberg, LA; Kamble, RT; Krishnan, AY; Kyle, RA; Marks, D; Nishihori, T; Pasquini, MC; Ramanathan, M; Lonial, S; Savani, BN; Saber, W; Sharma, M; Sorror, ML; Wirk, BM; Hari, PN
MLA Citation
Saad, A, Mahindra, A, Zhang, M-J, Zhong, X, Costa, LJ, Dispenzieri, A, Drobyski, WR, Freytes, CO, Gale, RP, Gasparetto, CJ, Holmberg, LA, Kamble, RT, Krishnan, AY, Kyle, RA, Marks, D, Nishihori, T, Pasquini, MC, Ramanathan, M, Lonial, S, Savani, BN, Saber, W, Sharma, M, Sorror, ML, Wirk, BM, and Hari, PN. "Hematopoietic cell transplant comorbidity index is predictive of survival after autologous hematopoietic cell transplantation in multiple myeloma." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20.3 (March 2014): 402-408.e1.
PMID
24342394
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
3
Publish Date
2014
Start Page
402
End Page
408.e1
DOI
10.1016/j.bbmt.2013.12.557

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

Older Patients with Myeloma Derive Similar Benefit from Autologous Transplantation

© 2014 American Society for Blood and Marrow Transplantation. Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people > 70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n= 5818), 60 to 69 years (n= 4666), and > 70 years (n= 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P= .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age > 70 years and 2% for other ages (P= not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age > 70 (P= not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age > 70 years (P= not significant). Postrelapse survival was significantly worse for the older cohort (P= .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS.

Authors
Sharma, M; Zhang, MJ; Zhong, X; Abidi, MH; Akpek, G; Bacher, U; Callander, NS; Dispenzieri, A; Freytes, CO; Fung, HC; Gale, RP; Gasparetto, C; Gibson, J; Holmberg, LA; Kindwall-Keller, TL; Klumpp, TR; Krishnan, AY; Landau, HJ; Lazarus, HM; Lonial, S; Maiolino, A; Marks, DI; Mehta, P; Mikhael Med, JR; Nishihori, T; Olsson, R; Ramanathan, M; Roy, V; Savani, BN; Schouten, HC; Scott, E; Tay, J; To, LB; Vesole, DH; Vogl, DT; Hari, P
MLA Citation
Sharma, M, Zhang, MJ, Zhong, X, Abidi, MH, Akpek, G, Bacher, U, Callander, NS, Dispenzieri, A, Freytes, CO, Fung, HC, Gale, RP, Gasparetto, C, Gibson, J, Holmberg, LA, Kindwall-Keller, TL, Klumpp, TR, Krishnan, AY, Landau, HJ, Lazarus, HM, Lonial, S, Maiolino, A, Marks, DI, Mehta, P, Mikhael Med, JR, Nishihori, T, Olsson, R, Ramanathan, M, Roy, V, Savani, BN, Schouten, HC, Scott, E, Tay, J, To, LB, Vesole, DH, Vogl, DT, and Hari, P. "Older Patients with Myeloma Derive Similar Benefit from Autologous Transplantation." Biology of Blood and Marrow Transplantation 20.11 (January 1, 2014): 1796-1803.
Source
scopus
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
11
Publish Date
2014
Start Page
1796
End Page
1803
DOI
10.1016/j.bbmt.2014.07.013

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

Multiple Myeloma, Version 1.2013 Featured Updates to the NCCN Guidelines

Authors
Anderson, KC; Alsina, M; Bensinger, W; Biermann, JS; Cohen, AD; Devine, S; Djulbegovic, B; Jr, FEA; Gasparetto, C; Hernandez-Illizaliturri, F; Huff, CA; Kassim, A; Krishnan, AY; Liedtke, M; Meredith, R; Raje, N; Schriber, J; Singhal, S; Somlo, G; Stockerl-Goldstein, K; Treon, SP; Weber, D; Yahalom, J; Yunus, F; Shead, DA; Kumar, R
MLA Citation
Anderson, KC, Alsina, M, Bensinger, W, Biermann, JS, Cohen, AD, Devine, S, Djulbegovic, B, Jr, FEA, Gasparetto, C, Hernandez-Illizaliturri, F, Huff, CA, Kassim, A, Krishnan, AY, Liedtke, M, Meredith, R, Raje, N, Schriber, J, Singhal, S, Somlo, G, Stockerl-Goldstein, K, Treon, SP, Weber, D, Yahalom, J, Yunus, F, Shead, DA, and Kumar, R. "Multiple Myeloma, Version 1.2013 Featured Updates to the NCCN Guidelines." JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK 11.1 (January 2013): 11-17.
PMID
23307977
Source
wos-lite
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
1
Publish Date
2013
Start Page
11
End Page
17

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

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

Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2013 Featured Updates to the NCCN Guidelines

Authors
Anderson, KC; Alsina, M; Bensinger, W; Biermann, JS; Cohen, AD; Devine, S; Djulbegovic, B; Jr, FEA; Gasparetto, C; Hernandez-Ilizaliturri, F; Huff, CA; Kassim, A; Krishnan, AY; Medeiros, BC; Meredith, R; Raje, N; Schriber, J; Singhal, S; Somlo, G; Stockerl-Goldstein, K; Treon, SP; Tricot, G; Weber, DM; Yahalom, J; Yunus, F; Kumar, R; Shead, DA
MLA Citation
Anderson, KC, Alsina, M, Bensinger, W, Biermann, JS, Cohen, AD, Devine, S, Djulbegovic, B, Jr, FEA, Gasparetto, C, Hernandez-Ilizaliturri, F, Huff, CA, Kassim, A, Krishnan, AY, Medeiros, BC, Meredith, R, Raje, N, Schriber, J, Singhal, S, Somlo, G, Stockerl-Goldstein, K, Treon, SP, Tricot, G, Weber, DM, Yahalom, J, Yunus, F, Kumar, R, and Shead, DA. "Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2013 Featured Updates to the NCCN Guidelines." JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK 10.10 (October 2012): 1211-1219.
PMID
23054875
Source
wos-lite
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
10
Issue
10
Publish Date
2012
Start Page
1211
End Page
1219

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

PANORAMA 2: A phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma.

Authors
Alsina, M; Schlossman, RL; Weber, DM; Coutre, SE; Lonial, S; Gasparetto, C; Warsi, G; Ondovik, MS; Mukhopadhyay, S; Paley, CS; Richardson, PGG
MLA Citation
Alsina, M, Schlossman, RL, Weber, DM, Coutre, SE, Lonial, S, Gasparetto, C, Warsi, G, Ondovik, MS, Mukhopadhyay, S, Paley, CS, and Richardson, PGG. "PANORAMA 2: A phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma." May 20, 2012.
PMID
23950178
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

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

Lenalidomide before and after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Although multiple myeloma remains incurable outside of allogeneic hematopoietic stem cell transplantation, novel agents made available only in the last few decades have nonetheless tremendously improved the landscape of myeloma treatment. Lenalidomide, of the immunomodulatory class of drugs, is one of those novel agents. In the non-transplant and relapsed/refractory settings, lenalidomide clearly benefits patients in terms of virtually all meaningful outcomes including overall survival. Data supporting the usage of lenalidomide as part of treatment approaches incorporating high-dose chemotherapy with autologous stem cell support (ASCT) are less mature as pertains to such long-term outcomes and toxicity, and lenalidomide is not currently approved by regulatory agencies for use in the context of ASCT in either the United States or Europe. That said, relatively preliminary efficacy data describing lenalidomide as a component of ASCT-based treatment approaches to MM are indeed promising, and consequently lenalidomide's role in ASCT-based treatment strategies is growing. In this review we summarize existing data that pertains to lenalidomide in the specific context of ASCT, and we share our thoughts on how our own group applies these data to approach this complex issue clinically.

