Long Term Follow-up Data after Consolidation Therapy with Ponatinib in Combination with Cytarabine in Patients with FLT3 Mutated Acute Myeloid Leukemia in First Complete Remission

Background

Ponatinib is a third-generation tyrosine kinase inhibitor targeting the BCR::ABL1 tyrosine kinase domain. Despite low activity against FLT3 based on the IC50 value (FLT3 IC50: 12.6 nM), ponatinb has been reported to have significant activity against the MV4-11 cell line which harbors FLT3-ITD and against primary blasts from FLT3-ITD acute myeloid leukemia (AML). We thus proposed to combine ponatinib with cytarabine in FLT3 mutated AML patients in first complete remission (CR). Classical FLT3 inhibitors were not clinically available in France at trial initiation.

Patients and methods

AML patients in first CR were eligible if they had intermediate risk karyotype with FLT3-ITD/TKD allelic ratio >10%, normal pancreatic and hepatic functions, controlled cardiovascular comorbidities, QTc < 470 ms and no CNS involvement. Patients aged 18-60y received high dose ARA-C (HDAC, 3g/m²/12h at D1, D3 and D5, 3 courses, cohort A) and patients aged above 60y received Intermediate dose ARA-C (IDAC, 1.5g/m²/12h D1, D3 and D5, 2 courses, cohort B). Ponatinib was given continuously during the consolidation phases. After amendment, a ponatinib maintenance was allowed for patients included in cohort A. Three dose levels of ponatinib were tested following a classical dose escalation schedule (3-3-3) in each age group: 15 mg/d, 30 mg/d and 45 mg/d. Allogenic hematopoietic stem cell transplant (Allo-HSCT) was allowed for eligible patients after consolidation 1. Primary end-point was dose limiting toxicity, secondary end-points were overall survival (OS), cumulative incidence of relapse (CIR) and measurable residual disease (MRD). NPM1 based MRD negativity (MRDneg) was defined by a ratio <0.01% or a >4log reduction in NPM1 initial signal.

Results

Forty seven patients were included from April 2014 to November 2018, 28 in cohort A (median age 50.1y) and 19 in cohort B (median age 64.8y). All patients had FLT3-ITD including 4 patients with additional TKD mutations. Others mutations (>1 case) included NPM1, DNMT3A, TET2, IDH1/2, PTPN11, RUNX1 and GATA2 in 35, 23, 10, 9, 3, 3 and 2 cases respectively.

Dose escalation of ponatinib in cohort A resulted in 1 dose limiting toxicity (DLT) (cardiac failure) at 45 mg/d. Thus, the recommended ponatinib daily dose was 30 mg/d for the remaining patients and no further DLT was recorded during consolidation 1. Three patients permanently stopped ponatinib (including 1 hypertension and 1 Allo-HSCT) and 5 patients had a transient stop. Dose escalation of ponatinib in cohort B resulted in 2 DLTs at 30 mg/d (atrial fibrillation and pulmonary embolism). Thus, the recommended ponatinib daily dose was 15 mg/d for the remaining patients. Three patients permanently stopped ponatinib (including 1 atrial fibrillation and 1 delayed hematological recovery) and 2 patients had a transient stop. Overall, 4 deaths related to the treatment procedures (including Allo-HSCT) were recorded.

After a median follow-up of 4.6y (0.6-7.3) for surviving patients, median overall survival was not reached and Kaplan-Meier estimate for survival at 5y was 61.3% (95% CI: 45.7-73.6). No statistical difference was observed for cohort A versus B (67.8% (95% CI: 47.3-81.8) versus 51.5% (95% CI: 27.1-71.3) respectively), despite a trend in favor of cohort A. Twenty four patients (51%) were allografted in first remission, 16 in cohort A (57%) and 8 in cohort B (42%). Survival at 5y after censoring for Allo-HSCT in first CR was 51.4% (95% CI: 29.5-69.6).

Thirty four patients were evaluable for NPM1 MRD during consolidation and 24 (70.5%) were MRDneg. All MRDpos except one allografted patients relapsed within 7 months post CR whereas CIR was 33.8% by 5y for MRDneg patients. As a consequence, 5y OS was significantly improved in MRDneg patients as compared to MRDpos patients (74.2% (95% CI: 51.2-87.5) versus 30% (95% CI: 7.1-57.8) respectively, P=0.007). Twenty four patients relapsed (51%), including 6 <12 months post CR. Median OS for relapsing patients was 8.7 months and 6 patients received Allo-HSCT in CR2.

Conclusion

The combination of ponatinib and high or intermediate dose cytarabine is feasible and safe in patient with FLT3 mutated AML in first CR. The recommended ponatinib daily dose in combination was 30 mg/d in patients aged 18-60y and 15 mg/d for patients aged above 60y. The high rate of MRD negativity (70%) combined with a 5y survival of 61% support the potential of ponatinib as an alternative FLT3 inhibitor in FLT3 mutated AML.