Risk of relapse and mortality after non-myeloablative allogeneic stem cell transplant for Acute Myeloid Leukemia and myelodysplastic syndrome after fludarabine, cyclophosphamide, and 200 centigray total body irradiation  with gvhd prophylaxis using post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil: Impact of maintenance chemotherapy

Abstract

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with high-risk myeloid malignancies, though with associated risk of transplant-related mortality (TRM). Nonmyeloablative (NMA) conditioning, such as fludarabine/cyclophosphamide and low-dose total body irradiation (Flu/Cy/2Gy TBI), may reduce TRM while preserving graft-versus-leukemia (GVL) effects. Patients with TP53-mutated (TP53mut) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) have poor outcomes, including high post-HSCT relapse rates. Post-HSCT maintenance chemotherapy may improve relapse-free survival (RFS). Methods: A total of 103 patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) underwent peripheral blood allo-HSCT between 2022 and 2025 using a NMA regimen of fludarabine on days -6 to -2, cyclophosphamide 50mg/kg on days -6, and 2 Gy single-fraction TBI. GVHD prophylaxis consisted of post-transplant cyclophosphamide (50 mg/kg on days +3 and +4), followed by sirolimus (day +5 to +90) and mycophenolate mofetil (day +5 to +35). Post-transplant maintenance therapy was administered using hypomethylating agents (HMAs) with/without venetoclax (14/28d), or FLT3 inhibitors for FLT3+ AML. Oral HMA agents were decitabine/cedazuridine (dec-c) 3d/28-day cycle, and oral azacitidine (Oral-Aza) for 14 days per 28-day cycle. Results: The majority of patients were transplanted with unrelated donors (74% matched vs 20% mismatched). Diagnoses included CMML (n=10), intermediate-risk AML (n=21), adverse-risk TP53-wild-type (Tp53wt) AML (n=20), TP53mutAML (n=14), TP53wt MDS (n=23), TP53mut MDS (n=12), and favorable-risk AML/MDS (n=3). For measurable residual disease (MRD), 36% had residual disease (MDS (66%), CMML (70%) with MRD+ in AML (12%). The majority of patients with AML were transplanted in complete Remission-1 (CR1) (75%), including patients with TP53mut AML (71%) and TP53wt AML (58%). There was no difference between patients with TP53mut AML or MDS and TP53wtAML and MDS by MRD status (30% vs 35%, p=0.64) or transplant in CR1 (70% vs 62%, p=0.44). Overall TRM was 3.8%, cumulative incidence of relapse (CIR) 37%, progression-free survival (PFS) 58%, and overall survival (OS) 72.8% at median follow-up of 12 months. Grade 2–4 acute GVHD occurred in 14%, and chronic GVHD in 23% of patients. Adverse-risk AML (both TP53mut and TP53wt) was significantly more likely to undergo transplant in complete remission vs those with MDS and CMML (54% vs 24%, p=0.002). Additionally, patients with AML were more likely to receive post-transplant maintenance compared to those with MDS (36% vs 17%, P=0.009). A total of 32 (31%) patients received post-HSCT maintenance chemotherapy: infusional HMA (n=2), recombinant-Granulocyte Colony Stimulating Factor (rhGCSF)/decitabine (n=2), gilteritinib (n=7), dec-c (n=9), oral-aza (2), and venetoclax/Azacitidine (n=8). For nine patients receiving dec-c, two (22%) patients relapsed: one with TP53mut MDS, and one with TP53mut AML. Relapse rates were similar with HMA monotherapy or combined with venetoclax, and were similar using oral or infusional HMA therapy. For the ten patients with CMML, 0/2 receiving maintenance relapsed compared to 6/8 in those not on maintenance. For MDS TP53wt, five (21%) patients relapsed, none following maintenance. In TP53mut MDS, the CIR was 83% with 8% RFS, though all had received maintenance therapy. In intermediate- and adverse-risk TP53wt disease AML, maintenance led to reduced relapse (4.7%) compared to TP53mutAML (43%, p=0.0006). In twenty patients with adverse-risk TP53wt AML, relapse rates were lower following maintenance therapy (10% vs 60%, p=0.019). In fourteen patients with TP53mut AML, relapse was frequent despite maintenance [n=6 (66%) vs n=2 (40%), p=0.68]. Maintenance therapy did not decrease relapse in TP53mut AML (43% relapsing after maintenance vs 17% relapses without maintenancep=0.037), with relapse on maintenance frequently (n=8, 75% vs 25%). Conclusion: NMA conditioning with Flu/Cy/2Gy TBI yields low NRM. Post-transplant maintenance therapy, particularly with HMAs and targeted agents, is associated with reduced relapse in intermediate-risk and adverse-risk TP53wt AML and MDS. However, outcomes remain poor for patients with TP53mut AML and MDS, indicating an urgent need for alternative or intensified maintenance strategies in these high-risk groups.