Authors
Tuchman, SA; Chao, NJ; Gasparetto, CG
MLA Citation
Tuchman, SA, Chao, NJ, and Gasparetto, CG. "Lenalidomide before and after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma." Adv Hematol 2012 (2012): 712613-.
PMID
22690220
Source
pubmed
Published In
Advances in Hematology
Volume
2012
Publish Date
2012
Start Page
712613
DOI
10.1155/2012/712613

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

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

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

Multiple myeloma clinical practice guidelines in oncology

Authors
Anderson, KC; Alsina, M; Bensinger, W; Biermanft, JS; Chanan-Khan, A; Cohen, AL; Devine, S; Djulbegovic, B; Jr, EAF; Gasparetto, C; Huff, CA; Kassim, A; Medeiros, BC; Meredith, R; Raje, N; Schriber, J; Singhal, S; Somlo, G; Stockerl-Goldstein, K; Treon, SP; Tricof, G; Weber, DM; Yahalom, JH; Yunus, F
MLA Citation
Anderson, KC, Alsina, M, Bensinger, W, Biermanft, JS, Chanan-Khan, A, Cohen, AL, Devine, S, Djulbegovic, B, Jr, EAF, Gasparetto, C, Huff, CA, Kassim, A, Medeiros, BC, Meredith, R, Raje, N, Schriber, J, Singhal, S, Somlo, G, Stockerl-Goldstein, K, Treon, SP, Tricof, G, Weber, DM, Yahalom, JH, and Yunus, F. "Multiple myeloma clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 9.10 (2011): 1146-1183.
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
10
Publish Date
2011
Start Page
1146
End Page
1183

Reply to A. Gratwohl

Authors
Lokhorst, H; Einsele, H; Vesole, D; Bruno, B; Miguel, JS; Perez-Simon, JA; Kröger, NM; Moreau, P; Gahrton, GCA; Gasparetto, C; Giralt, S; Bensinger, WI
MLA Citation
Lokhorst, H, Einsele, H, Vesole, D, Bruno, B, Miguel, JS, Perez-Simon, JA, Kröger, NM, Moreau, P, Gahrton, GCA, Gasparetto, C, Giralt, S, and Bensinger, WI. "Reply to A. Gratwohl." Journal of Clinical Oncology 29.16 (2011): e484-.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
16
Publish Date
2011
Start Page
e484
DOI
10.1200/JCO.2011.34.6718

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

International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma.

PURPOSE: To define consensus statement regarding allogeneic stem-cell transplantation (Allo-SCT) as a treatment option for multiple myeloma (MM) on behalf of International Myeloma Working Group. PATIENTS AND METHODS: In this review, results from prospective and retrospective studies of Allo-SCT in MM are summarized. RESULTS: Although the introduction of reduced-intensity conditioning (RIC) has lowered the high treatment-related mortality associated with myeloablative conditioning, convincing evidence is lacking that Allo-RIC improves the survival compared with autologous stem-cell transplantation. CONCLUSION: New strategies are necessary to make Allo-SCT safer and more effective for patients with MM. Until this is achieved, Allo-RIC in myeloma should only be recommended in the context of clinical trials.

Authors
Lokhorst, H; Einsele, H; Vesole, D; Bruno, B; San Miguel, J; Pérez-Simon, JA; Kröger, N; Moreau, P; Gahrton, G; Gasparetto, C; Giralt, S; Bensinger, W; International Myeloma Working Group,
MLA Citation
Lokhorst, H, Einsele, H, Vesole, D, Bruno, B, San Miguel, J, Pérez-Simon, JA, Kröger, N, Moreau, P, Gahrton, G, Gasparetto, C, Giralt, S, Bensinger, W, and International Myeloma Working Group, . "International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma." J Clin Oncol 28.29 (October 10, 2010): 4521-4530.
PMID
20697091
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
29
Publish Date
2010
Start Page
4521
End Page
4530
DOI
10.1200/JCO.2010.29.7929

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

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study.

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

Authors
Kumar, SK; Flinn, I; Noga, SJ; Hari, P; Rifkin, R; Callander, N; Bhandari, M; Wolf, JL; Gasparetto, C; Krishnan, A; Grosman, D; Glass, J; Sahovic, EA; Shi, H; Webb, IJ; Richardson, PG; Rajkumar, SV
MLA Citation
Kumar, SK, Flinn, I, Noga, SJ, Hari, P, Rifkin, R, Callander, N, Bhandari, M, Wolf, JL, Gasparetto, C, Krishnan, A, Grosman, D, Glass, J, Sahovic, EA, Shi, H, Webb, IJ, Richardson, PG, and Rajkumar, SV. "Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study." Leukemia 24.7 (July 2010): 1350-1356.
PMID
20508619
Source
pubmed
Published In
Leukemia
Volume
24
Issue
7
Publish Date
2010
Start Page
1350
End Page
1356
DOI
10.1038/leu.2010.116

"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

Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma.

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) comprise heterogeneous disorders with incompletely understood molecular defects and variable clinical features. We performed gene expression profiling (GEP) with microarray data to better dissect the molecular phenotypes, sensitivity to particular chemotherapeutic agents, and prognoses of these diseases. METHODS: Using gene expression and clinical data from 877 patients ranging from normal plasma cells (NPC) to relapsed MM (RMM), we applied gene expression signatures reflecting deregulation of oncogenic pathways and tumor microenvironment to highlight molecular changes that occur as NPCs transition to MM, create a high-risk MGUS gene signature, and subgroup International Staging System (ISS) stages into more prognostically accurate clusters of patients. Lastly, we used gene signatures to predict sensitivity to conventional cytotoxic chemotherapies among identified clusters of patients. RESULTS: Myc upregulation and increasing chromosomal instability (CIN) characterized the evolution from NPC to RMM (P < .0001 for both). Studies of MGUS revealed that some samples shared biologic features with RMM, which comprised the basis for a high-risk MGUS signature. Regarding MM, we subclassified ISS stages into clusters based on shared features of tumor biology. These clusters differentiated themselves based on predictions for prognosis and chemotherapy sensitivity (eg, in ISS stage I, one cluster was characterized by increased CIN, cyclophosphamide resistance, and a poor prognosis). CONCLUSION: GEP provides insight into the molecular defects underlying plasma cell dyscrasias that may explain their clinical heterogeneity. GEP also may also refine current prognostic and therapeutic models for MGUS and MM.

Authors
Anguiano, A; Tuchman, SA; Acharya, C; Salter, K; Gasparetto, C; Zhan, F; Dhodapkar, M; Nevins, J; Barlogie, B; Shaughnessy, JD; Potti, A
MLA Citation
Anguiano, A, Tuchman, SA, Acharya, C, Salter, K, Gasparetto, C, Zhan, F, Dhodapkar, M, Nevins, J, Barlogie, B, Shaughnessy, JD, and Potti, A. "Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma." J Clin Oncol 27.25 (September 1, 2009): 4197-4203.
PMID
19636021
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
25
Publish Date
2009
Start Page
4197
End Page
4203
DOI
10.1200/JCO.2008.19.1916

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

Multiple myeloma

Although MM is sensitive to both chemotherapy and radiation therapy, it remains incurable. However, treatment algorithms (based on published data and clinical experience) can be developed to optimize therapy, which include not only therapy for the underlying disease but also supportive therapy to enhance quality of life. Because myeloma is incurable, these guidelines prominently identify the clinical settings appropriate for treating patients enrolled in clinical research protocols. © Journal of the National Comprehensive Cancer Network.

