Allogeneic Hematopoietic Stem-Cell Transplantation (HSCT) in First Complete Remission Is Superior Compared to Chemotherapy/Autologous HSCT in Patients with Intermediate-Risk Cytogenetics Acute Myeloid Leukemia Lacking Mutations in NPM1, FLT3-ITD, and CEBPA: A Joint Study of AMLSG, Cetlam and Acute Leukemia Working Party of EBMT

Prognosis of acute myeloid leukemia (AML) is mainly determined by presenting cyto- and molecular genetics, as systematized in the recent European LeukemiaNet (ELN) risk classification. Moreover, mutational profiling is currently used to assign post-remission therapy, especially in the category of intermediate-risk cytogenetics (IR-AML), given the observed benefit of allogeneic hematopoietic stem-cell transplantation (alloHSCT) in first complete response in patients harboring high-risk molecular features such as FLT3-ITD and the lack of benefit in patients with a favorable genotype (i.e., mutated NPM1 and CEBPA biallelic mutation). Nonetheless, the prognosis for patients with an IR-AML lacking mutations of these three genes (“triple negative” AML) is uncertain, and optimal post-remission strategy for these bona fide intermediate-risk patients is mostly unknown.

In order to elucidate if alloHSCT could improve the prognosis of this molecular subgroup, we analyzed the outcome in a large series of patients with “de novo”, IR-AML (70% harboring a normal karyotype), diagnosed between 2000 and 2013, lacking mutations of NPM1, FLT3-ITD, and CEBPA (only patients with biallelic mutations were excluded), who had achieved a first complete remission after 1 or 2 courses of standard induction therapy. These 630 patients (median age, 52 years, range, 18-72; 58% male) have been included in the database of three different cohorts, the cooperative AML groups AMLSG (n=239) and Spanish CETLAM (n=146), and the HSCT registry of the ALWP-EBMT (n=245). The prognostic impact of alloHSCT in CR1 was analyzed as a time-dependent variable in univariable (Mantel-Byar method, Simon-Makuch plots) and multivariable (Cox with time dependent-variable) analyses.

After a median follow-up of 37 months, 3-year survival (OS), leukemia free-survival (LFS) and relapse incidence (RI) in the pooled two subgroups of AMLSG and CETLAM cooperative groups, regardless of post-remission therapy, was 53% [95% CI: 47-58], 36% [95% CI: 31-41], and 51% [95% CI=45-56], respectively (57±3%, 37.5±3%, and 44±4% in patients up to 60 year-old, respectively), without significant differences between both cohorts. In order to investigate the potential benefit of alloHSCT, we analyzed the entire group, including also patients from the ALWP-EBMT cohort. Remarkably, the outcome of patients from national cooperative groups AMLSG-CETLAM compared to registry ALWP-EBMT who received an alloHSCT in CR1 was not statistically different (3-year OS, LFS, and RI: 57 vs. 68%, p=0.13; 61 vs. 73%, p=0.08; and 22 vs. 19%, p=0.67). Patients who received an alloHSCT in CR1 (n=396) had an improved outcome compared to other post-remission options (high-dose cytarabine based chemotherapy, n=189; autoHSCT, n=45) with a higher OS (3-yr: 65 vs. 49%, p=7x10^-5) and LFS (3-yr: 60 vs. 26%, p<10^-13), and lower RI (3-yr: 23 vs. 72%, p<10^-16). Moreover, post-remission option (alloHSCT in CR1 vs. other), as time-dependent variable, was the strongest prognostic factor in the multivariate analysis in terms of OS (HR=0.61, 0.46-0.8; p=0.0003), LFS (HR=0.49, 0.37-0.65; p<0.0001), and RI (HR=0.24, 0.17-0.34, p<0.001). Other independent prognostic factors identified were age for OS (HR=1.24, 1.11-1.40 -by 10 years-; p=0.0004) and LFS (HR: 1.21, 1.08-1.34; p=0.0007), presenting WBC at diagnosis for OS (HR=1.29, 1-1.67 –over median-; p=0.05), and female gender for OS (HR=0.74, 0.57-0.97; p=0.03). Interestingly, the outcome after alloHSCT did not differ depending on donor type (2-yr RI, LFS, and OS: 14 vs. 19%, p=0.97; 67 vs. 68%, p=0.42; 73 vs. 72%, p=0.95 after alloHSCT with matched sibling, n=200, or an unrelated donor, n=183, respectively).

In conclusion, IR-AML patients with a triple negative genotype constitute a subgroup with a high risk of relapse after postremission therapy with high-dose cytarabine based chemotherapy or autoHSCT. This large study, involving patients from two cooperative groups and the EBMT registry, indicates that an alloHSCT in first CR is associated with a marked relapse reduction and survival benefit in the two cooperative group cohorts with prospective treatment data as well as in the whole cohort including the EBMT registry data.