Haploidentical Donor Transplantation with Posttransplantation Cyclophosphamide in Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Institutional Collaboration of 14 Centers

Introduction: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myeloid malignancies with overlapping dysplasia and proliferation and usually have a poor prognosis. While the curative potential of blood or marrow transplantation (BMT) is known, limitations of donor availability exist. In this multi-institutional study, we assessed the efficacy and safety of haploidentical donors in BMT for MDS/MPN; and evaluated clinical and molecular factors that affect outcomes.

Methods: In this retrospective cohort study, we analyzed the outcomes of adult MDS/MPN (blasts <20%) patients who underwent their first haploidentical BMT using posttransplantation cyclophosphamide (PTCy) at 14 institutions between 1/1/2010 and 12/31/2022. Univariate analysis was conducted via Cox proportional hazards model or Fine and Gray's regression model. Adjustments in multivariable analyses were based on significant results from univariate analysis and sample sizes of categorical groups.

Next generation sequencing (NGS) was available for 85 patients, and mutations in SETBP1, RUNX1, EZH2, NRAS, TP53, ASXL1, or STAG2 were considered "high-risk". Mutations in either EZH2, RUNX1, or SETBP1 were also evaluated separately based on our recent report showing a lower probability of treatment response with these mutations (Karantanos et al. Leukemia Lymphoma 2022).

Results: A total of 114 patients were included in the analysis. Diagnoses were chronic myelomonocytic leukemia (CMML, n=58, 51%), atypical chronic myeloid neoplasm (aCML, n=4, 3.5%), MDS/MPN, unclassifiable (MDS/MPN-U, n=47, 41%), and MDS/MPN with ring sideroblasts and thrombocytosis (RS-T, n=5, 4%). The median age at BMT was 62 years (range, 18-75 years), and 64% of patients were men.

The median follow-up was 2.41 years (range 14 days - 10.55 years) based on reversed Kaplan-Meier method. The median time to neutrophil engraftment was 18 days (IQ range 16 - 22 days), and platelet engraftment was 31 days (IQ range 22 - 40 days). Seven (6%) patients had graft failure. The probability (95% CI) of 3-year overall survival (OS) was 56% (47-67%), relapse-free survival (RFS) 48% (39-60%), nonrelapse mortality (NRM) 27% (18-36%), relapse 25% (16-34%) (Figure 1A), grade 3-4 acute graft versus host disease (GVHD) 11% (5-16%), chronic GVHD requiring systemic therapy 14% (7-21%). Six (5%) patients underwent donor lymphocyte infusion for mixed chimerism or relapse with transient improvement in donor chimerism in 3 patients. Nine (8%) patients (4 due to graft failure and 5 due to relapse) underwent a second BMT, 2 of whom were alive at the last follow-up (481 and 2337 days from the first BMT).

Outcomes for CMML, aCML, or MDS/MPN-U, and RS-T were not significantly different; and hence, were grouped for the remaining analysis. Univariate analysis for the pertinent patient, disease, and BMT-related factors for clinical outcomes of OS, RFS, relapse, and NRM, along with the number of patients in each subgroup, is shown in Figure 1B. Of note, MAC was significantly correlated with younger age (ANOVA P < 0.0001).

The multivariable analysis did not include NGS data due to missing data in 29 patients. As shown in Figure 1B, on multivariable analysis, age at BMT and enlarged spleen at BMT were associated with inferior OS (HR 1.62, 95% CI 1.08 - 2.45 and HR 2.8, 95%CI 1.54 - 5.09), and RFS (HR 1.63, 95%CI 1.1 - 2.42 and 2.61, 1.47 - 4.3), respectively. Increasing age was associated with higher NRM (HR 1.72, 95% CI 1.04 - 2.85), while an enlarged spleen with higher relapse (HR 2.94, 95% CI 1.32 - 6.51). RIC/NMAC was associated with higher relapses (HR 3.94, 95%CI 1.63 - 9.54) but lower NRM (HR 0.46, 95%CI 0.2 - 1.12) with similar OS (HR 1.08, 95%CI 0.57 - 2.04).

Conclusions: Despite a rare disease entity, this extensive report of haploidentical donor BMT in MDS/MPN was feasible with our robust multi-institutional collaboration. High-risk NGS, albeit available only in a subset of patients, appears to dominate the disease-related risk of relapse. Disease status (BM blasts and spleen size) and donor age are also important considerations, suggesting early referral for BMT is critical. We anticipate our results will encourage the use of haploidentical donor/PTCy BMT for MDS/MPN as the outcomes are similar to those previously reported in these diagnoses (Robin et al. Blood 2022, Sharma et al. Leukemia Lymphoma 2017).

Jain:CTI Biopharma, SyneosHealth, Incyte: Research Funding; Care Dx, Bristol Myers Squibb, Incyte, Abbvie, CTI, and Kite: Other: Advisory Board participation. Elmariah:Bristol Myers Squibb: Research Funding. Vachhani:Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grunwald:Daiichi Sankyo, Gamida Cell, Gilead Sciences, Incyte Corporation, Invitae, Karius, Novartis, Ono Pharmaceutical, Pfizer, Pharmacosmos, Premier, Sierra Oncology, Stemline Therapeutics: Consultancy; Medtronic: Current equity holder in private company; Genetech/Roche, Incyte Corporation, Janssen: Research Funding; AbbVie, Agios/Servier, Amgen, Astellas Pharma, Blueprint Medicines, Bristol Myers Squibb, Cardinal Health, CTI BioPharma, Daiichi Sankyo, Gamida Cell, Gilead Sciences, Incyte Corporation, Invitae, Karius, Novartis, Ono Pharmaceuticals, Pfizer, ,: Consultancy. Abedin:Incyte: Research Funding; AbbVie: Honoraria; Amgen: Honoraria; Stemline: Honoraria; AltruBio Inc.: Research Funding; Helsinn Healthcare: Research Funding; Pfizer: Research Funding; Actinium Pharmaceuticals: Research Funding. Gerds:Accurate Pharmaceuticals: Research Funding; Imago BioSciences: Research Funding; Kratos Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys/Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Gupta:Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Roche: Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria; Sierra Oncology: Consultancy; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board.