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:

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

Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation.

The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.
Authors
Ponce, DM; Politikos, I; Alousi, A; Carpenter, PA; Milano, F; MacMillan, ML; Barker, JN; Horwitz, ME; American Society for Transplantation and Cellular Therapy Cord Blood Special Interest Group,
MLA Citation
Ponce, Doris M., et al. “Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation.Transplant Cell Ther, vol. 27, no. 7, July 2021, pp. 540–44. Pubmed, doi:10.1016/j.jtct.2021.03.012.
URI
https://scholars.duke.edu/individual/pub1487846
PMID
34210500
Source
pubmed
Published In
Transplant Cell Ther
Volume
27
Published Date
Start Page
540
End Page
544
DOI
10.1016/j.jtct.2021.03.012

Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.

Authors
Pabon, CM; Li, Z; Hennig, T; de Castro, C; Neff, JL; Horwitz, ME; LeBlanc, TW; Long, GD; Lopez, RD; Sung, AD; Chao, N; Gasparetto, C; Sarantopoulos, S; Adams, DB; Erba, H; Rizzieri, DA
MLA Citation
Pabon, Cindy M., et al. “Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.Blood Cancer J, vol. 11, no. 5, May 2021, p. 92. Pubmed, doi:10.1038/s41408-021-00481-9.
URI
https://scholars.duke.edu/individual/pub1482850
PMID
33994546
Source
pubmed
Published In
Blood Cancer Journal
Volume
11
Published Date
Start Page
92
DOI
10.1038/s41408-021-00481-9

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