Post-transplant maintenance with sorafenib is safe and effective in pediatric patients with har FLT3/ITD AML: A report from the Children's oncology group protocol AAML1031

Abstract Introduction Patients with acute myeloid leukemia (AML) with an internal tandem duplication mutation of FLT3 (FLT3/ITD) have a high risk of relapse and cure with chemotherapy alone is rare. FLT3 tyrosine kinase inhibitors (TKIs) target the oncogenic FLT3 receptor to improve outcomes in this poor prognosis subset. COG AAML1031 studied the feasibility and efficacy of adding sorafenib to multi-agent chemotherapy in pediatric patients with FLT3/ITD AML and demonstrated improved disease-free survival compared to a similar a cohort of similar FLT3/ITD+ patients who did not receive TKI. The objective of this analysis was to examine the tolerability and efficacy of sorafenib, specifically when added as maintenance after hematopoietic cell transplantation (HCT). Methods On COG AAML1031, pediatric patients with FLT3/ITD AML (high allelic ratio (HAR) >0.4) were eligible to receive sorafenib plus conventional chemotherapy with each treatment course followed by allogeneic HCT. After HCT, patients could reinitiate sorafenib (starting at 100 mg/m2 with predefined escalation/de-escalation) between day +40-100 and receive for one year from restart. Criteria to restart included adequate hematopoietic recovery without evidence of relapse, no acute GVHD and adequate cardiovascular function (shortening fraction > 28%, no severe hypertension). Patients who received at least one dose of sorafenib after HCT were considered exposed. A control cohort was compiled of (1) patients from AAML0531 arm B who received identical chemotherapy, without sorafenib (n=13), (2) patients on AAML1031 with HAR FLT3/ITD who did not receive any sorafenib (n=6), and (3) patients on AAML1031 who only received pre-HCT sorafenib but did not restart after (n=25). All control patients had received allogeneic HCT on study in first remission. Cumulative incidence of relapse (CIR) after HCT was the primary outcome measure. Post-HCT sorafenib was treated as a time-dependent exposure and non-relapse mortality was a competing event. Results The analysis included 74 patients, 30 with post-HCT sorafenib exposure (post-HCT TKI) and 44 control patients (no post-HCT TKI); of the controls, 25 received pre-HCT sorafenib (pre-HCT TKI only) and 19 never received sorafenib (no TKI). Post-HCT TKI patients were more likely to be non-Hispanic white (83% versus 62%, p=0.012), but otherwise demographic, disease and transplant characteristics, as well as follow up time from HCT, were similar between the post-HCT TKI and control groups. Compared to subjects with pre-HCT TKI only, those who received post-HCT TKI were more likely to have received 3 full courses (87% versus 72%, p = 0.09). Median start day of TKI was 74 (range 42-110); one patient relapsed before day 40. The 5-year CIR for those with post-HCT TKI was 21% (95%CI 8-38%) and for controls was 34% (95%CI 21-48%); HR 0.70, p = 0.416. Median time to relapse was longer in patients who received maintenance (4 versus 15 months). 5-year overall survival (OS) also favored receipt of sorafenib, 90% (95%CI 71%-97%) versus 57% (95%CI 41-70%), OS log-rank p value 0.008. In a sensitivity analysis comparing the post-HCT TKI cohort to the cohort that received pre-HCT TKI only, CIR results were similar (HR = 0.67, p = 0.42) as were OS results (log rank p value .001, 5y OS 90% versus 44%). Sorafenib was well tolerated after HCT; 20/30 (66%) patients were able to complete the full year of treatment, although dose reductions compared to initial dose were common (30%, 24%, 15% in cycles 1-3, respectively). Only 1/3 of subjects experienced an AE of any grade in each cycle, none greater that grade 3, except for one grade 4 neutropenia in cycle 2. The most common grade 3 AE was ALT elevation (13%, cycle 1). The cumulative incidence of acute or chronic graft versus host disease (GVHD) was similar among patients who did and did not receive sorafenib, HR = 0.83 (95%CI 0.38-1.78, p=0.63). Conclusions This prospective study of post-HCT sorafenib maintenance therapy in de novo HAR FLT3/ITD+ pediatric AML demonstrated a clinically, but not statistically significant, reduction in relapse risk and an acceptable side effect profile. Patients who received sorafenib also have substantially improved OS but this may be in part due to a favorable clinical status among patients who restart sorafenib. Further work is needed to understand whether its benefit is limited to specific disease subsets and/or those with pre HCT MRD and to clarify the optimal duration of dosing.

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