Prior Azacitidine and Ongoing Transfusion Dependence in MDS Patients Are Associated with Inferior Survival after Allogeneic Stem Cell Transplant
Authors: Horton Miles , Leung Becky , Nelles Ricky , Rubic Matthew , McKinnely Christopher , Cibich Alia , Dowling Mark R , Hunt Stewart , Chee Lynette C.Y. , Scott Ashleigh P , Ritchie David S. , Hiwase Devendra , Purtill Duncan , Bhattacharya Abir , Kennedy Glen A , Bajel Ashish 
Published: December 2024

Background: Allogeneic stem cell transplantation (alloSCT) remains the only curative therapy for myelodysplastic syndromes (MDS). Outcomes in alloSCT for MDS are often pooled with AML, making the interpretation of risk factors and application to clinical practice challenging. Prior studies have demonstrated impact of adverse cytogenetics, molecular mutations, and high-risk subgroups on survival post alloSCT in MDS.

Aims: A retrospective study was conducted to describe current transplant practice in Australian centres and analyse outcomes of MDS patients undergoing alloSCT to identify factors predicting survival following transplant.

Methods: Consecutive patients with MDS who received alloSCT across five Australian transplant centres from 2013-2020 were included. Survival analysis with Kaplan-Meier and Cox proportional hazards was used and linear regression was implemented for variable selection prior to multivariate analysis. Analysis was performed using R (2024.04.2+764) and p value &lt; 0.05 was considered statistically significant.

Results: 289 patients (pts) who received their first alloSCT for MDS from 2013 to 2020 were included. Median age of the cohort was 55 years (19-75 yrs) with 38.4% female patients. MDS subtype at diagnosis (WHO 2016) included 65 (23.5%) MDS-EB1, 93 (33.6%) MDS-EB2, 76 (27.4%) MDS-MLD, 6 (2.2%) MDS-RS-SLD, 11 (3.9%) MDS-RS-MLD, 3 (1.1%) MDS-Del(5q) and 16 (5.8%) MDS-U. At diagnosis 55 (22.2%), 47 (18.9%) and 35 (14.1%) pts had intermediate, poor and very poor cytogenetics. IPSS-R risk stratification at diagnosis revealed 7 (2.6%) very low, 62 (23.3%) low, 73 (27.4%) intermediate, 82 (30.8%) high and 42 (15.78%) very high-risk pts. 140 (48.4%) patients had received azacitidine therapy prior to alloSCT, with a median of 6.8 cycles (1-35). A further 23 (7.9%) pts received chemotherapy, and 16 (5.5%) received other treatment (including lenalidomide) prior to alloSCT. 81 pts (43.08%) were transfusion dependant (WPSS criteria) at transplant.

Median time to transplant from diagnosis was 8.8 months (1.7-241.4). 31 pts (14.7%) had ≥10% BM blasts pre-SCT and 83 (37.2%) had an HCI-CI of ≥ 3. Majority 173 pts (59.9%) had matched unrelated donor transplants, with 11 (3.8%) mismatched unrelated donor, 88 (30.4%) matched sibling donor and 17 (5.9%) haploidentical donor transplants. 208 (79%) received reduced intensity conditioning, 179 (61.9%) pts received fludarabine and melphalan and 79 (27.3%) pts received in-vivo T cell depletion with ATG/thymoglobulin.

At a median follow up was 30 months, 151 patients were alive without progression/relapse, 83 died without progression/relapse and median overall survival was 83.9 months (62.3-105.7mnths). At 2-year post transplant overall survival was 62.4% (56.4-67.7), relapse-free survival was 58.9% (52.9-64.5), cumulative relapse/ progression rate was 21.1% (16.3-27.1), and non-relapse mortality was 29% (24.3-35.7),

Notably, univariate analysis of pre-transplant therapy demonstrated inferior survival in patients who received azacitidine (HR = 0.66 p = 0.016). This association was preserved when analysis was restricted to intermediate and higher IPSS-R groups (HR = 0.47 p = 0.002). Patients attaining &lt; 5% blasts with azacitidine prior to alloSCT showed a non-significant superior survival (HR = 1.77 p = 0.055). Ongoing transfusion dependence at transplant was associated with a non-significant trend towards inferior survival (HR = 0.68 p = 0.082).

Multivariate analysis with Cox proportional hazards was performed to evaluate whether adjustments to account for disease resolved the influence of prior azacitidine and transfusion dependence. This demonstrated inferior post alloSCT survival amongst patients who received prior azacitidine (HR = 0.25, p = 0.009) and patients who had transfusion dependence (HR = 0.33, p = 0.028) when adjusted for established disease- and patient-risk factors. Further unrelated donor type (HR = 0.37 p = 0.034), very poor cytogenetic (HR = 0.43 p = 0.002) and very high IPSS-R (HR = 0.52 p = 0.023) were significantly associated with inferior survival post-transplant in multivariate analysis. Further analysis will be undertaken to understand the association of azacitidine with inferior survival

Conclusion: Our multisite study identifies prior azacitidine therapy and ongoing transfusion dependence as associated with inferior post-transplant survival.