In patients with relapsed or refractory acute myeloid leukemia (R/R AML) encouraging results have been reported after allogeneic hematopoietic stem cell transplantation (HSCT) following a conditioning regimen with sequential melphalan, fludarabine and total body irradiation (FMTBI) (Steckel et al., Br. J. Haematol. 2018; 180:840–853). However, non-relapse mortality (NRM) was up to 45% in elderly patients (>59 years) and higher age was associated with inferior survival.
We hypothesized that in elderly patients with active disease or AML with unfavorable genetics, fludarabine and melphalan alone might enable similar long-term graft-versus-host-disease (GVHD) and relapse-free survival (GRFS) and be associated with lower NRM compared to FMTBI.
Between 01/2011–02/2019, 106 consecutive high-risk AML patients received conditioning with FMTBI (n = 58), i.e. melphalan (140 mg/m2, day −11) preceding fludarabine (30 mg/m2days −5 to −2) and total body irradiation (2–8 Gy starting on day −1) or FM (n = 48), i.e. fludarabine day −6 to −2 and melphalan (140 mg/m2, day −3) and a T cell-repleted graft from an HLA-matched donor. GVHD prophylaxis consisted of cyclosporine A or tacrolimus plus mycophenolate mofetil; additional antithymocyte globulin was administered in the unrelated donor setting. Active disease was defined as ≥5% bone marrow blasts or extramedullary disease.
Prior to conditioning, 72% of patients had active (n = 48) or measurable residual disease (MRD, n = 29) and 18% were in complete remission (without MRD marker: n = 15; MRD negative: n = 4). MRD was determined by qPCR analysis of mutated NPM1 (n = 25), CBFB-MYH11 (n = 3), MLL-PTD (n = 4) and JAK-V617F (n = 1). In the FM group, patients were older (58 vs. 48 years, p = 0.09) and significantly more patients had a high-risk Hematopoietic Cell Transplantation-Comorbidity Index (56% vs 22%), p = 0.02). Genetic risk according to European Leukemia Network criteria 2017 did not differ between the FM and FMTBI group (low/intermediate/high: 19%/42%/39% vs 33%/27%/ 40%; p = 0.18). Twenty-nine patients (27%) were grafted from a matched related donor, 65 patients (61%) from a 10/10 matched unrelated donor (MUD), and 12 patients (11%) from a 9/10 MUD and the vast majority received peripheral blood stem cells (99%). All patients engrafted. With a median follow-up of 30.8 months (range, 1.6–95.3), probabilities of overall and relapse-free survival at 3 years were comparable between the FM and FMTBI group (65.0 ± 7.1% vs 72.8 ± 8.2%; p = 0.452, and 61.1 ± 7.2% vs 68.3 ± 8.1%; p = 0.573, respectively). Similarly, non-relapse mortality at 3 years (15% vs. 4%; p = 0.11), cumulative incidences of acute GVHD grade 3–4 at day +100 (10% vs 5%; p = 0.31) and chronic severe GvHD at 1 year (19% vs 11%; p = 0.47) did not differ between groups. The combined endpoint GRFS was 51.2 ± 7.3 in the FM group and 49.9 ± 9.2% in the FMT group (p = 0.109), respectively.
Conclusion: Our data suggest that FM is well tolerated and associated with similar outcomes compared to FMT in our AML patients of whom >70% proceded to transplant with active or measurable residual disease. Especially elderly patients, who face a high risk of NRM, might not benefit from additional TBI. Thus, FM is a valid option for this vulnerable patient cohort resulting in a median GRFS of 40 months.