Fibroblast Growth Factor Receptor 1 Rearranged Myeloproliferative Neoplasm (MLN-FGFR1) in a Pediatric Patient; Challenging Diagnosis and Treatment Approach

Myeloproliferative neoplasms driven by Fibroblast Growth Factor Receptor 1 mutations (MLN-FGFR1) are rare, with less than 110 cases reported in literature worldwide^1,2. Chromosomal abnormalities at the 8p11 gene locus result in oncogenic fusion proteins involving FGFR1 that drive aggressive neoplasms that often progress into refractory leukemia. MLN-FGFR1 are defined by dysregulated function of tyrosine kinases and have historically been unresponsive to chemotherapeutic regimens, requiring allogenic hematopoietic stem cell transplant (HSCT) for durable remission^1-3. MLN-FGFR1 is exceedingly rare in the pediatric population and no clear guidelines exist for management. We present a therapeutic approach to a rare case of a 16-year-old with MLN-FGFR1. She presented with fatigue, weight loss, diffuse lymphadenopathy (cervical, mediastinal, axillary, inguinal), hepatosplenomegaly and petechiae concerning for acute onset leukemia/lymphoma. Initial laboratory evaluation demonstrated leukocytosis (WBC 60.4 k/mm³), anemia (Hgb 9.8 g/dL), thrombocytopenia (Plt 35 k/mm³), and eosinophilia (Eos 8.0%) with 6% abnormal cells on peripheral smear. Flow cytometry from peripheral blood demonstrated a blast population with immunophenotypic variability; 15.6% with myeloblast features and 2.6% with B-lymphoblast features. Bone marrow (BM) biopsy demonstrated 36% blasts by morphology with bilineage disease (B/myeloid). Lymph node biopsy demonstrated trilineage disease (T/B/myeloid) with 64% T-lymphoblast predominance. Cytogenetic evaluation revealed (8;13)(p11.2;q12) translocation [ZMYM2::FGFR1], which is the most common translocation associated with MLN-FGFR1⁴. FGFR1 translocation was evident by fluorescent in situ hybridization (FISH) in 96.5% of cells. She was also found to have RUNX1 mutation, which carries additional risk for progression of myeloid neoplasm and poor prognosis^4,5. Given her predominance of T-lymphoblastic disease, which is common in MLN-FGFR1, she was initiated on Induction therapy per Children's Oncology Group (COG) T-lymphoblastic lymphoma protocol AALL1231 [dexamethasone, vincristine, daunorubicin, asparaginase]. With initiation of therapy, she developed severe tumor lysis syndrome (TLS), resulting renal failure requiring initiation of dialysis, and ultimately mechanical ventilation for respiratory failure due to fluid overload. Once diagnosis was confirmed, a tyrosine kinase inhibitor was folded into therapy on Day 12 of Induction due to demonstrated efficacy in other MLN-FGFR1¹. Dasatinib was selected due to known safety in combination with pediatric chemotherapy backbones⁶. She had significant clinical improvement by Day 15 of Induction with near resolution of palpable lymphadenopathy, resolution of TLS and recovery of kidney and pulmonary function. End of Induction disease evaluation (Day 29) demonstrated 2.0% minimal residual disease (MRD) by BM morphology (myeloblasts, FGFR1 FISH positive 36%) and significant reduction in lymphadenopathy and hepatosplenomegaly on positron emission tomography (PET) compared to computed tomography (CT) at diagnosis. Given response to initial T-lymphoblastic therapy, decision was made to proceed with Consolidation per COG AALL1231 protocol. Mid-consolidation disease evaluation demonstrated 0.05% MRD by BM morphology (B-lymphoblasts, FGFR1 FISH positive 1%) and stability of lymphadenopathy and hepatosplenomegaly on PET. Due to high risk for refractory disease and poor prognostic markers, she will proceed to HSCT following completion of consolidation therapy while there is evidence of disease control. Transplant conditioning regimen will include total body irradiation (TBI), cyclophosphamide and thiotepa per institutional standard for acute lymphoblastic leukemia in first or second remission. Pemigatinib, an FDA-approved inhibitor of FGFR2, has demonstrated efficacy for durable cytogenetic response in adults with MPN driven by FGFR mutations^7,8. Pemigatinib will be used if needed as bridge to transplant, with plan to continue as monotherapy post-transplant for maintenance of remission. MPN-FGFR1 are rare especially in the pediatric population and present diagnostic and therapeutic challenges. We describe our approach to initial therapy and subsequent plan to manage this unique disease in an adolescent patient with a curative intent.

McCarty:Jazz Pharmaceuticals: Research Funding.

Pemigatinib is FDA approved for the treatment of FGFR1 rearranged MPN in adult patients. The off-label use in pediatrics is discussed in this abstract.