Successful first-line use of pemigatinib in myeloid/lymphoid neoplasm with FGFR1 rearrangement: Clinical insights Free

Introduction Myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement (MLN^FGFR1) comprise a heterogeneous group of rare, aggressive hematologic malignancies, caused by chromosomal translocations involving the 8p11 locus that result in the formation of tyrosine kinase fusion genes, ultimately leading to constitutive activation of FGFR1 and downstream signaling pathways. MLN^FGFR1 typically exhibit overlapping features of myeloproliferative neoplasms (MPNs), acute leukemias, and lymphoid malignancies, usually accompanied by eosinophilia. Although the disease usually follows an aggressive course with poor response to conventional chemotherapy or tyrosine kinase inhibitors (TKIs), such as imatinib, and allogeneic stem cell transplantation (allo-SCT) is required for long-term disease control, the development of targeted FGFR inhibitors has revolutionized treatment options. Pemigatinib, a potent selective inhibitor of FGFR1, has displayed promising activity and is now approved for the treatment of relapsed/refractory (R/R) MLN^FGFR1. We report a case of MLN^FGFR1, which was successfully treated with first-line pemigatinib.

Case summary A 69-year-old woman with a history of hyperlipidemia presented to the outpatient department with leukocytosis (white blood cell count: 34.2x10⁹/L) and elevated hemoglobin level (Hb: 16 g/dL), which were found during routine laboratory testing. Clinical examination revealed palpable cervical, axillary, and inguinal lymph nodes. Examination of a peripheral blood smear showed marked eosinophilia and a left shift. Molecular testing for BCR-ABL1 and JAK2 was negative. A positron emission tomography/computed tomography (PET/CT) demonstrated widespread hypermetabolic lymphadenopathy. A bone marrow biopsy revealed increased megakaryocytes, some with atypical forms, and a moderate increase in eosinophils, suggestive of MPN, whereas a biopsy of an axillary lymph node revealed the presence of T-lymphoblastic leukemia/lymphoma. Conventional cytogenetics and fluorescence in situ hybridization in a bone marrow sample demonstrated a t(8;13)(p11;q12) rearrangement, which results in the ZMYM2::FGFR1 fusion, thus confirming the diagnosis of MLN^FGFR1. The patient was started on pemigatinib at 13.5 mg daily, in combination with intrathecal therapy for central nervous system prophylaxis. Normalization of blood counts was observed within two weeks, and no palpable lymphadenopathy was noted at four weeks. Side effects included fatigue, hand-foot syndrome, nail changes, alopecia, dry eyes, and grade 2 hyperphosphatemia, which was managed with sevelamer and by reducing the dose to 9 mg daily. Due to grade 2 serous retinopathy, pemigatinib was interrupted and resumed at 4.5 mg daily. A repeat PET/CT at three months showed no evidence of metabolically active disease. Four months after pemigatinib initiation, the patient remains in complete remission.

Discussion The treatment of MLN^FGFR1remains challenging due to their aggressive nature, variable clinical presentation, and limited response to available treatments. Although management of other MLNs has been radically changed with the employment of TKIs, outcomes in MLN^FGFR1patients remain poor. Outcomes with conventional approaches, such as lineage-specific cytotoxic chemotherapy with or without multi-kinase inhibitors that display anti-FGFR1 activity, are suboptimal. Although allo-SCT remains the only curative option, older adults or those with comorbidities are not suitable candidates, whereas relapse rates are high, even among transplanted patients. Emergence of agents targeting the underlying molecular driver of MLN^FGFR1 has provided a novel treatment option. Pemigatinib has displayed high response rates in R/R MLN^FGFR1and is the only drug approved in this setting. Although the patient experienced multiple adverse events (AEs), consistent with reported AE rates, treatment was well tolerated, and toxicity was manageable.

Conclusion This case underscores the potential use of pemigatinib as a frontline treatment in MLN^FGFR1, particularly in patients unfit for intensive chemotherapy or allo-SCT. It also highlights the importance of early molecular diagnosis to enable timely and targeted treatment in these aggressive neoplasms, which may lead to complete metabolic responses. Molecular response with RT-qPCR for FGFR1 would be the next goal in the management of patients with MLN^FGFR1.