PF272 GLASDEGIB WITH LDAC IN NEWLY DIAGNOSED PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) UNSUITABLE FOR INTENSIVE CHEMOTHERAPY: EFFECTS ON TRANSFUSIONS AND MARROW RECOVERY VS LDAC ALONE

Background: The United States FDA recently approved glasdegib (GLAS) in combination with low‐dose cytarabine (LDAC) for AML in patients not suitable for intensive chemotherapy. Approval was based on a Phase 2 randomized trial showing overall survival benefit vs LDAC alone. No increased risk of infectious or bleeding complications was seen, with lower rates of hemorrhage (36% vs 42%) and pneumonia (19% vs 24%) with GLAS+LDAC vs LDAC alone. This is consistent with the mechanism of GLAS, which inhibits the hedgehog pathway (not implicated in normal hematopoiesis). Aims: To evaluate hematopoietic recovery and transfusion independence with GLAS+LDAC vs LDAC alone. Methods: This post hoc analysis included AML patients receiving GLAS 100 mg QD + LDAC (n = 75) or LDAC alone (n = 36) in the Phase 2 randomized trial (NCT01546038). We compared transfusion rates and recovery of 3 cell lineages, all at 2 thresholds: absolute neutrophil count (ANC; ≥1000 or 500/μL), hemoglobin (Hb; ≥10 or 9 g/dL), and platelets (≥100,000 or 50,000/μL); requiring measurements at ≥2 consecutive visits. Time to recovery and cycle analyses required ≥1 on‐study measurement; cycle analysis included only remaining patients at risk in that cycle. Patients receiving transfusions were not excluded from analyses. Results: The median treatment duration was 3 cycles (range 1–44) for the GLAS+LDAC arm and 2 (range 1–9) for the LDAC‐alone arm. For all 3 cell lineages, a higher proportion of patients had measurements above the thresholds at ≥2 consecutive visits with GLAS+LDAC, with greater differences for patients below threshold at baseline ( Table ). For ANC recovery, ≥1000/μL was achieved by 56% vs 38% of the GLAS+LDAC vs LDAC‐alone arms, and ≥500/μL by 65% vs 53%. For Hb, ≥10 g/dL was achieved by 32% vs 22%, and ≥9 g/dL by 61% vs 41%. For platelets, ≥100,000/μL was achieved by 42% vs 13%, and ≥50,000/μL by 53% vs 25%. Compared with LDAC‐alone, median time to recovery with GLAS+LDAC was longer for ANC, shorter for Hb, and similar for platelets ( Table ). For all 3 lineages, the proportion of patients achieving recovery in the GLAS+LDAC arm rose over cycles 2–3 and remained high (proportions to Cycle 44 generally: ANC ≥1000 >70%; ≥500 >80%; Hb ≥10 >50%; ≥9 >70%; platelets ≥100,000 >70%; ≥50,000 >80%). Patients in the GLAS+LDAC arm had fewer transfusions, regardless of study drug exposure ( Table ). Summary/Conclusion: Blood count recovery for ANC ≥1000/μL, Hb ≥10 g/dL, and platelets ≥100,000/μL with GLAS+LDAC was seen as early as Cycle 1 for a meaningful proportion of patients, and counts were maintained or continued to improve during subsequent cycles in the remaining patients at risk. ANC recovery, at both 500 and 1000/μL thresholds, occurred in most patients during Cycle 2. Count recovery was consistent in all 3 lineages, and at different thresholds, regardless of baseline counts. The frequency of count recovery for GLAS+LDAC is higher than the 24% CR/CRi rate reported in this study, consistent with observed clinical benefit even in those not achieving complete remission. More GLAS+LDAC patients were transfusion‐independent and when exposure‐adjusted, LDAC‐alone patients required transfusions twice as often; although quality of life was not measured, it is reasonable to expect improved quality of life and resource utilization with decreased transfusion requirements. The GLAS+LDAC combination is a promising option to minimize cytopenias in the upfront treatment of AML patients not suitable for intensive chemotherapy.