Post-Transplantation Prophylaxis Resulted in Similar Outcomes for Mismatched and Matched Donor Stem Cell Transplants

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The Main Cause of Non-Relapse Mortality after CAR T Cell Therapy is Not What You Think

Post-transplantation cyclophosphamide (PTCy) led to similar overall survival (OS) and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) in patients who received a hematopoietic stem cell transplant (HCT) from a matched unrelated donor (MUD) and those who received a single human leukocyte antigen (HLA) locus mismatched transplant from an unrelated donor (MMUD), according to a large retrospective study co-led by Memorial Sloan Kettering Cancer Center (MSK). (1)

For the study, published recently in the Journal of Clinical Oncology, the research team analyzed outcome data for 10,025 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2017 and 2021. They compared results for patients who underwent MUD (an 8 of 8 HLA allele match) or single HLA locus MMUD transplantation (a 7 of 8 match) and were treated with either PTCy or the standard calcineurin inhibitor (CNI) as GVHD prophylaxis.  (1)

“In addition to revealing PTCy led to similar outcomes for recipients of MUD and MMUD transplants with a single HLA locus mismatch, we discovered PTCy was beneficial regardless of patient ancestry,” said co-first author, bone marrow transplant specialist and cellular therapist Brian Shaffer, MD. “Our findings demonstrate that including MMUDs matching 7 of 8 markers would expand access to HCT greatly for patients from all racial and ethnic ancestry groups.”

MSK is currently participating in two prospective clinical trials testing alternative strategies to reduce the risk of GVHD in MUD and MMUD settings. 

HCT and the Rationale for Post-Transplant Cyclophosphamide Prophylaxis

HCT is an essential consolidation treatment for many patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and myelodysplastic syndromes (MDS). Transplants from related or unrelated donors matching 8 of 8 HLA alleles (HLA-A, -B, -C, and -DRB1) result in the best outcomes. (2)(3)

As sibling donors are only available to about 30% of patients, many individuals requiring an allogeneic transplant must rely on unrelated donors. (4) However, the probability of finding an MUD matching 8 of 8 HLA alleles in the National Marrow Donor Program (NMDP) registry varies greatly by ancestry. For example, for patients with non-Hispanic white ancestry, the odds are about 75%, but for non-white and Hispanic patients, the odds are only about 15% to 45%. (5) (6) If no matched donor is identified, mismatched related (haploidentical) and MMUDs become the sole graft source.  (7)

Historically, survival rates have been inferior for HCT using a MMUD matching 7 of 8 HLA alleles due to increased GVHD, infections, and graft failure when conducted with standard CNI-based GVHD prophylaxis.  (8) (9) (10) However, previous evidence has shown that PTCy improves outcomes after haploidentical (4 of 4 HLA match)  (11) (12) and several studies have suggested that a similar strategy is effective with MMUD.  (13) (14) (15) Additionally, the NMDP-sponsored 15-MMUD study, in which 48% of enrolled patients were from minority ancestries, showed that PTCy prophylaxis resulted in promising OS in adults who received MMUD bone marrow grafts matched at 7 or fewer HLA alleles.  (16) (17)  

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Study Design

Dr. Shaffer and colleagues examined clinical data in the CIBMTR database for 10,025 adult patients diagnosed with AML, ALL, or MDS who underwent a first allogeneic HCT between January 2017 and June 2021. They included patients who received either CNI or PTCy as GVHD prophylaxis. Patients who received CNI-based transplants were also treated with either cyclosporine or tacrolimus with other agents, including methotrexate or mycophenolate mofetil with or without anti-thymocyte globulin. PTCy-based transplants included CNI or sirolimus, with or without mycophenolate mofetil and anti-thymocyte globulin.