Authors
Anderson, KC; Alsina, M; Bensinger, W; Biermann, JS; Chanan-Khan, A; Cohen, AD; Devine, S; Djulbegovic, B; Gasparetto, C; Huff, CA; Jagasia, M; Medeiros, BC; Meredith, R; Raje, N; Schriber, J; Singhal, S; Somlo, G; Stockerl-Goldstein, K; Tricot, G; Vose, JM; Weber, D; Yahalom, J; Yunus, F
MLA Citation
Anderson, KC, Alsina, M, Bensinger, W, Biermann, JS, Chanan-Khan, A, Cohen, AD, Devine, S, Djulbegovic, B, Gasparetto, C, Huff, CA, Jagasia, M, Medeiros, BC, Meredith, R, Raje, N, Schriber, J, Singhal, S, Somlo, G, Stockerl-Goldstein, K, Tricot, G, Vose, JM, Weber, D, Yahalom, J, and Yunus, F. "Multiple myeloma." JNCCN Journal of the National Comprehensive Cancer Network 7.9 (2009): 908-942.
PMID
19878637
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
7
Issue
9
Publish Date
2009
Start Page
908
End Page
942

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

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

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

Morphologic examination of sequential bone marrow biopsies after nonmyeloablative stem cell transplantation complements molecular studies of donor engraftment.

CONTEXT: Nonmyeloablative stem cell transplantation (NMSCT) is a mode of immunotherapy increasingly employed in treating hematologic, lymphoid, and solid tumors. Patients are monitored principally by molecular analysis of donor engraftment. OBJECTIVE: To determine the role of morphologic examination of bone marrow after NMSCT. DESIGN: Seventy-three patients undergoing NMSCT under the Campath 1H (humanized anti-CD52 antibody) protocol were studied. Pretransplant and sequential posttransplant bone marrow specimens were evaluated and the findings were correlated with corresponding engraftment data. RESULTS: Pretransplant bone marrow specimens from 43% of the patients were involved by disease, and these marrow specimens were significantly more cellular than those that were free of disease. Morphologically detectable disease was still present in day 14 posttransplant marrow specimens in more than one half of these patients, but there was no difference in engraftment in those with or without marrow disease. Early posttransplant marrow in nearly one half of the patients showed myeloid hyperplasia and atypical localization of immature myeloid precursors. Marrow cellularity for the first 2 months after NMSCT was significantly lower in those patients receiving stem cells mismatched at 1 to 3 loci as compared with those who received fully matched grafts (mean cellularity, 38.1% vs 54.1% at day 14). Marrow failure without recurrent disease at 3 to 6 months after transplant was detected by engraftment study in only approximately 15% of cases. Similarly, early recurrence of disease was detected first by morphologic examination in 4 of 13 cases before a decline in donor engraftment occurred. CONCLUSION: Morphologic examination of bone marrow provides additional information that is complementary to donor engraftment analysis for optimal management after NMSCT.

Authors
Lagoo, AS; Gong, JZ; Stenzel, TT; Goodman, BK; Buckley, PJ; Chao, NJ; Gasparetto, C; Long, GD; Rizzieri, DA
MLA Citation
Lagoo, AS, Gong, JZ, Stenzel, TT, Goodman, BK, Buckley, PJ, Chao, NJ, Gasparetto, C, Long, GD, and Rizzieri, DA. "Morphologic examination of sequential bone marrow biopsies after nonmyeloablative stem cell transplantation complements molecular studies of donor engraftment." Arch Pathol Lab Med 130.10 (October 2006): 1479-1488.
PMID
17090189
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
130
Issue
10
Publish Date
2006
Start Page
1479
End Page
1488
DOI
10.1043/1543-2165(2006)130[1479:MEOSBM]2.0.CO;2

Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer.

PURPOSE: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as > or =4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day -5), HDC (days -5 to -2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. RESULTS: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day -4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. CONCLUSIONS: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Authors
Nieto, Y; Vredenburgh, JJ; Shpall, EJ; Bearman, SI; McSweeney, PA; Chao, N; Rizzieri, D; Gasparetto, C; Matthes, S; Barón, AE; Jones, RB
MLA Citation
Nieto, Y, Vredenburgh, JJ, Shpall, EJ, Bearman, SI, McSweeney, PA, Chao, N, Rizzieri, D, Gasparetto, C, Matthes, S, Barón, AE, and Jones, RB. "Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer." Clin Cancer Res 10.21 (November 1, 2004): 7136-7143.
PMID
15534084
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
21
Publish Date
2004
Start Page
7136
End Page
7143
DOI
10.1158/1078-0432.CCR-04-0891

Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma.

We report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of (131)I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T(1/2), 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a "blocking" antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.

Authors
Rizzieri, DA; Akabani, G; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Anderson, E; Lagoo, A; Clayton, S; Pegram, CN; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Anderson, E, Lagoo, A, Clayton, S, Pegram, CN, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma." Blood 104.3 (August 1, 2004): 642-648.
PMID
15100153
Source
pubmed
Published In
Blood
Volume
104
Issue
3
Publish Date
2004
Start Page
642
End Page
648
DOI
10.1182/blood-2003-12-4264

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

Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma.

BACKGROUND: Many patients with recurrent, intermediate or high-grade non-Hodgkin lymphoma (NHL) may not respond to or are not candidates for aggressive salvage chemotherapy. Effective, less toxic regimens are needed. Although high-dose taxanes have not been reported to be very effective for the treatment of lymphoma, different delivery rates may allow for different mechanisms of action to be manifest and result in a different toxicity profile and response rate. The current study tested this hypothesis by using low-dose, weekly paclitaxel in patients with recurrent or refractory NHL. METHODS: Adults age > 18 years with refractory or recurrent, aggressive NHL who were not considered curable with standard high-dose therapy received paclitaxel at a dose of 80 mg/m2 weekly for 5 weeks for 2 cycles. RESULTS: Thirty-four patients with refractory NHL and 4 patients with recurrent disease were treated. Approximately 45% of the patients had achieved a prior disease remission. The median number of prior regimens received was 3, 74% of the patients had an International Prognostic Index of > or = 3 at the time of study entry, and 29% had failed high-dose therapy with autologous hematopoietic support. Only one patient encountered severe toxicity (sepsis). Myelosuppression was reported to occur in approximately 20% of patients. A total of 10 patients (26%) achieved a complete disease response and 4 patients (11%) achieved a partial response. CONCLUSIONS: In the current study, low-dose, weekly paclitaxel therapy was found to provide a well tolerated and less toxic approach to the treatment of refractory NHL, with encouraging responses noted in heavily pretreated patients. However, evaluation in patients with an earlier stage of disease is warranted.

Authors
Rizzieri, DA; Sand, GJ; McGaughey, D; Moore, JO; DeCastro, C; Chao, NJ; Vredenburgh, JJ; Gasparetto, C; Long, GD; Anderson, E; Foster, T; Toaso, B; Adams, D; Niedzwiecki, D; Gockerman, JP
MLA Citation
Rizzieri, DA, Sand, GJ, McGaughey, D, Moore, JO, DeCastro, C, Chao, NJ, Vredenburgh, JJ, Gasparetto, C, Long, GD, Anderson, E, Foster, T, Toaso, B, Adams, D, Niedzwiecki, D, and Gockerman, JP. "Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma." Cancer 100.11 (June 1, 2004): 2408-2414.
PMID
15160345
Source
pubmed
Published In
Cancer
Volume
100
Issue
11
Publish Date
2004
Start Page
2408
End Page
2414
DOI
10.1002/cncr.20245

Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation.

