Treosulfan-Based Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Patients with Myelodysplastic Syndrome (MDS): Promising Survival Outcome Including Patients with High-Risk Disease

Introduction: AlloHCT plays an important role in the treatment of MDS and represents the only curative treatment option so far. Conditioning therapy with fludarabine/treosulfan for elderly (≥ 50 years) and/or comorbid (HCT-CI >2) patients with AML or MDS undergoing alloHCT showed improved outcomes compared to fludarabine/busulfan conditioning in randomized phase III study (NCT00822393). In this retrospective study, we analyzed MDS patients treated with a fludarabine/treosulfan conditioning aiming to verify the study results in a real-world setting.

Patients and Methods: Between August 2017 and July 2022, 83 elderly and / or comorbid patients (pts) with MDS underwent alloHCT at our center receiving conditioning treatment with 30 mg/m² BSA intravenous fludarabine (day -6 to d-2) and 10g/m² treosulfan (day -4 to d-2). Graft versus-host disease (GvHD) prophylaxis consisted of cyclosporin and methotrexate. Additionally, patients transplanted from an unrelated donor received anti-thymocyte globulin (3 x 10 mg/kg ATG/Neovii). Evaluation of remission and transplant function after transplant was scheduled 2, 3-4 months and later every 3 months including bone marrow evaluation with FACS-sorted lineage-specific donor chimerism (DCC). Incomplete DCC was defined as <95%, measured by VNTR-PCR and was an indication for preemptive immune intervention (rapid tapering of immunosuppressive medication and/or donor lymphocyte infusion).

Results: Median age of the patients was 63 years (range 39-76 years; 2 patients were <50 years of age), median HCT-CI was 2 (range 0-7) and median follow-up of surviving patients was 745 days (range 98-1692). According to the IPSS-R classification 42 pts (51%) had a very high risk (VHR), 22 pts (27%) a high risk (HR), 16 pts (19%) an intermediate risk (IR) and 3 pts (4%) a low risk (LR) disease. Prior start of conditioning 41 pts (49%) had bone marrow blast counts of 10-19%, 18 pts (22%) 5-9% and 24 pts (29%) <5%. As expected, disease biology defined by cyto- and molecular genetic changes varied, with cytogenetically defined high-risk mutations found in 42 patients. Most frequent molecular genetic mutations were detected in ASXL1 (27 pts) and TP53 (17 pts) genes. All patients received G-CSF mobilized stem cell graft from either HLA-identical sibling donors (19%), 10/10 HLA matched unrelated (63%) or 9/10 HLA matched unrelated donors (18%).

Kaplan-Meier estimates for relapse-free survival (RFS) at 1 and 2 years were 82% (95% CI 73-90%) and 66% (95% CI 55-78%), for overall survival (OS) 86% (95% CI 78-94%) and 72% (95% CI 61-83%), respectively. Cumulative incidences of relapse at 1 and 2 years were 8% (95% CI 4-17%) and 15% (95% CI 8-27%), for non-relapse mortality (NRM) 10% (95% CI 5-20%) and 19% (95% CI 11-30%), respectively. Patients with VHR MDS showed a significant lower OS after 2 years compared to HR or IR MDS (57% vs 81% vs 93%, p < .05). Interestingly, bone marrow blast count prior conditioning, age, donor type and HCT-CI had no impact on survival. Cytogenetically defined high and very high-risk mutations as well as presence of TP53 were associated with inferior survival outcomes. Acute GvHD grade 2-4 occurred in 13 pts (grade 3 and 4 in 5 pts.). Mild chronic GvHD was diagnosed in 9 pts, moderate in 10 pts and severe in 10 pts.

2 months after transplantation 11 pts had an incomplete CD3 DCC and 15 pts an incomplete CD34 DCC. At 3-4 months incomplete CD3 DCC could be detected in 6 pts and for CD34 in 10 pts. Incomplete DCC was not associated with an increased risk of relapse, most likely due to early preemptive immune interventions.

Conclusions: Our data verify the favorable outcome data for MDS patients treated with treosulfan-based conditioning prior to alloHCT. Moreover, survival after alloHCT seemed to depend on disease biology, defined by cytogenetic and molecular changes, rather than on disease burden defined by bone marrow blast count. In context with recent published study data, future treatment strategies should focus on timely realization of alloHCT, when indicated, post-transplant maintenance and not on pre-transplant treatment intensification.

Floeth:Medac: Other: Travel support; Takeda: Honoraria. Schliemann:Roche: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; BMS: Consultancy, Other: travel grants; Boehringer-Ingelheim: Research Funding; Astrazeneca: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Lenz:Takeda: Honoraria, Speakers Bureau; Miltenyi: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Constellation: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; University Hospital Münster: Current Employment. Stelljes:BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Medac: Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria.