Contributions
Abstract: EP474
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
patients (pts) with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis. In this setting, response to salvage chemotherapy (CHT) alone has been unsatisfactory and first generation FLT3-inhibitors have shown limited activity in monotherapy. New selective and strong inhibitors, including the recently approved gilteritinib, are rapidly changing the treatment paradigm, being able to induce remission in a significant proportion of pts with limited toxicities. However, little is known about the efficacy and safety of intensive CHT combined with FLT3-inhibitors in R/R AML population.
Aims
we assessed the safety and efficacy of salvage chemotherapy in combination with the FLT3-inhibitor sorafenib in R/R AML pts.
Methods
we retrospectively analyzed R/R FLT3-ITD AML patients aged ≥ 18 years treated with intensive chemotherapy and sorafenib at our institution from July 2015 to December 2020. All patients had received a 3+7-like induction regimen with or without a FLT3 inhibitor. In case of refractoriness to induction or relapse, patients were treated with fludarabine and high-dose cytarabine-based chemotherapy plus sorafenib, at the dose of 400 mg BID for 14 days continuously after the end of CHT. The dose of sorafenib could be reduced in frailer patients.
Results
twenty-two pts were included, (male 59%), with a median age of 50 years (21-73). Eight pts (36%) harbored a NPM1 mutation, 6 pts other molecular anomalies (MLL-PTD in 5, IDH1 and IDH2 in 1 each) and in 4 cases cytogenetic alterations were identified (+6, +8; -7; del7q). Sixty-four per cent of the pts (n=14) were refractory to induction, while 36% (n=8) relapsed after having achieved a remission. Complete remissions (CR) plus CR with incomplete hematologic recovery (CRi) after salvage CHT combined with sorafenib was of 63% (64% in refractory cases vs. 62.5% in relapsed ones). Patients with NPM1 mutation had a CR/CRi rate of 88% vs. 50% in the remaining ones. After a median follow up of 45 months, median overall survival (OS) after salvage therapy was of 13 months, with 4-year OS of 35.9%. For the 14 patients achieving CR/CRi, median relapse-free survival (RFS) was of 5 months, with 4-year RFS of 35.7%. Consolidation with allogeneic stem cell transplantation (HSCT) was performed in 13 pts (59%), 4 of them with active disease. Median OS of transplanted pts was not reached, with 4-year OS of 50.4%. The most common toxicities of CHT plus sorafenib were neutropenic fevers (95%), gastrointestinal (54%) and hepatic (54%) and cutaneous (27%) toxicities, pneumonia (27%) and cardiac complications (18%). Grade 4 toxicities were observed in 3 pts (1 pneumonia, 1 neutropenic enterocolitis, 1 QTc prolongation).
Conclusion
sorafenib in association with high-dose CHT represented a feasible second line option for the treatment of FLT3-ITD positive R/R AML, with encouraging rates of CR/CRi, especially in NPM1-mutated cases, and roughly 50% of transplanted patients experiencing long-term survival. Toxicities were not negligible, but in line with those expected after intensive CHT in this population. The potential benefit of combining FLT3 inhibitors with intensive chemotherapy should be further explored in this setting for fit patients, and this strategy is currently under investigation in clinical trials testing new FLT3 inhibitors.
Keyword(s): AML, Chemotherapy, Flt3 inhibitor, Flt3-ITD
Abstract: EP474
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
patients (pts) with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis. In this setting, response to salvage chemotherapy (CHT) alone has been unsatisfactory and first generation FLT3-inhibitors have shown limited activity in monotherapy. New selective and strong inhibitors, including the recently approved gilteritinib, are rapidly changing the treatment paradigm, being able to induce remission in a significant proportion of pts with limited toxicities. However, little is known about the efficacy and safety of intensive CHT combined with FLT3-inhibitors in R/R AML population.
Aims
we assessed the safety and efficacy of salvage chemotherapy in combination with the FLT3-inhibitor sorafenib in R/R AML pts.
Methods
we retrospectively analyzed R/R FLT3-ITD AML patients aged ≥ 18 years treated with intensive chemotherapy and sorafenib at our institution from July 2015 to December 2020. All patients had received a 3+7-like induction regimen with or without a FLT3 inhibitor. In case of refractoriness to induction or relapse, patients were treated with fludarabine and high-dose cytarabine-based chemotherapy plus sorafenib, at the dose of 400 mg BID for 14 days continuously after the end of CHT. The dose of sorafenib could be reduced in frailer patients.
Results
twenty-two pts were included, (male 59%), with a median age of 50 years (21-73). Eight pts (36%) harbored a NPM1 mutation, 6 pts other molecular anomalies (MLL-PTD in 5, IDH1 and IDH2 in 1 each) and in 4 cases cytogenetic alterations were identified (+6, +8; -7; del7q). Sixty-four per cent of the pts (n=14) were refractory to induction, while 36% (n=8) relapsed after having achieved a remission. Complete remissions (CR) plus CR with incomplete hematologic recovery (CRi) after salvage CHT combined with sorafenib was of 63% (64% in refractory cases vs. 62.5% in relapsed ones). Patients with NPM1 mutation had a CR/CRi rate of 88% vs. 50% in the remaining ones. After a median follow up of 45 months, median overall survival (OS) after salvage therapy was of 13 months, with 4-year OS of 35.9%. For the 14 patients achieving CR/CRi, median relapse-free survival (RFS) was of 5 months, with 4-year RFS of 35.7%. Consolidation with allogeneic stem cell transplantation (HSCT) was performed in 13 pts (59%), 4 of them with active disease. Median OS of transplanted pts was not reached, with 4-year OS of 50.4%. The most common toxicities of CHT plus sorafenib were neutropenic fevers (95%), gastrointestinal (54%) and hepatic (54%) and cutaneous (27%) toxicities, pneumonia (27%) and cardiac complications (18%). Grade 4 toxicities were observed in 3 pts (1 pneumonia, 1 neutropenic enterocolitis, 1 QTc prolongation).
Conclusion
sorafenib in association with high-dose CHT represented a feasible second line option for the treatment of FLT3-ITD positive R/R AML, with encouraging rates of CR/CRi, especially in NPM1-mutated cases, and roughly 50% of transplanted patients experiencing long-term survival. Toxicities were not negligible, but in line with those expected after intensive CHT in this population. The potential benefit of combining FLT3 inhibitors with intensive chemotherapy should be further explored in this setting for fit patients, and this strategy is currently under investigation in clinical trials testing new FLT3 inhibitors.
Keyword(s): AML, Chemotherapy, Flt3 inhibitor, Flt3-ITD