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of conventional bone marrow/stem cell and solid organ transplantation. However, not much is known about PTLD following the more recently introduced nonmyeloablative allogeneic stem cell transplantation (NMST). This study reports the findings from two cases of PTLD following NMST and compares them to the one previously reported case. The donor origin of the PTLD was determined using short tandem repeat analysis, and B- and T-cell clonalities were evaluated by polymerase chain reaction. Two cases of PTLD evolved in a total of 70 patients who have undergone NMST at our institution from 1999 to 2003. Both patients received conditioning with Fludarabine/Cytoxan/Campath 1H (alemtuzumab, anti-CD52 antibody) and T-cell-depleted donor cells with Campath-1H. Both PTLDs were EBV positive (by immunohistochemistry and in situ hybridization) with diffuse large B-cell lymphoma morphology. Our findings indicate the incidence of PTLD following NMST is 3% (2 of 70 patients from our institution and 1 of 30 from the previously reported case). All three PTLDs arose 6 to 7 months after NMST and were rapidly fatal. The pathology of the PTLD in all cases was donor origin, EBV positive, diffuse large B-cell lymphoma.

Authors
Snyder, MJ; Stenzel, TT; Buckley, PJ; Lagoo, AS; Rizzieri, DA; Gasparetto, C; Vredenburgh, JJ; Chao, NJ; Gong, JZ
MLA Citation
Snyder, MJ, Stenzel, TT, Buckley, PJ, Lagoo, AS, Rizzieri, DA, Gasparetto, C, Vredenburgh, JJ, Chao, NJ, and Gong, JZ. "Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation." Am J Surg Pathol 28.6 (June 2004): 794-800.
PMID
15166672
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
28
Issue
6
Publish Date
2004
Start Page
794
End Page
800

Stem cell transplantation for multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is the second most common hematologic malignancy, affecting approximately 14,000 new patients in the United State per year. The median overall survival is 5 years, and cure is a realistic goal for only a small minority of patients. METHODS: A review of the literature was conducted that focused on treatment strategies for MM involving administration of high doses of chemotherapy followed by autologous or allogeneic hematopoietic stem cell transplant. RESULTS: For over three decades, the standard treatment for MM has been a regimen of melphalan and prednisone (MP). Complete responses (CRs) have been rare, and 50% of patients have had disease that was resistant to treatment with MP. Attempts have been made to improve the outcome of MM by administering other combinations of standard doses of chemotherapy, but these treatments are equivalent in terms of overall survival. For patients who are candidates, high-dose therapy followed by autologous stem cell transplantation results in higher CR rates and improved long-term survival compared to treatment with standard doses of chemotherapy alone. While this strategy represents an advance in the treatment of MM, evidence-based reviews indicate that there are a number of issues to consider regarding the induction therapy, the collection of stem cells, and the timing, type, and number of high-dose therapies to use in this type of treatment strategy. CONCLUSIONS: Advances have been made in autologous transplantation, allogeneic transplantation, anti-MM agents, and immunotherapy for MM. Combining these different strategies to achieve synergistic responses is an exciting possibility.

Authors
Gasparetto, C
MLA Citation
Gasparetto, C. "Stem cell transplantation for multiple myeloma." Cancer Control 11.2 (March 2004): 119-129. (Review)
PMID
15024348
Source
pubmed
Published In
Cancer control : journal of the Moffitt Cancer Center
Volume
11
Issue
2
Publish Date
2004
Start Page
119
End Page
129

Unrelated umbilical cord blood transplantation in adult patients.

Since January 1996, we have administered myeloablative therapy followed by infusion of unrelated umbilical cord blood cells in 57 adult patients with high-risk disease. The median age was 31 years (range, 18-58 years), and the median weight was 70 kg (range, 46-110 kg). Two patients were treated for genetic disorders and 55 for advanced hematologic malignancies. The preparative regimens were total body irradiation or busulfan based, both with antithymocyte globulin. HLA matching between donor and recipient was 3 of 6 in 3 patients, 4 of 6 in 44 patients, 5 of 6 in 8 patients, and 6 of 6 in 2 patients. The median nucleated cell dose was 1.50 x 10(7)/kg (range, 0.54-2.78 x 10(7)/kg), and the median CD34(+) cell dose was 1.37 x 10(5)/kg (range, 0.02-12.45 x 10(5)/kg). All patients received granulocyte colony-stimulating factor after transplantation until neutrophil recovery. Graft-versus-host disease prophylaxis consisted of cyclosporine and steroids. The median number of days to an absolute neutrophil count of 500/microL was 26 (range, 12-55 days). The median time to an untransfused platelet count of >20000/microL was 84 days (range, 35-167 days). Seventeen patients developed grade II to IV acute GVHD. The median survival of the entire group was 91 days (range, 10-2251 days). Eleven patients were alive at a median follow-up of 1670 days (range, 67-2251 days), 1 with autologous recovery and 1 with relapsed lymphoma. The actuarial projected 3-year survival is 19%. Infection was the primary cause of death. These results suggest that unrelated umbilical cord blood transplantation is a viable option for adult patients and should be explored in patients with earlier-stage disease.

Authors
Long, GD; Laughlin, M; Madan, B; Kurtzberg, J; Gasparetto, C; Morris, A; Rizzieri, D; Smith, C; Vredenburgh, J; Halperin, EC; Broadwater, G; Niedzwiecki, D; Chao, NJ
MLA Citation
Long, GD, Laughlin, M, Madan, B, Kurtzberg, J, Gasparetto, C, Morris, A, Rizzieri, D, Smith, C, Vredenburgh, J, Halperin, EC, Broadwater, G, Niedzwiecki, D, and Chao, NJ. "Unrelated umbilical cord blood transplantation in adult patients." Biol Blood Marrow Transplant 9.12 (December 2003): 772-780.
PMID
14677117
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
9
Issue
12
Publish Date
2003
Start Page
772
End Page
780
DOI
10.1016/j.bbmt.2003.08.007

4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia.

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 microg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach.

Authors
Rizzieri, DA; Talbot, JT; Long, GD; Vredenburgh, JJ; Gasparetto, C; Smith, CS; Colvin, MO; Adams, D; Morris, A; Dodge, R; Loftis, J; Waters-Pick, B; Reese, M; Carawan, H; Koh, LP; Chao, NJ
MLA Citation
Rizzieri, DA, Talbot, JT, Long, GD, Vredenburgh, JJ, Gasparetto, C, Smith, CS, Colvin, MO, Adams, D, Morris, A, Dodge, R, Loftis, J, Waters-Pick, B, Reese, M, Carawan, H, Koh, LP, and Chao, NJ. "4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia." Biol Blood Marrow Transplant 9.3 (March 2003): 183-188.
PMID
12652469
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
9
Issue
3
Publish Date
2003
Start Page
183
End Page
188
DOI
10.1053/bbmt.2003.50011

Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia.

