Improved outcomes among newly diagnosed patients with FMS‐like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification

Abstract

Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance.The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT. | INTRODUCTIONMutations in the fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML), identified in approximately 30% of cases. 1-3 FLT3 mutations occur commonly in two regions: the juxta membrane domain leading to internal tandem duplication (FLT3-ITD), representing the most common type of FLT3 mutation, seen in approximately 25% of all cases; and the tyrosine kinase domain (FLT3-TKD), which occurs in approximately 7%-10% of cases. 1,2 FLT3-ITD mutations have been found to be adverse in

A dynamic 3‐factor survival model for acute myeloid leukemia that accounts for response to induction chemotherapy

“…9,10 The diminishing prognostic role of FLT3-ITD mutations under contemporary therapy in AML has been underlined in a recent report and underscores the need to account for not only response to but also type of induction chemotherapy, in assessing prognostic relevance. 11 Regardless, the observations from the current study highlight the value of considering post-treatment variables as formal components of survival prediction in AML, a concept that is also being pursued in acute lymphoblastic leukemia 12,13 and chronic myeloid leukemia. [14][15][16] In this regard, it should be noted that CR/CRi is a morphologic definition whose value as a prognostic marker might be further enhanced by targeting molecular or cytogenetic remission, as well as assessment of minimal residual disease (MRD); unfortunately, MRD data were not readily available in the current retrospective study.…”

“…The inclusion of response to treatment as a risk variable, in the Mayo 3‐factor model, might have also modified the pattern of survival impact from mutations 9,10 . The diminishing prognostic role of FLT3 ‐ITD mutations under contemporary therapy in AML has been underlined in a recent report and underscores the need to account for not only response to but also type of induction chemotherapy, in assessing prognostic relevance 11 . Regardless, the observations from the current study highlight the value of considering post‐treatment variables as formal components of survival prediction in AML, a concept that is also being pursued in acute lymphoblastic leukemia 12,13 and chronic myeloid leukemia 14–16 .…”

Research Progress of B-Cell Lymphoma/Leukemia-2 Inhibitor Combined with Azacytidine in the Targeted Therapy of Acute Myeloid Leukemia

“…AML is predominantly occurring in older adults and is mostly unsuitable for intensive therapy, due to a variety of poor prognostic factors, including a high proportion of poor cytogenetics, changes associated with myelodysplastic abnormalities, a high ECOG-PS score, and a combination of severe underlying disease [ 16 ]. The active ingredient of azacytidine and B-cell lymphoma/leukemia-2 inhibitors binds to RNA and DNA by interfering with RNA transcription and DNA of actively proliferating cells.…”

“…In a Canadian CCO study on the efficacy of azacytidine on AML/MDS, the ORR was 28.0%, and the median survival time was 11.6 months [ 19 ]. AZA-001 studies showed that azacytidine and B-cell lymphoma/leukemia-2 inhibitors had an ORR of 29.0% and a median survival of 24.5 for treatment of high-risk MDS months; AZA-AML-001 study [ 16 ] shows ORR in the treatment of AML patients with azacytidine and B-cell lymphoma/leukemia-2 inhibitors. At 27.8%, the median survival time was 10.8 months, which was an improvement in response rate compared with traditional supportive care, and azacytidine significantly improved patients' objective response rate, survival rate, and clinical outcome.…”

Therapeutic Advances in Immunotherapies for Hematological Malignancies

“…At this stage, none of the immunotherapies used to treat hematological malignancies can completely replace allogeneic stem cell transplantation, but on the basis of their specific and clear mechanisms of action, they can be developed into more effective therapies with fewer side effects. Currently, patients undergoing immunotherapy treatment are sometimes at risk of serious side effects and, realistically, there are many hematologic malignancies with poor prognoses [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ] even with novel therapies. In light of these challenges, it is important to consider what efforts can establish more curative immunotherapies for hematological malignancies.…”