Limited Efficacy of Ponatinib in Myeloproliferative Neoplasms Associated with FGFR1 Fusion Genes

The WHO classification (2008) defines "myeloid/lymphoid neoplasm with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1" as a rare subtype of myeloid neoplasms. Whilst patients with PDGFRA or PDGFRB rearrangements respond very well to imatinib, the optimal therapy for patients with FGFR1 rearrangements, which we refer to as FGFR1 fusion gene positive MLN-eo (FGFR1⁺ MLN-eo), remains to be defined. Encouraging in-vitro data using inhibitors of the FGFR1 tyrosine kinase prompted the implementation of ponatinib, which inhibits FGFR1, into therapeutical strategies. In a recent report, the clinical activity of ponatinib was reported in a single patient who concomitantly received high-dose chemotherapy and allogeneic stem cell transplantation (ASCT, Khodadoust et al, Leukemia 2015). We sought to evaluate efficacy of ponatinib in seven consecutive FGFR1⁺ MLN-eo patients. Median age was 52 years (range, 48-74) with a male predominance (n=5). Median observation time after diagnosis was 10 months (range, 5-36). All patients presented with left-shifted leukocytosis but only three patients [all with t(8;13)] had eosinophilia of >0.5 x 10⁹/l. Bone marrow biopsy revealed a hypercellular marrow consistent with myeloproliferative neoplasm in all patients. Five patients presented with concomitantly diagnosed lymphoid neoplasms, i.e. T-lymphoblastic lymphoma (T-LBL, n=3), biclonal accelerated phase (n=1) or lymphoid blast phase of MPN/B-cell acute lymphoblastic leukemia (B-ALL, n=1). Cytogenetic analysis revealed a reciprocal translocation with involvement of chromosome band 8p11 in all patients [t(8;13)(p11;q12), n=3; t(8;22)(p11;q11), n=2; t(1;8;22)(?;p11;q11), n=1; t(6;8)(q27;p11), n=1]. On molecular level, RT-PCR identified the associated fusion genes ZMYM2-FGFR1 (n=3), BCR-FGFR1 (n=3), and FGFR1OP-FGFR1 (n=1), respectively. In one patient with T-LBL, the FGFR1 rearrangement was revealed by FISH analysis in 80% of lymph node cells indicating an origin of both MPN and T-LBL from the same progenitor/stem cell (myeloid/lymphoid stem cell neoplasm) and T-LBL as a feature of extramedullary lymphoid blast phase. All patients were initially treated with chemotherapy-based regimens including hydroxyurea (n=4) and/or high-dose chemotherapy (n=3), the latter exclusively in patients with concomitant aggressive lymphoid neoplasms. Lack of complete response, e.g. persisting features of MPN, relapse or progression led to the off-label use of ponatinib at a dose of 30mg/day (n=2) or 45mg/day (n=5). Median duration of treatment was 8 weeks (range, 2-52). A temporary partial hematologic response (control of peripheral blood cell count) was observed in 6 of 7 patients. One patient did not respond at all and died within a few weeks while on ponatinib due to progressive disease. Three of the 6 responders had cytogenetic analysis at a median of 3 months after the start of ponatinib. One patient with t(8;13) achieved a partial cytogenetic response (50% of metaphases positive after 3 months of treatment); in all other patients no cytogenetic response was observed. Four patients underwent ASCT and are in complete molecular remission and alive after a median time of 19 months (range, 8-36) after diagnosis and 13 months (range, 4-29) after ASCT. For one patient with BCR-FGFR1-positive MLN-eo without concomitant lymphoid disease ASCT is planned. One patient is on supportive care. Conclusion: Unexpectedly, response to standard dose ponatinib in FGFR1⁺ MLN-eo has been poor. There was either progressive disease or no evidence for sustained hematologic or cytogenetic response. However, there was also no evidence for a sustained complete remission on intensive chemotherapy in patients with full myeloid/lymphoid phenotype. Hence, ASCT currently remains the only option to achieve long-term remission and possibly cure in FGFR1⁺ MLN-eo.