PURPOSE: The purpose of this study was to determine the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with fludarabine at 25 mg/m(2) daily for 5 days in the treatment of relapsed or refractory acute myelogenous leukemia. EXPERIMENTAL DESIGN: Eighteen patients with relapsed or refractory acute myelogenous leukemia were enrolled. The median age was 54.5 years (range, 21-80 years). Patients received a 30-min infusion of fludarabine at 25 mg/m(2) daily for 5 days. i.v. gemcitabine was given as a single infusion at 10 mg/m(2)/min with the duration adjusted following a modified continuous reassessment method. RESULTS: After 18 patients, the maximum recommended duration of infusion of gemcitabine in combination with fludarabine was selected as a 15-h infusion given at 10 mg/m(2)/min (9,000 mg/m(2)). Severe stomatitis or esophagitis was the most common nonhematological dose-limiting toxicity. Myelosuppression was universal. Febrile neutropenia was common, and 3 of 18 (17%) patients developed bacteremia. Occasional nausea, vomiting, or diarrhea was also reported. There were three complete responses and two partial responses for an overall response rate of 28%. CONCLUSIONS: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 15 h with 25 mg/m(2)/day fludarabine for 5 days is a tolerable induction regimen for relapsed or refractory leukemia. Stomatitis, esophagitis, febrile neutropenia, and myelosuppression should be anticipated; however, this regimen may be beneficial in patients with relapsed or refractory leukemia.

Authors
Rizzieri, DA; Ibom, VK; Moore, JO; DeCastro, CM; Rosner, GL; Adams, DJ; Foster, T; Payne, N; Thompson, M; Vredenburgh, JJ; Gasparetto, C; Long, GD; Chao, NJ; Gockerman, JP
MLA Citation
Rizzieri, DA, Ibom, VK, Moore, JO, DeCastro, CM, Rosner, GL, Adams, DJ, Foster, T, Payne, N, Thompson, M, Vredenburgh, JJ, Gasparetto, C, Long, GD, Chao, NJ, and Gockerman, JP. "Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia." Clin Cancer Res 9.2 (February 2003): 663-668.
PMID
12576433
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
2
Publish Date
2003
Start Page
663
End Page
668

Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia.

Twenty-three adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) were treated for up to 12 weeks with the anti-CD52 monoclonal antibody alemtuzumab. Patients were a median of six years from diagnosis and had been treated with a median of four chemotherapy regimens (median of 24 total cycles) prior to enrollment. Fourteen patients (61%) had received prior monoclonal antibody therapy with rituximab. Adverse symptoms were primarily mild to moderate fever, rigor/chills, nausea/vomiting, or fatigue/malaise in up to 86% of patients. Patients with low blood counts at the initiation of alemtuzumab tolerated therapy well. A total of 17 patients were evaluable for disease response. Nine patients (53%) responded with complete remissions in the peripheral blood. Of these nine, five were evaluated by bone marrow biopsy with four complete responses (CR) and one partial response. Six of the nine presented with nodal disease at the start of alemtuzumab therapy with three CRs and three partial responses. Alemtuzumab is a monoclonal antibody that offers effective treatment for chemotherapy refractory CLL and PLL and is generally well tolerated in the outpatient setting.

Authors
McCune, SL; Gockerman, JP; Moore, JO; Decastro, CM; Bass, AJ; Chao, NJ; Long, GD; Vredenburgh, JJ; Gasparetto, C; Adams, D; Payne, N; Rizzieri, DA
MLA Citation
McCune, SL, Gockerman, JP, Moore, JO, Decastro, CM, Bass, AJ, Chao, NJ, Long, GD, Vredenburgh, JJ, Gasparetto, C, Adams, D, Payne, N, and Rizzieri, DA. "Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia." Leuk Lymphoma 43.5 (May 2002): 1007-1011.
PMID
12148879
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
43
Issue
5
Publish Date
2002
Start Page
1007
End Page
1011
DOI
10.1080/10428190290021597

Mobilization of dendritic cells from patients with breast cancer into peripheral blood stem cell leukapheresis samples using Flt-3-Ligand and G-CSF or GM-CSF.

Treatment with myeloablative chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation followed by vaccination with autologous dendritic cells (DCs) treated with tumor antigens is a promising therapeutic strategy for several types of cancer. Obtaining sufficient numbers of both PBSCs and DCs is central to this approach. Previously, it has been shown that administration of Flt-3-Ligand (FL) combined with either G-CSF or GM-CSF mobilizes large numbers of PBSCs in patients with cancer. In the current study, we sought to determine whether these same cytokines could simultaneously mobilize DCs into the PBSC leukapheresis collection. DCs were analysed in PBSC leukapheresis samples obtained from five patients with high-risk breast cancer who received G-CSF alone as priming prior to leukapheresis, four patients who received FL+G-CSF and five patients who received FL+GM-CSF. DCs were defined as cells with a lin(dim/-) HLA-DR+ CD11c+ phenotype. The proportions of DCs in the FL+G-CSF and FL+GM-CSF samples were significantly higher than in pre-mobilization peripheral blood and G-CSF leukapheresis samples. The mean yield of DCs/kg in the FL+GM-CSF samples was also significantly higher than the mean yield of DCs in the G-CSF samples. The FL+G-CSF and FL+GM-CSF mobilized DCs were immature by morphologic and phenotypic criteria but stimulated allogeneic T-cells at levels similar to DCs generated in culture from PBMCs. Overnight culture?of the immature DCs obtained from patients receiving either FL+G-CSF or FL+GM-CSF in TNF-alpha?resulted in the generation of mature DCs. In summary, administration of FL in combination with GM-CSF and G-CSF to patients with breast cancer can mobilize large numbers of immature DCs into PBSC leukapheresis collections.

Authors
Gasparetto, C; Gasparetto, M; Morse, M; Rooney, B; Vredenburgh, JJ; Long, GD; Rizzieri, DA; Loftis, J; Chao, NJ; Smith, C
MLA Citation
Gasparetto, C, Gasparetto, M, Morse, M, Rooney, B, Vredenburgh, JJ, Long, GD, Rizzieri, DA, Loftis, J, Chao, NJ, and Smith, C. "Mobilization of dendritic cells from patients with breast cancer into peripheral blood stem cell leukapheresis samples using Flt-3-Ligand and G-CSF or GM-CSF." Cytokine 18.1 (April 7, 2002): 8-19.
PMID
12090755
Source
pubmed
Published In
Cytokine
Volume
18
Issue
1
Publish Date
2002
Start Page
8
End Page
19

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells.

T-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.

Authors
Chao, NJ; Liu, CX; Rooney, B; Chen, BJ; Long, GD; Vredenburgh, JJ; Morris, A; Gasparetto, C; Rizzieri, DA
MLA Citation
Chao, NJ, Liu, CX, Rooney, B, Chen, BJ, Long, GD, Vredenburgh, JJ, Morris, A, Gasparetto, C, and Rizzieri, DA. "Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells." Biol Blood Marrow Transplant 8.5 (2002): 249-256.
PMID
12064361
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
8
Issue
5
Publish Date
2002
Start Page
249
End Page
256

Successful allogeneic engraftment of mismatched unrelated cord blood following a nonmyeloablative preparative regimen.

Reduction in the toxicity of allogeneic transplantation with nonmyeloablative induction regimens has expanded the scope of practice to older and more debilitated patients. However, the limited availability of matched sibling donors requires that alternative donor sources be investigated. Reported here are 2 cases of patients with advanced hematologic malignancies without matched siblings, partially matched family members, or matched unrelated donors who successfully underwent nonmyeloablative conditioning therapy followed by infusion of partially matched, unrelated-donor cord blood cells. The patients are in remission and remain 100% donor as assessed by short tandem repeat analysis of the marrow 6 and 12 months following transplantation.

Authors
Rizzieri, DA; Long, GD; Vredenburgh, JJ; Gasparetto, C; Morris, A; Stenzel, TT; Davis, P; Chao, NJ
MLA Citation
Rizzieri, DA, Long, GD, Vredenburgh, JJ, Gasparetto, C, Morris, A, Stenzel, TT, Davis, P, and Chao, NJ. "Successful allogeneic engraftment of mismatched unrelated cord blood following a nonmyeloablative preparative regimen." Blood 98.12 (December 1, 2001): 3486-3488.
PMID
11719394
Source
pubmed
Published In
Blood
Volume
98
Issue
12
Publish Date
2001
Start Page
3486
End Page
3488

Enrichment of peripheral blood stem cells in a primate model following administration of a single dose of rh-IL-1 beta.

