Allogeneic Stem Cell Transplantation For Cytogenetically Normal Acute Myeloid Leukemia: Impact Of FLT3 and NPM1 Mutational Status

Cytogenetic abnormalities as detected by conventional karyotyping are among the strongest predictors for the long-term outcome of patients (pts) with acute myeloid leukemia (AML). However, up to 50% of pts are cytogenetically normal (CN) and the screening for mutations of the FLT3 and the NPM1 genes allowed to further dissect this heterogeneous group. Allogeneic stem cell transplantation (alloSCT) has become an integral part of the post-remission therapy for pts with intermediate or high-risk AML in case an HLA-compatible donor is available. Here, we analyzed the impact FLT3 and NPM1 mutations on the outcome of pts with CN-AML who underwent alloSCT at our center between 2006 and 2013.

Follow-up data of all pts were prospectively collected in a computer database and retrospectively analyzed as of June 30^th, 2013. 101 pts (46 female, 55 male) with a median age of 54 (range: 18-75) years with CN-AML were included. 71 pts had de novo AML, whereas 30 pts had secondary or therapy-related AML. All pts were treated in a German multicenter AML trial and received at least two courses of induction therapy. The FLT3 and NPM1 mutational status was as follows: 14 pts were FLT3-mutated/NPM1 wild-type, 15 pts were NPM1 mutated/FLT3 wild-type, 22 pts were FLT3-mutated/NPM1 mutated, and 50 pts were wild-type for both FLT3 and NPM1. At alloSCT, 62 pts were in first complete remission (CR1), 16 pts were in CR2, and 23 pts had refractory disease. In 96 pts alloSCT was performed using peripheral blood stem cells (PBSCs), 5 pts received a bone marrow (BM) graft. Conditioning consisted of standard myeloablative conditioning (MAC) (6x2 Gy TBI and 2x60 mg/m2 cyclophosphamide) in 24 pts. 77 pts received reduced intensity conditioning (RIC) (2x4 mg/kg oral busulfan, 6x30 mg/m2 fludarabine and 4x10 mg/kg ATG). A matched related donor was available for 27 pts, whereas 55 pts or 19 pts were transplanted from a matched-unrelated or mismatched unrelated donor.

After a median follow-up of 11 (range: 1-83) months for the surviving pts, 64 pts are alive and in CR. Causes of death were relapse or NRM in 26 pts or 12 pts, respectively. At 1, 3 and 5 years projected overall survival (OS) or disease-free survival (DFS) of the entire cohort was 67% (57-77%), 58% (46-69%), and 54% (42-67%) or 60% (51-71%), 57% (47-68%), or 50% (37-54%). At the same time points the cumulative incidence of relapse (CIR) or non-relapse mortality (CINRM) was 27% (19-38%), 30% (22-43%), and 37% (36-52%) or 12% (6-21%) remaining stable thereafter. Subgroup analysis showed that the presence of a NPM1 mutation in the absence of mutated FLT3 is associated with a significantly lower CIR, i.e. 8%, at 3 years. In the other subgroups the CIR ranges between 32% for pts lacking FLT3 and NPM1 mutations and 37% for pts carrying both mutations (p=0.002). In univariate analysis, pts with refractory disease had a significantly lower DFS (p=0.0002) and a higher relapse incidence (p=0.0001) as compared to pts transplanted in CR. All other factors examined, i.e. AML subtype, stem cell source, type of conditioning, donor/HLA-match were not associated with OS, DFS, or relapse incidence. Notably, there was no correlation between FLT3 or NPM1 mutational status and remission status at the time of alloSCT. OS did not differ significantly between the four subgroups due to an increased NRM in patients with NPM1-mutated CN-AML. Finally, in multivariate analysis only remission status was identified as an independent prognosticator for DFS and relapse incidence, whereas alloSCT from a mismatched unrelated donor predicted a higher NRM.

Taken together, our results indicate that pts with high-risk AML, as defined by the presence of a FLT3-mutation, may achieve durable long-term remissions following either MAC and RIC-alloSCT from related an unrelated donors. In turn, the presence of a mutation of the FLT3 gene may not per se predict a poor outcome in this setting. In contrast, remission status is among the strongest predictors for long-term outcome in patients with CN-AML undergoing alloSCT.

No relevant conflicts of interest to declare.