FLT3|General AML

Chemotherapy and sorafenib for elderly AML patients with FLT3 mutations: CALGB 11001 study

FMS-like Tyrosine Kinase 3 (FLT3) mutations occurs in approximately 30% of Acute Myeloid Leukemia (AML) and results to poor prognosis, survival and relapse in these group of patients. The overall outcomes of older AML patients with standard chemotherapy and post-remission therapy is poor.

Geoffrey L. Uy from the Washington University School of Medicine, St Louis, and colleagues published data from their phase 2 study (NCT01253070) conducted by The Cancer and Leukemia Group B (CALGB) in Blood Advances in January 2017.

In this phase 2 study, the effect of sorafenib, (an oral multikinase inhibitor) in combination with daunorubicin and cytarabine-based induction and post-remission therapy was investigated on the survival outcomes of fifty-four FLT3-mutated AML patients (median age = 67 years). The primary endpoint of this study was Overall Survival (OS) at 1 year in FLT3- Internal Tandem Mutation (ITD) AML patients.

The key results are:
  • Median Overall Survival (OS) for FLT3-ITD (n = 39) and FLT3- Tyrosine Kinase Domain (TKD) (n = 15) patients; 15 months vs 16.2 months
  • 1- year Disease Free Survival (DFS)  for FLT3-ITD (n = 29) and FLT3-TKD (n = 11)patients; 52% vs 36%
  • 1- year Event Free Survival (EFS)  for FLT3-ITD (n = 39) and FLT3-TKD (n = 15)patients; 39% vs 27%
  • In all patients (n = 54), 2- year EFS and OS were 20% and 27% respectively
  • Age ≥ 70 years was associated with OS (HR = 2.6, P = 0.01), DFS (HR = 2.5, P = 0.04) and EFS (HR = 2.7, P = 0.01)
  • Median OS in FLT3-ITD patients ≥ 70 years (n = 22) versus patients aged 60-69 (n = 17); 9.7 months vs 19.9 months
  • Median EFS in FLT3-ITD patients ≥ 70 years (n =22) versus patients aged 60-69 (n =17); 2.2 months vs 12.7 months
  • After censoring at the time of transplant, 1- year EFS, OS and DFS were 29%, 52% and 40% in FLT3-ITD patients respectively
  • After censoring at the time of transplant, 1- year EFS, OS and DFS were 11%, 70% and 16% in FLT3-TKD patients respectively
  • During sorafenib maintenance, AEs included grade1 diarrhea, fatigue and transaminitis3 patients (rash, n =2) discontinued sorafenib secondary to AEs

The authors noted that the survival outcomes compared favorably to previous outcomes observed in older FLT3-ITD mutated AML patients treated in historical CALGB trials.

In conclusion, addition of sorafenib to chemotherapy is feasible, tolerable and may improve the survival outcomes of older patients with FLT3-mutated AML.

Abstract

The Cancer and Leukemia Group B (CALGB), now part of the Alliance for Clinical Trials in Oncology, conducted a multicenter, single-arm, phase 2 study in patients ≥60 years with FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML). In this study, sorafenib was added to daunorubicin and cytarabine-based induction and consolidation chemotherapy and was also continued for 12 months of maintenance therapy. The primary end point of the study was overall survival (OS) at 1 year in the FLT3 internal tandem duplication (FLT3-ITD) cohort. Fifty-four patients with a median age of 67 years (range, 60.3-82.7 years) were enrolled; 39 were FLT3-ITD patients (71%) and 15 were FLT3-TKD (29%) patients. The observed 1-year OS (95% confidence interval [CI]) was 62% (45%-78%) for the FLT3-ITD patients (meeting the primary end point 62% vs 30% for a historical control group, P < .0001) and 71% (42%-92%) for the FLT3-TKD patients. The median disease-free survival and OS were 12.2 months (95% CI, 5-16.9) and 15.0 months (95% CI, 10.4-20.1), respectively, in the FLT3-ITD group and 9.6 (95% CI, 1.9 to not available [NA]) and 16.2 months (95% CI, 5.0 to NA) for the FLT3-TKD group. This study suggests that the addition of sorafenib to chemotherapy for FLT3-ITD AML is feasible and may improve the survival of older adults with FLT3-mutated AML. This trial was registered at www.clinicaltrials.gov as #NCT01253070.

References
  1. Uy G L. et al. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Advances. 2017 January 24; 1(5): 331-340. DOI: 10.1182/bloodadvances.2016003053.