Gatekeeper V561M mutations as a mechanism of resistance to relapsed/refractory hematologic malignancies treated with Pemigatinib

Pemigatinib was approved in 2022 for treatment of relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Preclinical studies identified V561M as a gatekeeper mutation in the FGFR1 kinase domain, leading to increased PI3K/AKT signaling via PTEN inactivation. We describe two patients with hematologic malignancies treated with pemigatinib who experienced subsequent disease progression upon acquisition of FGFR1 V561M mutations.

Patient 1 is a 53 yo man found to have neutrophilia with left shift with mild eosinophilia during an unrelated hospitalization. Bone marrow (BM) demonstrated 10% myeloblasts and a BCR-FGFR1 rearrangement, consistent with a diagnosis of myeloid/lymphoid neoplasm with eosinophilia and FGFR1 fusion. Multiple extramedullary paraspinal masses were evident on CT imaging. He began treatment with single agent Pemigatinib, achieving complete remission in BM and extramedullary sites. Two months later, a pre-transplant BM evaluation demonstrated progression to AML, with FGFR1 V561M mutation evident on molecular sequencing. He was salvaged with HiDAC+mitoxantrone and has survived 18 months since allograft without maintenance therapy.

Patient 2 was a 58 yo male initially diagnosed with B-cell acute lymphoblastic leukemia who received induction with conventional chemotherapy but experienced multiple relapse episodes, ultimately treated with brexucabtagene autoleucel. Post-brexu-cel relapse occurred 5 months after infusion with a mixed phenotype acute leukemia (MPAL) harboring a BCR::FGFR1 fusion. He was successfully salvaged with azacitidine, venetoclax and pemigatinib. Two months later, he experienced another lineage switch episode, developing T-ALL without molecular or immunophenotypic evidence of prior B-ALL or MPAL. An FGFR1 V561M mutation was detected at the time of T-ALL development. He expired shortly thereafter due to stroke.

To our knowledge, these are the first clinical descriptions of acquired V561M escape variants to pemigatinib treatment in patients with hematologic malignancies. These findings highlight the utility of longitudinal molecular sequencing in patients receiving pemigatinib and may inform development of next-generation kinase inhibitors.