The investigators compared outcomes for patients who received a MUD (8/8 match) or MMUD (7/8 match). The researchers also analyzed 50,000 preliminary donor searches performed in world registries from 2022 to 2023 to estimate the potential impact of their findings on donor availability.  (18)

The primary study objectives were to compare OS and GRFS between MUD and MMUD allogeneic HCT, based on receipt of CNI or PTCy. OS was defined as the time from transplant to death from any cause. GFRS was defined as survival without grade 3 or grade 4 acute GVHD, moderate or severe chronic GVHD requiring systemic treatment, or relapse. ([ii], [iii]) Secondary endpoints included relapse, non-relapse mortality, grades 2 to 4 and grades 3 to 4 acute GVHD, and moderate or severe chronic GVHD. 

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Study Findings

Among 10,025 HCT recipients in total:

  • 7,272 received MUD transplants with CNI
  • 1,681 received MUD transplants with PTCy
  • 613 received MMUD transplants with CNI
  • 459 received MMUD with PTCy

The mean patient age was 61, ranging from 18 to 83, and the median follow-up was 37 months.

  • Among patients who received PTCy, those who had MMUD HCT had a similar OS (hazard ratio (HR): 0.96, p = 0.60) and GRFS (HR: 0.90, p = 0.1) as those who received MUD HCT.
  • When compared to MUD HCT with CNI, OS was improved after MUD HCT with PTCy (HR = 0.88, p = 0.004), and GRFS was better with PTCy following either MUD (HR: 0.61, p < 0.0001) or MMUD (HR: 0.68, p < 0.0001). 

The impact of these results on donor availability in the NMDP and World Marrow Donor Association registries was dramatic. Dr. Shaffer and colleagues considered only donors under 35 with a 75% probability of matching to the specified degree. The proportion of recipients having at least one unrelated donor improved for all major ancestry groups when both MMUDs and MUDs were included. For example, including MMUDs increased the median number of available donors from 2 to 74 for those of African American ancestry, from 29 to 1,226 for non-Hispanic whites, from 6 to 151 for Asian/Pacific Islanders, from 5 to 147 for white Hispanics, and from 6 to 362 for Native Americans.

“Our retrospective study findings suggest that PTCy is an acceptable alternative to CNI-based prophylaxis in MUD HCT recipients and superior for MMUD HCT,” Dr. Shaffer said. “The National Marrow Donor Program plans to use these results as part of a national campaign to improve minority donor participation in the registry.”

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Prospective Trials of PTCy after MMUD Transplants 

Prospective clinical trials investigating PTCy in a broader range of patients receiving MMUD transplants and a lower dose of PTCy are available at MSK as follows: 

ACCESS: A Multi-Center, Phase 2 Trial of HLA-MMUD Hematopoietic Cell Transplantation with PTCy for Patients with Hematologic Malignancies. The trial (NCT04904588) opened in September 2021 with a goal of recruiting 300 patients in total across adult and pediatric cohorts. The investigators are evaluating survival and clinical outcomes for patients receiving partially matched MMUDs (ranging from 4 to 7 of 8 HLA alleles) and PTCy based on age and transplant type (bone marrow versus peripheral blood). The trial is now closed for adult patients, but the pediatric study arm continues to recruit pediatric and young adult patients 1 to 21 years of age. Dr. Shaffer, the principal investigator of the trial at MSK, is collaborating with MSK Kids pediatric hematologist-oncologist Kevin Curran, MD on the pediatric arm. MSK Kids is a leading center focused on improving outcomes for pediatric patients with hematologic malignancies.

OPTIMIZE: A Phase 2 Study of Lower-Dose PTCy to Prevent GVHD in Adults Receiving HCT from MMUDs. This trial (NCT06001385) is testing a lower dose of PTCy to see if PTCy-associated toxicity can be lowered while maintaining the survival and GVHD outcomes observed with full dose PTCy. Patients eligible to participate are those receiving partially matched MMUDs (ranging from 4 to 6 of 8 HLA alleles). Dr. Shaffer is also the principal investigator of this study at MSK, which opened in December 2023 and aims to recruit 190 patients.

The authors acknowledged that CIBMTR is supported by the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Health Resources and Services Administration; the Office of Naval Research; the Biomedical Advanced Research and Development Authority, the NMDP Foundation. For other supporting organizations, refer to the paper. Access disclosures for Dr. Shaffer. 

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