Mitchell Horwitz

Overview:

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

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1992

Rush University

Medical Resident, Medicine

Northwestern University

Grants:

A Phase 2/3, Multicenter, randomized, double-blind, placebo-controlled, study to evaluate the safety and efficacy of Alpha-! Antitrypsin for the Prevention of GVHD

Administered By
Duke Cancer Institute
Awarded By
CSL Behring LLC
Role
Principal Investigator
Start Date
End Date

A phase III Randomized Open-Label Multi-Center study of ruxolitinib vs. best available therapy in patients with corticosteroid-refractory chronic graft vs host disease after allogenic stem cell transplantation

Administered By
Duke Cancer Institute
Awarded By
Incyte Corporation
Role
Principal Investigator
Start Date
End Date

A Blinded, Prospective Non-Interventional Observational Study for the Evaluation of a GVHD Negative Outcome Score (GNOS) in Matched Unrelated or Haploidentical Hematopoietic Stem Cell Transplant

Administered By
Duke Cancer Institute
Awarded By
Washington University in St. Louis
Role
Principal Investigator
Start Date
End Date

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

Administered By
Duke Cancer Institute
Awarded By
Gamida Cell Ltd
Role
Principal Investigator
Start Date
End Date

A Randomized, Phase II, Multicenter, Open Label, Study Evaluating Sirolimus and Prednisone in Patients with Refined Minnesota Standard Risk, Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease (GMT CTN Protocol 1501

Administered By
Duke Cancer Institute
Awarded By
National Marrow Donor Program
Role
Principal Investigator
Start Date
End Date

Publications:

Lymphoid and myeloid immune cell reconstitution after nicotinamide-expanded cord blood transplantation.

Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR: > 50 × 106/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13-63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.
Authors
de Koning, C; Tao, W; Lacna, A; van Veghel, K; Horwitz, ME; Sanz, G; Jagasia, MH; Wagner, JE; Stiff, PJ; Hanna, R; Cilloni, D; Valcárcel, D; Peled, T; Galamidi Cohen, E; Goshen, U; Pandit, A; Lindemans, CA; Jan Boelens, J; Nierkens, S
MLA Citation
de Koning, Coco, et al. “Lymphoid and myeloid immune cell reconstitution after nicotinamide-expanded cord blood transplantation.Bone Marrow Transplant, vol. 56, no. 11, Nov. 2021, pp. 2826–33. Pubmed, doi:10.1038/s41409-021-01417-4.
URI
https://scholars.duke.edu/individual/pub1489796
PMID
34312498
Source
pubmed
Published In
Bone Marrow Transplant
Volume
56
Published Date
Start Page
2826
End Page
2833
DOI
10.1038/s41409-021-01417-4

Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study.

Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval [CI], 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299.
Authors
Horwitz, ME; Stiff, PJ; Cutler, C; Brunstein, C; Hanna, R; Maziarz, RT; Rezvani, AR; Karris, NA; McGuirk, J; Valcarcel, D; Schiller, GJ; Lindemans, CA; Hwang, WYK; Koh, LP; Keating, A; Khaled, Y; Hamerschlak, N; Frankfurt, O; Peled, T; Segalovich, I; Blackwell, B; Wease, S; Freedman, LS; Galamidi-Cohen, E; Sanz, G
MLA Citation
Horwitz, Mitchell E., et al. “Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study.Blood, vol. 138, no. 16, Oct. 2021, pp. 1429–40. Pubmed, doi:10.1182/blood.2021011719.
URI
https://scholars.duke.edu/individual/pub1485962
PMID
34157093
Source
pubmed
Published In
Blood
Volume
138
Published Date
Start Page
1429
End Page
1440
DOI
10.1182/blood.2021011719

Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome.

Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.
Authors
Herrera, AF; Ahn, KW; Litovich, C; Chen, Y; Assal, A; Bashir, Q; Bayer, R-L; Coleman, M; DeFilipp, Z; Farhadfar, N; Greenwood, M; Hahn, T; Horwitz, M; Jacobson, C; Jaglowski, S; Lachance, S; Langston, A; Mattar, B; Maziarz, RT; McGuirk, J; Mian, MAH; Nathan, S; Phillips, A; Rakszawski, K; Sengeloev, H; Shenoy, S; Stuart, R; Sauter, CS; Kharfan-Dabaja, MA; Hamadani, M
MLA Citation
Herrera, Alex F., et al. “Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome.Blood Adv, vol. 5, no. 18, Sept. 2021, pp. 3528–39. Pubmed, doi:10.1182/bloodadvances.2021004865.
URI
https://scholars.duke.edu/individual/pub1495945
PMID
34496026
Source
pubmed
Published In
Blood Adv
Volume
5
Published Date
Start Page
3528
End Page
3539
DOI
10.1182/bloodadvances.2021004865

Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation.

Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplantation (alloHSCT), defined as those living ≥5 years post-transplantation, is significantly lower compared with that of the age-matched general population despite a relatively low primary disease relapse rate at >2 years post-transplantation. Among several factors, patient sex is increasingly recognized as a prognostic indicator of long-term survival. We examined the influence of patient sex and donor-recipient sex matching on overall survival (OS) in a landmark analysis of long-term survivors. Using our institutional database supplemented with individual patient record review, we retrospectively investigated the relative influence of recipient sex and donor-recipient sex matching on outcomes of long-term survivors of alloHSCT between 1994 and 2014. Over this 20-year period, 247 met inclusion criteria for analysis; males and females had similar demographic and treatment characteristics. However, significantly more deaths after the 5-year landmark occurred in male recipients. Interestingly, donor sex did not have a significant impact on OS in multivariate analysis, and differences in OS of donor-recipient sex pairs was driven by recipient sex. In addition to recipient sex, only chronic graft-versus-host disease (cGVHD) retained significance as a covariate with an impact on OS in multivariate analysis. Men experienced slightly higher, but statistically nonsignificant, rates and increased severity of cGVHD, and had higher cGVHD-related mortality compared with females. In this long-term survival analysis of adult alloHSCT recipients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplantation. This outcome is independent of other common pretransplantation prognostic indicators, such as donor sex or performance status at transplantation. The inferior survival in males is consistent with survival outcomes described in the transplantation literature. Increasing evidence suggests a biological basis for long-term sex-determined outcomes, possibly owing to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Larger studies are warranted to validate these retrospective clinical results.
Authors
Islam, P; Tang, H; Jin, H; Cao, F; Bohannon, LM; Ren, Y; Chao, NJ; Choi, T; Gasparetto, C; Horwitz, ME; Long, GD; Lopez, RD; Rizzieri, DA; Sarantopoulos, S; Sung, AD
MLA Citation
Islam, Prioty, et al. “Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation.Transplant Cell Ther, vol. 27, no. 9, Sept. 2021, pp. 784.e1-784.e7. Pubmed, doi:10.1016/j.jtct.2021.06.012.
URI
https://scholars.duke.edu/individual/pub1485675
PMID
34146734
Source
pubmed
Published In
Transplant Cell Ther
Volume
27
Published Date
Start Page
784.e1
End Page
784.e7
DOI
10.1016/j.jtct.2021.06.012

Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.

Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies but is associated with significant morbidity and mortality. Although deaths during the first year after transplantation are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased graft-versus-host disease, and lower relapse rates. Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplantation versus matched related donor (MRD) and matched unrelated donor (MUD) transplantation in patients with hematologic malignancies over a 20-year period. In this single-center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant program from January 1, 1996, to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 after HCT, received an allogeneic HCT for a disease other than a hematologic malignancy, or received cells from a haploidentical or mismatched adult donor. UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank P = .03, median overall survival: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (hazard ratio, 0.69; 95% confidence interval, 0.47-0.99; P = .049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and nonrelapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.
Authors
Bohannon, L; Tang, H; Page, K; Ren, Y; Jung, S-H; Artica, A; Britt, A; Islam, P; Siamakpour-Reihani, S; Giri, V; Lew, M; Kelly, M; Choi, T; Gasparetto, C; Long, G; Lopez, R; Rizzieri, D; Sarantopoulos, S; Chao, N; Horwitz, M; Sung, A
MLA Citation
Bohannon, Lauren, et al. “Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.Transplant Cell Ther, vol. 27, no. 8, Aug. 2021, pp. 669.e1-669.e8. Pubmed, doi:10.1016/j.jtct.2021.05.002.
URI
https://scholars.duke.edu/individual/pub1482829
PMID
33991725
Source
pubmed
Published In
Transplant Cell Ther
Volume
27
Published Date
Start Page
669.e1
End Page
669.e8
DOI
10.1016/j.jtct.2021.05.002