Profiling mutations in patients with acute myeloid leukemia (AML) can be used to inform therapeutic approaches. Because most patients with AML who achieve complete remission with induction therapy eventually relapse, and most die from relapsed disease, new treatment options must be evaluated.
Ross L. Levine, MD, a physician and scientist at Memorial Sloan-Kettering Cancer Center, New York City, reviewed the prognostic significance of novel AML alleles.
Risk Stratification
Integrated genetic analysis from 502 patients with AML who were enrolled in the Eastern Cooperative Oncology Group (ECOG) E1900 clinical trial revealed genes with prognostic importance. Mutations within 18 genes were analyzed.
Mutations in IDH2 R140, but not in IDH2 R172 or IDH1, were associated with improved survival, and mutations in ASXL1 and PHF6 were associated with worse overall survival (OS).
The risk can be further refined in patients with intermediate-risk AML by more extensive analysis of genetic mutations than is currently used in the clinical setting, Dr Levine said.
He said that 3 distinct risk groups can be identified in FLT3 internal tandem duplication (ITD)-negative intermediate-risk AML based on mutation status; TET2, ASXL1, PHF6, and partial tandem duplications in MLL are high-risk mutations that are associated with worse survival in the group of intermediate-risk patients with wild-type FLT3-ITD.
Patients without FLT3-ITD mutations and with NPM1 and IDH mutations represent a favorable-risk subset. In contrast, patients who were negative for FLT3-ITD mutations but had NPM1 mutation and no IDH mutations had a much less favorable outcome.
In the ECOG E1900 trial, a post hoc analysis of mutational status showed that high-dose daunorubicin improved outcomes markedly for patients with DNMT3A mutations. Patients with NPM1 or DNMT3A mutations, or MLL translocations, had a 3-year OS of 44% with high-dose daunorubicin induction chemotherapy compared with a 25% OS in patients treated with standard-dose daunorubicin.
Extensive mutations analysis could be used to identify the patients who are the most likely to benefit from standard AML therapy or from allogeneic stem-cell transplantation, believes Dr Levine.
Minimal Residual Disease
Minimal residual disease (MRD) after treatment in patients with AML predicts failure to maintain a morphologic complete response (CR) and negatively affects survival. The best method to monitor MRD is still controversial, said Elisabeth Paietta, PhD, Professor, Department of Oncologic Medicine, Albert Einstein College of Medicine, Bronx, NY. MRD assessment assays are immunophenotypic or are done by multiparameter flow cytometry or by polymerase chain reaction to detect recurrent gene mutations or leukemia fusion transcripts.
Even if clones that are present at the time of an AML diagnosis can be detected through sensitive assays, therapeutic options for patients with MRD are limited at present. Intensive therapeutic approaches have not worked in patients with MRD, noted Dr Paietta. Immunotherapy may represent a promising approach to managing patients with MRD after chemotherapy.
Newer cytotoxic chemotherapies for the treatment of relapsed AML include clofarabine with or without cytarabine; tosedotat, an orally available aminopeptidase inhibitor associated with a 27% overall response rate in a phase 1/2 study of patients with relapsed AML; and FLT3 inhibitors, which may have a role as a bridge to transplantation, said Jeffrey Szer, MBBS, FRACP, MD, Professor and Director, Department of Clinical Hematology and Bone Marrow Transplant Service, the Royal Melbourne Hospital, Parkville, Australia.
Inhibitors of mTOR, such as everolimus (Zortress, Afinitor) and sirolimus, have potential benefit, given the role of the mTOR pathway in cytarabine activity. Hypomethylating agents are being studied as maintenance therapy after allogeneic stem-cell transplant.
Allogeneic stem-cell transplant has an established track record in the cure of patients with relapsed and refractory AML, although subsequent relapse does occur. The successful use of transplant will require patients with relapsed AML to achieve a state of a second CR or MRD.