In a pre-clinical primate model, the effect of a single intravenous injection of rh-GM-CSF (50 micrograms/kg), rh-IL3 (20 micrograms/kg), rh-IL-1 beta (1 micrograms/kg), rh-G-CSF (50 micrograms/kg) and rh-pIXY 321 (50 micrograms/kg) on peripheral blood mononuclear cell and hematopoietic stem cell concentration was determined. The results indicated that administration of a single dose of rh-IL-1 beta increased the concentrations of hematopoietic stem cells, including CFU-GM progenitors and precursors to CFU-GM. No toxicity was noted with this procedure. None of the remaining cytokines tested caused a significant increase in the peripheral blood hematopoietic stem cell concentration when administered in this manner and only G-CSF caused an increase in peripheral blood mononuclear cell concentrations. Autologous transplantation with limiting numbers of peripheral blood mononuclear cells (1 x 10(7) cells/kg) collected either 24 or 72 h following injection of 1 microgram/kg rh-IL-1 beta conferred a survival advantage to recipients compared with controls. These results imply that a single intravenous administration of rh-IL-1 beta may increase the concentration of peripheral blood stem cells to levels sufficient for transplantation.

Authors
Gasparetto, C; Smith, C; Gillio, A; Stoppa, AM; Moore, MA; O'Reilly, RJ
MLA Citation
Gasparetto, C, Smith, C, Gillio, A, Stoppa, AM, Moore, MA, and O'Reilly, RJ. "Enrichment of peripheral blood stem cells in a primate model following administration of a single dose of rh-IL-1 beta." Bone Marrow Transplant 14.5 (November 1994): 717-723.
PMID
7534159
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
14
Issue
5
Publish Date
1994
Start Page
717
End Page
723

ICAM-1 (CD54) expression on B lymphocytes is associated with their costimulatory function and can be increased by coactivation with IL-1 and IL-7.

Recent studies have demonstrated that acute lymphoblastic leukemia-derived pre-B cell lines are deficient in their costimulatory function for T cell proliferation in response to the mitogen Con A and the superantigens TSST-1 and SEB. Stimulation of these pre-B cells with IL-7 increased their costimulatory function which involved the B7/CD28 pathway. In the present study, we stimulated T cells with Con A, TSST-1, and SEB in the presence of peripheral blood B lineage cells that do not constitutively express B7/BB1 on their surface and investigated whether their costimulatory function could also be enhanced by IL-7. We found that, in the presence of IL-1, stimulation with IL-7 increased the costimulatory function of B cells and their surface expression level of ICAM-1 (CD54). We then investigated whether costimulatory B cell function could be inhibited by blocking the ICAM-1/LFA-1 pathway. Addition of anti-ICAM-1 mAb to the coculture of T and B cells inhibited T cell proliferation by approximately 20%. In contrast, addition of anti-LFA-1 beta (CD18) mAb, directed against the T cell ligand of ICAM-1, inhibited T cell proliferation almost completely. To determine the role of ICAM-1 in costimulatory B cell function, we sorted B cells into ICAM-1low-and ICAM-1high-expressing populations. We found that B cells expressing high levels of surface ICAM-1 elicited significantly higher T cell responses than those with low levels, suggesting that the expression level of ICAM-1 on peripheral blood B cells correlates with their costimulatory function.

Authors
Dennig, D; Lacerda, J; Yan, Y; Gasparetto, C; O'Reilly, RJ
MLA Citation
Dennig, D, Lacerda, J, Yan, Y, Gasparetto, C, and O'Reilly, RJ. "ICAM-1 (CD54) expression on B lymphocytes is associated with their costimulatory function and can be increased by coactivation with IL-1 and IL-7." Cell Immunol 156.2 (July 1994): 414-423.
PMID
7912996
Source
pubmed
Published In
Cellular Immunology
Volume
156
Issue
2
Publish Date
1994
Start Page
414
End Page
423
DOI
10.1006/cimm.1994.1186

Dyshematopoiesis in combined immune deficiency with congenital neutropenia.

This report describes a patient with combined immune deficiency associated with congenital neutropenia (CID/CN) and reports a partial characterization of his hematopoietic abnormalities. The CID/CN syndrome described is characterized by neutropenia and by deficiencies in B-lymphoid and T-lymphoid cell number and function. Red cell and platelet counts were normal. In vitro assays indicate that the myeloid lineage was developmentally arrested at the level of the committed monocyte/granulocyte progenitor (CFU-GM), while precursors to the CFU-GM progenitor were normal. In vitro studies showed that the defect in myeloid development was not corrected with G-CSF or GM-CSF. However, combinations of cytokines present in conditioned media from the T-cell lines MO or C5MJ, or defined multiple cytokine combinations containing IL-1, IL-3, GM-CSF, kit ligand, IL-6, and IL-9, restored myelopoiesis in-vitro. In contrast, C5MJ-conditioned media did not correct deficiencies in immune function in the patient's lymphocytes and accessory cells. No abnormalities in the production of G-CSF, GM-CSF, M-CSF, or IL-1 from the patient could be identified to account for the defects in myelopoiesis orimmune function.

Authors
Gasparetto, C; Smith, C; Firpo, M; Dennig, D; Small, T; Gillio, AP; Lichtenberg, R; O'Reilly, RJ; Moore, MA
MLA Citation
Gasparetto, C, Smith, C, Firpo, M, Dennig, D, Small, T, Gillio, AP, Lichtenberg, R, O'Reilly, RJ, and Moore, MA. "Dyshematopoiesis in combined immune deficiency with congenital neutropenia." Am J Hematol 45.1 (January 1994): 63-72.
PMID
8250011
Source
pubmed
Published In
American Journal of Hematology
Volume
45
Issue
1
Publish Date
1994
Start Page
63
End Page
72

The in vitro growth of murine high proliferative potential-colony forming cells is not enhanced by growth in a low oxygen atmosphere.

The growth of primitive murine hematopoietic progenitors, high proliferative potential colony-forming cells (HPP-CFC), has been reported to be improved in low O2 tension cultures. In this report we investigated the growth of HPP-CFC stimulated by combinations of interleukin (IL)-1, IL-6, kit-ligand (KL), granulocyte (G) colony-stimulating factor (CSF), macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF) and IL-3 in clonal cultures incubated at 7% or 21% O2 tension. Neither the numbers of HPP-CFC colonies nor the number of cells per HPP-CFC colony differed significantly between cultures grown under 7% or 21% O2 tension. The mean number of cells per HPP-CFC colony was found to range from 3.9 x 10(4) to 2.2 x 10(5). The smallest HPP-CFC colonies were stimulated by the cytokine combination IL-1 + IL-6 + KL, whereas the largest colonies were stimulated by a combination of all seven cytokines tested. The growth of erythroid colonies from murine or human bone marrow did, however, show some enhancement when cultured at a lower O2 tension. These results demonstrate that the growth of murine HPP-CFC was not compromised when cultured at ambient O2 concentration.

Authors
Muench, MO; Gasparetto, C; Moore, MA
MLA Citation
Muench, MO, Gasparetto, C, and Moore, MA. "The in vitro growth of murine high proliferative potential-colony forming cells is not enhanced by growth in a low oxygen atmosphere." Cytokine 4.6 (November 1992): 488-494.
PMID
1292631
Source
pubmed
Published In
Cytokine
Volume
4
Issue
6
Publish Date
1992
Start Page
488
End Page
494

A phase I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer.

