Purpose: Acute myeloid leukemia (AML) is a highly heterogeneous disease. In addition to patient-related factors (co-morbidities, age, physical performance) and disease-specific variables (genetic risk profile) response to treatment is an important prognostic factor. In particular, the rapid achievement of hematologic remission by induction therapy was shown to predict overall outcome irrespective of the type of post-remission therapy employed. Here, we specifically investigated the impact of achieving early remission (ER), i.e. absence of leukemic blasts in the bone marrow at the end of the first course of induction therapy, as compared to delayed remission (DR) on the outcome of patients with AML who underwent allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) at our center.
Patients and Methods: We retrospectively analyzed 132 consecutive patients (ER: N=79, DR: N=53) with AML and an intermediate risk karyotype transplanted at our center between 1994 and 2013. Median age at alloSCT was 48 years. Before referral to transplantation, all patients were treated in a German multicenter AML trial. Patients aged <60 years were treated according to a double induction strategy, which consisted of one course of “7+3” followed by one course of high-dose cytarabine (HD-AraC) (3000 mg/m²). Patients aged ≥60 years were treated with a single course of “7+3”. In case of residual leukemic blasts, i.e. 5% or more in the bone marrow on day +16, first induction was followed by either one additional course of the same regimen or one course of HD-AraC (1000 mg/m2). Depending on the timing of alloSCT, one (N=78) or two (N=7) additional courses HD-AraC consolidation were given. For transplantation, myeloablative conditioning (MAC) (N=58) consisted of 12 Gy total body irradiation (TBI) and 120 mg/m2 cyclophosphamide (CY). Reduced-intensity conditioning (RIC) (N=74) consisted of fludarabine (FLU) 150 mg/m2, oral busulfan (BU) 8 mg/kg and anti-thymocyte globulin (ATG)(Fresenius®) 40 mg/kg. Transplants were from related (N=60) or unrelated (N=72) donors and were HLA-matched (10/10 antigens) (N=119) or HLA-mismatched (N=13) according to high-resolution molecular typing. Immunosuppression consisted of short course methotrexate (MTX) and cyclosporine in patients treated with MAC or cyclosporine and mycophenolate mofetil (MMF) in patients treated with RIC prior to alloSCT.
Results: After a median follow-up of 56 (4-220) months for the surviving patients, 87 patients (66%) are alive and in CR. 26 patients (20%) relapsed after a median interval of 8 (1-133) months, whereas 19 patients (14%) died from NRM. Projected overall survival (OS) of the entire cohort after 1, 3, 5 and 10 years was 81%, 68%, 65%, and 61%. At the same time points the cumulative incidence of relapse (CI-R) or non-relapse mortality (CI-NRM) was 12%, 19%, 22%, and 22% or 13%, 13%, 13%, and 17%. In contrast to patients showing DR, patients achieving ER had a significantly higher 3-year OS and disease-free survival (DFS) of 76% versus 54% (p=0.03) and 76% versus 53% (p=0.03). Likewise, 3 years after alloSCT the CI-R was significantly lower in the ER subgroup as compared to patients achieving DR, i.e. 10% versus 35% (p=0.004). In contrast, NRM did not differ significantly between the ER and the DR subgroup. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, p=0.002) and a higher CI-R (HR 3.55, p=0.002). Notably, there was no significant difference in OS, DFS, or CI-R between patients treated with MAC versus RIC in the ER or the DR subgroup.
Conclusions: Taken together, these data indicate that rapid achievement of remission may predict a favorable outcome in patients with intermediate risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be necessarily overcome by alloSCT.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.