Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with De Novo and Secondary Acute Myeloid Leukemia

Abstract

We report the results of 256 patients (median age = 59; range, 5–74 years) with de novo AML in first complete remission (CR1; n=100), beyond CR1 (n=79) and with treatment-related or secondary AML (n=77) who underwent allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related (n=109) or from unrelated donors (n=147). Indications of allogeneic HCT in CR1 were persistent cytogenetic or molecular evidence of disease, poor-risk cytogenetics at diagnosis, treatment-related or secondary AML and age more than 60 years. Younger patients were included if they had comorbid conditions that excluded them from conventional allogeneic HCT. Sixteen patients were mismatched with their donors for ≥ one HLA antigen, while the remainder were matched 10/10 at the antigen level. Conditioning consisted of low-dose total body irradiation (TBI; 2 Gy) on day 0 either alone (n=28) or combined with fludarabine, 30 mg/m2/day on days −4 to −2 (n=228). Calcineurin inhibitors (cyclosporine or tacrolimus) and mycophenolate mofetil were used for postgrafting immunosuppression. Durable engraftment was observed in 94% of patients. With a median follow-up of 35 (range, 3 – 111) months in surviving patients, the estimated progression-free and overall survivals at 5 years were 32% (95% CI: 25–38%) and 32% (95% CI: 25–38%), respectively. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 40% (95% CI: 33–46%) and 29% (95% CI: 22–35%), respectively. Estimated 5-year survival rates, progression-free survival, relapse/progression rate, and non-relapse mortality according to disease status are shown in Table 1; Table 2 shows the same indices according to donor type. The cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) in patients with related donors were 40% and 13%, and in those with unrelated donors were 58% and 14%, respectively. The cumulative incidence of chronic extensive GVHD at 5 years was 44% in patients with related donors, and 42% in patients with unrelated donors. Age > 60 years at the time of HCT did not have an impact on the outcome (univariate analysis). Additional analyses regarding the impact of HCT comorbidity scores and minimal residual disease at the time of HCT are in progress. Based on this multicenter analysis, we conclude that allogeneic HCT from related or unrelated donors, utilizing a conditioning regimen of low dose TBI (2 Gy) with fludarabine provides long term remission in elderly and/or medically infirm patients with AML, who were not considered candidates for conventional HCT.Table 1. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to disease status. CR1: 1st remission; >CR1: subsequent remission, induction failure/persistent disease; sAML: treatment-related and secondary AML.Disease Statusn%OS (95% CI)%PFS (95% CI)RR (95% CI)NRM (95% CI)CR110033 (20–46)34 (23–46)36 (26–47)30 (19–40)>CR17938 (26–49)35 (23–46)40 (29–52)25 (15–35)sAML7720 (8–32)23 (11–35)45 (32–57)32 (20–45)Table 2. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to donor type.Donor Typen%OS (95% CI)%PFS (95% CI)RR (95% CI)NRM (95% CI)HLA-identical related10934 (23–44)34 (24–45)47 (37–58)18 (10–26)HLA-matched unrelated13131 (22–40)30 (21–39)37 (29–46)33 (24–72)HLA mismatched unrelated1624 (0–50)24 (0–50)6 (0–18)70 (43–97)