We studied escalating doses of recombinant human interleukin-1 beta (IL-1 beta) alone and after a myelosuppressive dose of 5-fluorouracil (5-FU) in patients with gastrointestinal cancer. Transient neutropenia, monocytopenia, and lymphocytopenia were observed followed by a 1.3- to 6.0-fold (mean, 3.46-fold) dose-dependent neutrophil leukocytosis (P less than .00001) on the days of IL-1 beta administration. Increases in platelet counts were observed at a median of 14 days (range, 6 to 23) after IL-1 beta administration. Transient hypoglycemia, rebound hyperglycemia, elevations in serum cortisol, and C-reactive protein were observed. Side effects included fever, rigors, and headache in the majority of patients. Hypotension was observed in three of five patients at the highest dose level (0.1 micrograms/kg) and was dose-limiting. Fewer days of neutropenia were noted after 5-FU plus IL-1 beta than after 5-FU alone; however, this difference did not reach statistical significance. These data show that IL-1 beta has stimulatory effects in human hematopoiesis.

Authors
Crown, J; Jakubowski, A; Kemeny, N; Gordon, M; Gasparetto, C; Wong, G; Sheridan, C; Toner, G; Meisenberg, B; Botet, J
MLA Citation
Crown, J, Jakubowski, A, Kemeny, N, Gordon, M, Gasparetto, C, Wong, G, Sheridan, C, Toner, G, Meisenberg, B, and Botet, J. "A phase I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer." Blood 78.6 (September 15, 1991): 1420-1427.
PMID
1884014
Source
pubmed
Published In
Blood
Volume
78
Issue
6
Publish Date
1991
Start Page
1420
End Page
1427

Purification and partial characterization of a human hematopoietic precursor population.

This study reports the development of an assay, the Pre-colony-forming unit (CFU) assay, which detects human hematopoietic precursors. The Pre-CFU assay is based on the observation that precursors to CFU-granulocyte-macrophage (CFU-GM) that are undetectable in clonogenic assays differentiate into CFU-GM preferentially following treatment in suspension culture with recombinant human interleukin-1 alpha (rhIL-1 alpha) combined with rhIL-3. Using the Pre-CFU assay, hematopoietic precursors were detected in human bone marrow depleted of CFU-GM progenitors and differentiated hematopoietic elements via 4-hydroperoxycyclophosphamide treatment coupled with selection for CD34+ cells (4-HCresistant/CD34+ marrow). Additionally, the Pre-CFU assay detected recovery of hematopoiesis substantially earlier than the CFU-GM assay in primates following myeloablation with 5-fluorouracil. The Pre-CFU assay was used to asses purification of a phenotypically defined hematopoietic precursor population, the lin-CD34+ population. The lin-CD34+ population lacks detectable surface markers for T-cell, B-cell, natural killer cell, and myeloid lineage, possesses the CD34 antigen, is devoid of CFU-GM progenitors, and yields Pre-CFU assay values comparable with 4-HCresistant/CD34+ marrow. Using a combination of phenotypic analysis and Pre-CFU assay analysis, the action of rhIL-1 alpha plus rhIL-3 treatment on lin-CD34+ cells was further characterized. The data indicate that rhIL-1 alpha plus rhIL-3 treatment induces proliferation and differentiation of early hematopoietic precursors into progenitors and terminally differentiated cells, without inducing a significant expansion of the precursor population itself.

Authors
Smith, C; Gasparetto, C; Collins, N; Gillio, A; Muench, MO; O'Reilly, RJ; Moore, MA
MLA Citation
Smith, C, Gasparetto, C, Collins, N, Gillio, A, Muench, MO, O'Reilly, RJ, and Moore, MA. "Purification and partial characterization of a human hematopoietic precursor population." Blood 77.10 (May 15, 1991): 2122-2128.
PMID
1709369
Source
pubmed
Published In
Blood
Volume
77
Issue
10
Publish Date
1991
Start Page
2122
End Page
2128

Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination.

We report the results of a preclinical study comparing four different purging protocols using a promyelocytic human cell line HL-60 and myeloid leukemic progenitor cells (colony-forming unit-leukemic [CFU-L]) from acute myelogenous leukemia (AML) patients assayed in semisolid culture. We studied the antileukemic effect of (1) Single-cycle complement-mediated lysis by two different monoclonal antibodies (MoAbs) (M195 [CD33] and F23 [CD13] 40 micrograms/mL), reactive with distinct antigens found on early myeloid cells and monocytes, used alone and in combinations; (2) 4-Hydroperoxycyclophosphamide (4-HC) (80 mumol/L or 100 mumol/L) alone; or (3) combined with VP-16 (5 micrograms/mL) and (4) a cocktail of 1 through 3 as above (combined immunochemotherapy). More than 4 logs of HL-60 tumor cell elimination were observed after 1 hour of incubation with both MoAbs plus 4-HC + VP-16 while the single treatment (immunotherapy or chemotherapy) provided 1.5 and 3.5 logs of colony-forming inhibition, respectively. When the same protocols were tested on cryopreserved leukemic cells from eight patients with AML, we observed a mean value of CFU-L inhibition of 92.3% +/- 2.5% SD, 95.5% +/- 1.4% SD, and 99% +/- 0.8% SD after MoAbs and complement lysis, 4-HC, and 4-HC + VP-16 treatment, respectively. The combined treatment of MoAbs and 4-HC + VP-16 produced more than 3-log reduction of CFU-L colony formation. By comparison, the mean recovery of committed normal bone marrow progenitors after incubation with MoAbs and complement was 12% for CFU-granulocyte-macrophage (CFU-GM), 22.9% for burst-forming unit erythroid (BFU-E), and the recovery following 4-HC + VP-16 treatment was 4.4% for CFU-GM and 5.6% BFU-E. In subsequent experiments, highly purified CD34+ blast cells, enriched by positive selection, and stimulated in liquid culture by cytokines (interleukin-1 [IL-1], IL-3, and combination of both) or MO-conditioned medium (MoCM), demonstrated that immunochemotherapy spares hematopoietic colony-forming cells earlier than day 14 CFU-GM, in vitro.

Authors
Lemoli, RM; Gasparetto, C; Scheinberg, DA; Moore, MA; Clarkson, BD; Gulati, SC
MLA Citation
Lemoli, RM, Gasparetto, C, Scheinberg, DA, Moore, MA, Clarkson, BD, and Gulati, SC. "Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination." Blood 77.8 (April 15, 1991): 1829-1836.
PMID
2015406
Source
pubmed
Published In
Blood
Volume
77
Issue
8
Publish Date
1991
Start Page
1829
End Page
1836

Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates.

Interleukin-3 (IL-3) is a hematopoietic growth factor that supports the growth of early hematopoietic progenitors in vitro. In vivo administration of recombinant human interleukin-3 (rhIL-3) to normal primates results in a modest and delayed leukocytosis secondary to increases in neutrophils, basophils, and eosinophils. We postulated that the effects of rhIL-3 might be more pronounced in hematologically stressed primates, and therefore administered rhIL-3 to primates after intensive myelosuppressive therapy. Primates received either cyclophosphamide (CPM) at 60 mg/kg or 5-fluorouracil (5-FU) at 75 mg/kg i.v. on two consecutive days. Subsequently, rhIL-3 was administered intravenously or subcutaneously at 20 micrograms/kg per d for 14 d. Compared to controls, all rhIL-3 treated primates experienced higher absolute neutrophil count (ANC) nadirs and dramatic decreases in the period of severe neutropenia (ANC less than 500) after myelosuppressive therapy. RhIL-3 administration resulted in a significant basophilia and eosinophilia, which resolved after discontinuation of the drug. RhIL-3 did not enhance erythroid recovery. Platelet recovery was earlier in rhIL-3-treated animals. However, variations in the platelet recovery observed in control animals, precluded accurate estimation of this effect or its significance. Our results indicate that the administration of rhIL-3 following intensive myelosuppressive therapy dramatically enhances myeloid recovery and ablates the predicted period of prolonged severe neutropenia.

