Identification of TPR::FGFR1 fusion in an unusual case of concurrent acute B lymphoblastic leukemia and T-lymphoblastic lymphoma: Case report and review of literature

Abstract Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLNAF) are rare, with only approximately 100 cases reported worldwide.1 A wide range of clinical manifestations have been reported at the time of presentation, which are then characteristically followed by an aggressive clinical course, often with progression to acute myeloid leukemia (AML) within 1-2 years.2 The most commonly reported initial phenotypes include eosinophilia with features suggestive of MPN in bone marrow7. While patients may also present with T-cell lymphoblastic lymphoma (T-LBL), myelodysplastic syndrome (MDS), and B-cell acute lymphoblastic leukemia (B-ALL)1-3, a mixed B and T-cell neoplasm upon initial diagnosis is very rare4, as was seen in our patient. At least 13 gene rearrangement partners of FGFR1 have been described, most commonly t(8;13)(p11;q12), involving the MYM2 gene, which is reported in 50% of MLNAF cases.7 Rarely, the fusion partner of FGFR1 is TPR, which has been described in fewer than 10 cases. Of these reported cases with FGFR1::TPR fusion, the patients initially presented with MPN and/or AML .1,7,8 RUNX1 mutations are strongly associated with FGFR1 rearrangement, likely due to increased proliferation of the clone with FGFR1 fusion, which then contributes to disease progression.3,5,6 Concurrent B/T lymphoblastic leukemia is very rare and comprises approximately 4% of mixed phenotype acute leukemias (MPAL).10Although lymph node involvement has been reported in MPAL with T-lineage differentiation, most cases represent as biphenotypic leukemia with predominantly single blast population in the bone marrow expressing both B and T-lineage specific immunophenotype.11,12. We describe the first case of TPR:FGFR1 fusion arising in myeloid neoplasm post-cytotoxic therapy in a patient with concurrent B-ALL and T-LBL. This patient initially presented with mild leukocytosis and was noted to have lymphadenopathy and splenomegaly. He was diagnosed with T-lymphoblastic lymphoma (positive for T cell markers CD1A and TDT; negative for PAX5) off of an inguinal lymph node biopsy, with concurrent diagnosis of B lymphoblastic leukemia found in the bone marrow (positive for CD19, CD10, TdT, and PAX5). The bone marrow chromosomal analysis revealed a complex karyotype at the time of diagnosis: t(1;14), +8; + 21. Molecular testing identified a RUNX1 mutation (VAF 28.5%), as well as NF-1 and SH2B3 alterations. No FGFR1 mutation was detected. Peripheral blood flow cytometry revealed a minute population of B lymphoblasts but no circulating T lymphoblasts. The patient was treated with Children's Oncology AALL 0434 protocol but was switched to HyperCVAD after 1 cycle due to refractory disease. He continued to be MRD positive after 6 cycles of treatment and was switched to Blinatumumab. Bone marrow biopsy after 1 cycle of Blinatumumab showed 11% myeloblasts concerning for therapy related myelodysplastic syndrome with excessive blasts, so he was started on azacitadine and venetoclax. His WBC count and blasts continued to rise despite treatment and repeat bone marrow biopsy showed a new TPR:FGFR1 rearrangement in addition to MECOM:MNBL1 fusion, so he was transitioned to Pemigatinib with plan to proceed with allogenic stem cell transplant. He received FLAG-Ida-Ven followed by bone marrow transplant but passed away approximately two months later due to disease progression.We describe and review literature on the first case of TPR:FGFR1 fusion arising post-cytotoxic therapy in a composite nodal T-LBL and bone marrow B-ALL.