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:

Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome.

PURPOSE: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown. METHODS: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died. RESULTS: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication. CONCLUSION: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.
Authors
Dillon, LW; Gui, G; Logan, BR; Fei, M; Ghannam, J; Li, Y; Licon, A; Alyea, EP; Bashey, A; Devine, SM; Fernandez, HF; Giralt, S; Hamadani, M; Howard, A; Maziarz, RT; Porter, DL; Warlick, ED; Pasquini, MC; Scott, BL; Horwitz, ME; Deeg, HJ; Hourigan, CS
MLA Citation
Dillon, Laura W., et al. “Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome.Jco Precis Oncol, vol. 5, 2021. Pubmed, doi:10.1200/PO.20.00355.
URI
https://scholars.duke.edu/individual/pub1482174
PMID
34036237
Source
pubmed
Published In
Jco Precision Oncology
Volume
5
Published Date
DOI
10.1200/PO.20.00355

A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT. METHODS: Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3-4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls. RESULTS: Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1-2 match. Grade 3-4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival. CONCLUSIONS: Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.
Authors
Ramalingam, S; Siamakpour-Reihani, S; Bohannan, L; Ren, Y; Sibley, A; Sheng, J; Ma, L; Nixon, AB; Lyu, J; Parker, DC; Bain, J; Muehlbauer, M; Ilkayeva, O; Kraus, VB; Huebner, JL; Spitzer, T; Brown, J; Peled, JU; van den Brink, M; Gomes, A; Choi, T; Gasparetto, C; Horwitz, M; Long, G; Lopez, R; Rizzieri, D; Sarantopoulos, S; Chao, N; Sung, AD
MLA Citation
Ramalingam, Sendhilnathan, et al. “A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant.Plos One, vol. 16, no. 6, 2021, p. e0252995. Pubmed, doi:10.1371/journal.pone.0252995.
URI
https://scholars.duke.edu/individual/pub1487527
PMID
34170918
Source
pubmed
Published In
Plos One
Volume
16
Published Date
Start Page
e0252995
DOI
10.1371/journal.pone.0252995

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