Authors
Gillio, AP; Gasparetto, C; Laver, J; Abboud, M; Bonilla, MA; Garnick, MB; O'Reilly, RJ
MLA Citation
Gillio, AP, Gasparetto, C, Laver, J, Abboud, M, Bonilla, MA, Garnick, MB, and O'Reilly, RJ. "Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates." J Clin Invest 85.5 (May 1990): 1560-1565.
PMID
2332507
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
85
Issue
5
Publish Date
1990
Start Page
1560
End Page
1565
DOI
10.1172/JCI114605

High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates.

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.

Authors
Laver, J; Duncan, E; Abboud, M; Gasparetto, C; Sahdev, I; Warren, D; Bussel, J; Auld, P; O'Reilly, RJ; Moore, MA
MLA Citation
Laver, J, Duncan, E, Abboud, M, Gasparetto, C, Sahdev, I, Warren, D, Bussel, J, Auld, P, O'Reilly, RJ, and Moore, MA. "High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates." J Pediatr 116.4 (April 1990): 627-632.
PMID
1690796
Source
pubmed
Published In
The Journal of Pediatrics
Volume
116
Issue
4
Publish Date
1990
Start Page
627
End Page
632

Effects of hematopoietic growth factors following myeloablation in a primate model.

The complex effects of hematopoietic growth factors (granulocyte and granulocyte-macrophage colony-stimulating factors and interleukin 3 and interleukin 1 beta) following myeloablation in juvenile male cynomolgus monkeys was studied. Since the effects of a given cytokine in vivo do not necessarily reflect the in vitro situation, and since cytokines are frequently species specific, extrapolation from rodent models to man may be fraught with inaccuracies. A primate model, therefore, was developed which has provided useful preclinical information on hematopoietic responses, dose response relationships and toxicities associated with administration of recombinant hematopoietic growth factors. This information has direct application to human trials.

Authors
O'Reilly, RJ; Gillio, A; Gasparetto, C
MLA Citation
O'Reilly, RJ, Gillio, A, and Gasparetto, C. "Effects of hematopoietic growth factors following myeloablation in a primate model." Int J Cell Cloning 8 Suppl 1 (January 1990): 262-267.
PMID
1691247
Source
pubmed
Published In
International Journal of Cell Cloning
Volume
8 Suppl 1
Publish Date
1990
Start Page
262
End Page
267
DOI
10.1002/stem.5530080724

Effects of interleukin-1 on hematopoietic progenitors: evidence of stimulatory and inhibitory activities in a primate model.

The effects of recombinant human interleukin-1 rhIL-1 beta (rhIL-1b) on hematopoietic recovery following chemotherapy in a primate model were investigated. Cynomolgus monkeys received 1 microgram/kg/day rhIL-1b intravenously for 2, 7, and 14 days following 5-Fluorouracil (5-FU) treatment (75 mg/kg x 2 days). Compared with controls, a significantly shortened time to achieve an absolute neutrophil (ANC) count over 500/microL was observed in animals receiving 2- and 7-day courses of rhIL-1b (17 v 30 days), while animals receiving a 14-day course of rhIL-1b achieved an ANC over 500/microL by 23 days. Concomitantly, a marked increase in granulocyte-macrophage colonies (CFU-GM) was observed at 14 days following 5-FU in animals receiving 2- and 7-day rhIL-1b courses. In animals receiving a 14-day rhIL-1b course, a significant increase in CFU-GM relative to control was not seen until 21 days post 5-FU. Utilizing a serum-free colony assay system, a 50% inhibition of normal marrow CFU-GM growth was observed with the addition of sera obtained on day 9 post 5-FU from animals receiving rhIL-1b for 14 days. Sera obtained at any time from animals receiving 2- and 7-day rhIL-1b treatment did not show any growth inhibition. Addition of antibodies to TNFa to the coculture assay abrogated the CFU-GM growth inhibition. TNFa levels in sera with the inhibitory activity was relatively high (918 pg/mL). Our data indicate that rhIL-1b enhances hematopoietic recovery following 5-FU if administered for short periods of time (less than 7 days), whereas prolonged administration has a counterproductive effect that is due in part to the induction of TNFa production.

Authors
Gasparetto, C; Laver, J; Abboud, M; Gillio, A; Smith, C; O'Reilly, RJ; Moore, MA
MLA Citation
Gasparetto, C, Laver, J, Abboud, M, Gillio, A, Smith, C, O'Reilly, RJ, and Moore, MA. "Effects of interleukin-1 on hematopoietic progenitors: evidence of stimulatory and inhibitory activities in a primate model." Blood 74.2 (August 1, 1989): 547-550.
PMID
2787677
Source
pubmed
Published In
Blood
Volume
74
Issue
2
Publish Date
1989
Start Page
547
End Page
550

Effects of IL-1 on hematopoietic progenitors after myelosuppressive chemoradiotherapy.

Recently it has been recognized that IL-1 plays an important role in hematopoietic regulation. Administration of 5-fluorouracil (5-FU) to mice causes prolonged neutropenia. rHIL-1 injected to mice after 5-FU, accelerated the recovery of hematopoietic progenitors and blood neutrophils. The combination of rhIL-1 and rhG-CSF reduced the neutropenic period significantly. Sublethal irradiation of mice induced profound neutropenia for 3 weeks which was associated with 80% mortality. Administration of rhIL-1 20 hours prior to or 2 hours post irradiation resulted in a significantly improved survival and rapid recovery of the neutrophil count. IL-1 administered alone or in combination with other colony stimulating factors to spontaneous breast tumor bearing mice following 5-FU therapy resulted in a rapid recovery of neutrophils, improved survival, and markedly reduced the tumor mass. Experiments in primates demonstrated that rhIL-1 administered to 5-FU treated animals shortened the neutropenic period from 30 to 17 days and increased the number of marrow progenitors responsive to other CSFs. Prolonged administration of IL-1 (14 days) to these animals resulted in a delayed neutrophil recovery as compared to animals receiving short courses of IL-1. rhIL-1 administered to primates receiving marrow grafts after lethal irradiation, did not result in rapid hematopoietic recovery. In humans, studies with CD-34 positive marrow cells showed that IL-1 had a radioprotective effect on a committed and early marrow progenitors. These data show the therapeutic potential of IL-1 in the treatment of chemoradiotherapy induced myelosuppression.

Authors
Laver, J; Abboud, M; Gasparetto, C; Gillio, A; Smith, C; O'Reilly, RJ; Moore, MA
MLA Citation
Laver, J, Abboud, M, Gasparetto, C, Gillio, A, Smith, C, O'Reilly, RJ, and Moore, MA. "Effects of IL-1 on hematopoietic progenitors after myelosuppressive chemoradiotherapy." Biotherapy 1.4 (1989): 293-300.
PMID
2484306
Source
pubmed
Published In
Biotherapy (Dordrecht, Netherlands)
Volume
1
Issue
4
Publish Date
1989
Start Page
293
End Page
300
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