Dynamics and Prognostic Impact of Peripheral Blood Blast Clearance in Patients with Acute Myeloid Leukemia (AML) Receiving FLT3 Inhibitor Therapy in Combination with Induction Chemotherapy
Authors: Benton Christopher B. , Qiu Peng , Ravandi Farhad , Kantarjian Hagop M. , Garcia-Manero Guillermo , Pierce Sherry A. , Borthakur Anisha , Konopleva Marina , Cortes Jorge E. , Andreeff Michael , Quintás-Cardama Alfonso 
Published: October 2019

Abstract
Abstract 1417

Background:
We have previously shown that for patients with acute myeloid leukemia (AML) treated with induction chemotherapy with cytarabine (ara-C) plus an anthracycline, the day of blast clearance from peripheral blood (PB) is a powerful prognostic marker. Earlier PB blast (but not white blood cell [WBC]) clearance portends improved overall survival (OS). We expanded our investigation to include patients with AML undergoing induction chemotherapy with ara-C (1.5g/m2 ×3 days) plus idarubicin (12mg/m2×3 days) that is, the AI regimen, plus sorafenib (400mg orally twice daily).

Patients and Methods:
We reviewed the clearance of PB blast and WBC (PB blasts = 0%, WBC≤0.1×109/dL), for patients with AML (except APL) undergoing AI alone (n=168) or AI+sorafenib (n=75). Patient characteristics for the AI alone group (n=168) were as follows: median age 55 years (range, 19–72), diploid cytogenetics (n=57, 34%), poor cytogenetics (n=61, 36%), FLT3-ITD positive (n=15, 9%), FLT3-negative (n=122, 73%), median WBC 5.0×109/dL (range, 0.3–132.3), median platelets 37×109/dL (range, 1–581), median hemoglobin 9.1g/dL (range, 4.0–13.2), median PB blasts 15% (range, 1–96), median BM blasts 42% (range, 1–96). Patient characteristics for the AI+sorafenib group (n=75) were as follows: median age 52 years (range, 18–66), diploid cytogenetics (n=38, 51%), poor cytogenetics (n=10, 13%), FLT3-ITD (n=25, 33%), FLT3-negative (n=48, 64%) median WBC 5.9×109/dL (range, 0.6–228.5), median platelets 51×109/dL (range 7–306), median hemoglobin 9.2g/dL (range, 7.4–12.6), median PB blasts 21% (range 0–98), median BM blasts 56% (range 6–98).

Results:
The overall response rate (ORR=CR+CRp) in the AI group was 63% (58%+5%) and 50 patients (30%) were resistant to therapy. The ORR in the AI+sorafenib group was 79% (72%+7%) and 11 patients (15%) were resistant. We analyzed OS by dividing patients based on the day of PB blast clearance: group 1 (0–1 days), 2 (2–3 days), 3 (4–5 days), 4 (6–8 days), and 5 (>8 days). For the patients receiving AI induction therapy, a total of 32, 59, 38, 18, and 2 patients were included in groups 1–5, and median OS for groups 1–4 were 167, 48, 67, and 25 weeks respectively. A logrank test comparison revealed these four OS curves were significantly different (p-value=0.0015). For the AI treatment group, earlier blast disappearance corresponded with better OS. In contrast, for patients in the AI+sorafenib group, the correlation between day of PB blast clearance and OS was less clear. A total of 10, 23, 25, 6, and 3 patients were included in groups 1–5. The median OS for groups 1, 3, and 4 were 101, 74, and 66 weeks respectively, and the median survival for group 2 could not be estimated because the curve did not fall below 0.5. The difference between these four survival curves was not significantly different (p-value=0.35). Survival differences for the AI group were more clearly demarcated when patients were divided based on blast disappearance within 0–5 days or >5 days (p-value=0.0004). A similar analysis in the AI+sorafenib group revealed no significantly different OS (p-value=0.13). Among patients in the AI+sorafenib treatment group, the mean day of blast disappearance for FLT3-ITD versus FLT3-negative patients was 5.2 vs. 4.5 days, and this difference was not statistically significant (p-value=0.33). While FLT3-ITD patients who cleared their blasts within 0–3 days (n=10) tended to have better OS survival than FLT3-ITD patients who cleared their blasts after 3 days (n=13), the difference in OS curves did not reach significance (p-value=0.18).

Conclusion:
The day of PB blast clearance is prognostic among patients receiving classic induction chemotherapy, where early clearance predicts better long-term outcomes. The addition of a targeted agent to a standard induction regimen limits the prognostic power of early PB blast clearance. We are currently investigating a novel mathematical approach to evaluate the prognostic value of clearance of peripheral blasts compared to WBC after initiation of therapy in patients receiving targeted agents during induction therapy; the approach aims to integrate the prognostic impact of FLT3 and NPM1 in combination with cytoreduction kinetics to better identify prognostically distinct groups.

Disclosures:
Off Label Use: Plerixafor plus G-CSF as a part of conditioning in allogenic transplant for AML/MDS.