Targeting MYB with REM-422 for Pediatric T-Cell Acute Lymphoblastic Leukemia Treatment

Introduction: While survival rates for pediatric acute lymphoblastic leukemia (ALL) have improved dramatically over the past 60 years, outcomes remain poor for certain patients, particularly those with relapsed/refractory T-cell ALL (T-ALL). MYB is a transcription factor involved in the regulation of hematopoietic stem and progenitor cells, which exhibits strong dependency in lymphohematopoietic neoplasms. REM-422 is an orally available small molecule degrader of MYB mRNA that is currently being evaluated in Phase 1 clinical trials (NCT06118086 and NCT06297941). Therefore, it was of interest to test the in vivo activity of REM-422 against the PIVOT pediatric ALL patient-derived xenografts (PDXs). Methods: MYB mRNA expression was assessed via RNA sequencing and expressed as fragments per kilobase of transcript per million mapped reads (FPKM, Rokita et al., Cell Rep., 2019). MYB protein expression was assessed by immunoblotting using a MYB monoclonal antibody (clone D2R4Y). For in vivo efficacy testing in NSG mice, REM-422 was administered at 5 mg/kg via oral gavage, daily for 3 weeks. A single mouse trial design (1 vehicle control, 1 drug treated mouse per PDX) was used for testing across pediatric ALL PDXs. Standard PIVOT methods were used to assess event-free survival (EFS). Stringent objective response (OR) measures modeled after the clinical setting were also used to evaluate activity (Houghton et al., Pediatr. Blood Cancer, 2007). Results: MYB mRNA expression was significantly higher in 90 pediatric ALL PDXs (mean 153 FPKM, range 16.0-321) compared with 154 PDXs derived from pediatric solid tumors (mean 4.0 FPKM, range 0.04-240, P<0.001), with no significant differences in expression between pediatric ALL subtypes. Ex vivo exposure of 2 PDXs to REM-422 for 6-24h resulted in almost complete ablation of MYB protein levels. REM-422 was well tolerated in NSG mice, with no overt signs of toxicity or weight loss >5%, and with all intended doses administered. In the efficacy study, 28 of 30 planned PDXs were evaluated. REM-422 extended mouse median EFS by 20.7 days compared with vehicle control-treated mice (P<0.0001). While REM-422 extended survival in both the T and B-lineage PDXs, the 10 T-lineage PDXs (Treated-Control [T-C] 33.0 days, T/C 3.6, P<0.0001) exhibited a better overall response compared with the B-lineage PDXs (T-C 19.4 days, T/C 2.5, P=0.0004). Moreover, REM-422 elicited ORs in 8/10 T-lineage (2 Partial Responses [PRs], 3 Complete Responses [CRs] and 3 Maintained CRs [MCRs]) compared with only 2/18 B-lineage (1 PR, 1 MCR) PDXs. Conclusions: REM-422 exhibited potent single-agent in vivo activity against a large panel of pediatric T-ALL PDXs, supporting its potential clinical evaluation in this disease. Future research directions will include efforts to identify effective combinations with targeted and/or standard-of-care drugs. Citation Format: Richard B. Lock, Kathryn Evans, Ben Watts, Miguel Agoncillo, Christopher M. Smith, Steven Neuhauser, Timothy M. Stearns, Emily L. Jocoy, Jee Young Kwon, Jeffrey H. Chuang, Samantha Levin-Furtney, Beverly A. Teicher, Charles Kung, Carol J. Bult, Malcolm A. Smith. Targeting MYB with REM-422 for the treatment of pediatric T-cell acute lymphoblastic leukemia - A report from the Pediatric Preclinical Testing Consortium (PIVOT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4030.