Long-term survival after luveltamab tazevibulin, a novel folate receptor-α (FRα) targeting antibody drug conjugate (ADC) in children with CBFA2T3::GLIS2 acute myeloid leukemia (AML).

e22007 Background: CBFA2T3::GLIS2 (CBF/GLIS2) rearranged AML is a highly refractory AML subtype arising in infants and young children. The CBF/GLIS2 fusion is associated with overexpression of FRα. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR = 4), which induces cytotoxic and immunologic cell death. Since 2021, luvelta was used alone or in combination with AML therapy to treat children with CBF/GLIS2 AML in the context of a compassionate use program. Data from the first 25 children were reported in December 2023 Blood 142 (Supplement 1): 4295. These children represent a heterogenic group with varying prior treatments and disease burden. They included 17 children who started luvelta with ≥5% bone marrow (BM) blasts and 8 children who had < 5% BM blast with persistent MRD positivity. Luvelta was mostly given at doses of 4.3 or 5.2 mg/kg every 2-4 weeks (4 received fractionated doses on days 1, 3, 5 per cycle). Out of 25 children, 21 received ≥ 1 dose of monotherapy initially, while 4 received combination with AML chemotherapy. All participants were followed for long-term survival. Objectives: Determine long-term overall survival (OS) in the first 25 children who received luvelta for CBF/GLIS2 AML. Methods: All clinical data was reported by compassionate use Investigators. OS was calculated from the date of the first dose of luvelta. Results: As of July 15, 2024, 7 of 25 children were alive, with a median OS of 8.8 months (95% confidence interval [CI] 5.3 -20.4). Among the 7 surviving children, 2 received luvelta as monotherapy while 5 received luvelta in combo either from the beginning of treatment or after failing monotherapy. Most of the deaths occurred in children who did not respond (N = 11) or recurred after luvelta (N = 5); two occurred post-transplant, 1 from progression and 1 from infection. Median OS was 9.7 months (95% CI 5.7-29.8) in the 21 children who received non-fractionated doses every 2 to 4 weeks. Overall, MRD negativity was achieved in 10 of the 25 children: the median OS was 29.8 months (95% CI 6.2-Not Reached [NR]) in those who became MRD negative and 5.3 months (95% CI 1.5-8.6) in those who did not. Nine children received hematopoietic stem cell transplants after morphologic and/or molecular response to luvelta. Post transplant median OS was 22.1 months (95% CI 1.8-NR). Five children received post-transplant maintenance. Conclusions: Luvelta alone or in combination with AML chemotherapy could achieve MRD negativity in more than one third of CBF/GLIS2 AML patients, allowing transplant and resulting survival of more than 2 years. Additional children have received luvelta through compassionate use since 2023 and the pivotal phase 1/2 trial for these patients is now open and enrolling (clinicaltrials.gov NCT06679582).