Results of a Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients (Pts) with Activating FLT3 Mutations

摘要: Introduction FLT3-ITD (Internal tandem duplication) and FLT3-TKD (tyrosine kinase domain, D835) mutations are frequently seen in AML; FLT3-ITDs associated with inferior survival. Development of mutation during FLT3 inhibitor-therapy is up to 22% patients tyrosine inhibitor (TKI) treatment failure (Cancer 2014). Crenolanib besylate an orally bioavailable TKI activity against both mutations. We evaluated the clinical efficacy crenolanib relapsed/refractory AML pts activating Methods This was a single center phase II open label study administered at 200 mg/m2/day three times day continuously 28 cycles. mutated (either FT3-ITD or FLT3-TKD) primary AML, therapy-related following antecedent hematological disorder were included. Pts ≥18 years age ECOG PS 0-2. CNS disease excluded. relapsing post-allogeneic stem cell transplant could be included if they >30 days post-transplant. 38 enrolled 2 parallel cohorts which 34 evaluable, 13 cohort A (FLT3 TKI-naive) 21 B (progressed on prior TKI). Results Median 61 (30 – 87). Patients had undergone median 3.5 therapies (range 1 8); 38% diploid 23% complex cytogenetics. Among available information, NPM1 identified 62% (10/16) DNMT3A 57% (8/14). baseline marrow blast % 58% (7 97%). Of patients, therapy sorafenib 57%, quizartinib 14%, PLX3397 5% midostaurin 10%. 9% received 3 TKIs, respectively. 10 progressed post-transplant (SCT) (3 allogeneic A; 6 allogeneic, autologous B). duration 9 wks 5 24), remain study. Reasons for cessation progression 66%, no response 16%, toxicity 6%, deterioration due other co-morbidities 3% lost follow receive SCT. At 14 weeks (wks), ORR 47%: 12% achieved complete incomplete count recovery (CRi), 32% improvement (Hi) (85% them >50% decrease count) morphologic leukemia-free state (MLFS). 21% progressive response. The event-free survival (EFS) 8 overall (OS) 19 whole cohort. by was: achieving (CRi MLFS) superior EFS (median 22 vs non-responders, p=0.003), trend toward OS responders 55 versus 15 wks, p=0.166). 4 responded (CRi, Hi). mutations, 1/1 pt CRi 5/6 Hi. not influenced cytogenetics, number presence were, ITD (19 wks; 7 wks), D835 (6 wks) (12 p=0.908; 0.391 main grade toxicities GI side effects (abdominal pain nausea). There death attributed related toxicity. Conclusions well-tolerated heavily pre-treated, patients. results inhibitor-naive suggests that on-target inhibition likely primarily responsible drug efficacy. Combination (e.g., chemotherapy hypomethylating agents) potentially provide additive treatment-naive pts. Disclosures No relevant conflicts interest declare.