Subject terms
death, neutropenia, factor-mutant AML, AML, MDS, CMML
NEUTROPENIA, ADVERSE EVENTS, DISEASE, AML, CARDIAC ARREST, SOLID TUMOR, REMISSION, EVENTS, CMML, DISEASE CHARACTERISTIC, MULTI-ORGAN FAILURE
Treatment options for relapsed and/or refractory (R/R) MDS and AML are limited. Mutations in genes encoding RNA splicing factors are encountered frequently in patients with AML and in up to 60% of MDS patients [RBM39 is a splicing factor essential for survival of AML cells with splicing factor mutations [We conducted an investigator-initiated phase II trial (NCT05024994) of E7820 in patients with R/R splicing factor-mutant AML, MDS, or CMML. Supplementary Table The study protocol was developed by the authors in collaboration with Eisai Pharmaceuticals and was approved by our Institutional Review Boards. All patients provided informed consent. The study was conducted in accordance with the Declaration of Helsinki.The primary objective was to evaluate efficacy of E7820 as measured by overall response rate (ORR) within 6 cycles of therapy. The ORR was defined as a composite of CR + CRh per 2017 ELN response criteria for AML patients and as CR + PR for MDS and CMML per the International Working Group 2006 criteria for MDS and 2015 criteria for CMML [This study used an optimal Simon two-stage design. In the absence of an effective salvage therapy for patients with HMA failure and ORR of <10% with intensive chemotherapy or lower-intensity therapy, we used a null unpromising ORR of 10% and a promising rate of 30% to inform the sample size calculation. Per the study design 12 patients were enrolled in the first stage of the study. If no more than one patient achieved a response, the study was planned to close due to lack of efficacy; otherwise, an additional 23 patients were planned to be accrued. As none of the first 12 patients enrolled achieved an objective response, the study was closed for futility.Twelve patients were treated (7 AML, 5 MDS) with a median age of 77 years (range 71–85). Patients had received a median of 3 lines of prior therapy (range 1–6). Mutations in Baseline patient and disease characteristics.Among the first 12 patients enrolled, no patient met the primary endpoint leading to study termination for futility. Two patients did not have a repeat BM assessment and were classified as not having achieved a response per study protocol. One patient achieved a transient marrow complete remission (mCR) without hematologic improvement (blast count reduction from 8 to 3%) but had an increase in blast count at subsequent BM assessment 2 cycles later. All other patients had stable or progressive disease as their best response. Serial mutational analysis revealed an overall modest decrease of 4.9% in splicing factor mutation allele frequency (Supplementary Fig. At a median duration of follow up of 13.1 months, the median overall survival (OS) from time of E7820 initiation to death was 3.8 months (95% confidence interval: 1.5 months – not reached; Supplementary Fig. The safety profile of E7820 was in line with prior solid tumor studies [Grade 3 or higher adverse events occurred in 10 patients (83.3%) and were classified as possibly treatment-associated in 4 patients (33%). There were two grade 5 events (multi-organ failure and cardiac arrest), which were unrelated to treatment.There were 21 serious AEs that occurred in 8 patients (66.7%); three of which were classified as treatment-associated (1 case each of grade 3 AST elevation, grade 2 ALT elevation, and grade 4 neutropenia). The transaminase elevations observed in a single patient were transient and resolved with holding of E7820.Western blotting of peripheral blood (PB) mononuclear cells (MNCs) pre-treatment and on-treatment revealed >50% RBM39 degradation at cycle 2 day 1 of therapy (Fig. 