Intensity-Adjusted Salvage Chemotherapy Plus FLT3-Inhibitor Gilteritinib in Relapsed/Refractory Acute Myeloid Leukemia with Mutated FLT3-ITD/TKD (SAPPHIRE-G)

Background The addition of cytarabine, daunorubicin, idarubicin, or azacitidine to gilteritinib potentiated apoptosis. Gilteritinib combined with cytarabine, daunorubicin, idarubicin, or azacitidine, inhibited anti-apoptotic protein expression in MV4-11 cells. These preclinical trials suggest the synergistic effect of FLT3 inhibitors with chemotherapeutic agents and needs for further investigation. Gilteritinib therapy promotes differentiation of leukemic blasts in a sizeable subset of relapsed/refractofy (R/R) FLT3mut acute myeloid leukemia (AML). because differentiated AML cells are more susceptible to chemotherapeutic agents. The addition of idarubicin with FLAG (FLAG- IDA) is a usual salvage chemotherapy in R/R AML. We wanted to know the safety and efficacy of the combination of gilteritinib with salvage chemotherapy. Intensive chemotherapy ineligible patients can benefit with low-dose cytarabine which is one of the salvage chemotherapy for R/R AML. In this study, we studied the safety and efficacy of the gilteritinib combined with intensity-adjusted salvage chemotherapies in R/R AML patients. Methods Inclusion criteria were R/R FLT3-ITD/TKD mutated AML; No prior exposure to G ilteritinib (prior exposure of other FLT3-inhibitors was permitted including quizartinib or midostaurin); Mean QTcF interval of ECG of 480 ms or shorter. Patients must be 19 years of age or older. The salvage chemotherapy was decided by the investigator's choice according to intensive chemotherapy eligibility; FLAG-IDA + gilteritinib for intensive chemotherapy eligible patients, or low-dose cytarabine + gilteritinib for intensive chemotherapy ineligible patients. Gilteritinib was combined by intensity-adjusted salvage chemotherapy in R/R AML. Gilteritinib was given 120mg daily on D6-D26 for 3 weeks (D4 to D24 during FLAG-Ida consolidation). When LoDAC was chosen as the salvage regimen, the Gilteritinib starting day was day 11 for 3 weeks. Primary end point was complete remission (CR) rate in intention to treat group (ITTG). Secondary end points were composite CR (cCR; CR+CRh+CRi) and overall response (CR+CRh+CRi+PR) in per-protocol group (PPG), safety evaluation in safety group (SG), progression-free survival (PFS), overall survival (OS). Results Total 27 patients (ITTG) were enrolled in this study. One patient did not receive any study treatment because of early death prior to study drug administration. Therefore 26 patients (PPG) received the planned salvage therapy. The median age was 63 years (range, ). Male patients were 15/27 (55.6%). Eight (29.6%) were primary refractory AML, 16 were first relapsed AML and 3 patients were multiple relapsed AML at the time of study enrollment. Sixteen (59.3%) patients had received intensive chemotherapy (ICTG; FLAG-Ida + Gilteritinib) and 10 (37.0%) patients had received low intensive therapy (LITG; low-dose cytarabine + Gilteritinib) and 1 patient did not receive any planned therapy. In ITTG, CR rates were 10/27 (37.0%). Composite CR (cCR; CR+CRh+CRi) rate was 15/27 (55.6%) and overall response rate (ORR) including cCR and PR was 16/27 (59.3%). In PPG, CR, cCR and ORR were 10/26 (38.5%), 15/26 (57.7%) and 17/26 (61.5%), respectively. When considering ICTG only, CR, cCR and ORR were 8/16 (50.0%), 11/16 (68.8%) and 11/16 (68.8%), respectively. When considering LITG only, CR, cCR and ORR were 2/10 (20.0%), 4/10 (40.0%) and 5/10 (50.0%), respectively. When comparing first relapsed AML and refractory/multiple relapsed AML in PPG (n=26), CR rate (p=0.530), cCR rate (p=0.599) and ORR (p=0.428) were similar. Also, when comparing ICTG and LCTG, CR rate (p=0.218), cCR rate (p=0.228) and ORR (p=0.339) showed no statistically significant differences. Five patients (19.2%) and 1 patient (3.8%) could be bridged to allogeneic or autologous hematopoietic cell transplantation, respectively. Median overall survival (OS) in PPG, ICTG and LITG were 2.8, 2.2, and 3.1 months, respectively. Even though median survival was short, 35% in ICTG showed long-term survival. Median OS in patients who had achieved ORR were 12.0 months. Conclusion Gilteritinib combined with chemotherapy in R/R AML showed not only for chemotherapy-eligible patients who had received intensive chemotherapy but also for chemotherapy-ineligible patients who had received low-dose cytabine.