Myeloid/Lymphoid Neoplasms (MLNs) with Fibroblast Growth Factor Receptor 1 (FGFR1) Rearrangement (MLN^FGFR1): A US Real-World Retrospective Cohort Study

Background: Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN^FGFR1), also known as 8p11 myeloproliferative syndrome, is an aggressive hematologic malignancy comprising a range of presentations that share a characteristic FGFR1 rearrangement at the 8p11 locus. Currently, 16 known FGFR1 fusion partners account for the phenotypic diversity. Presentations include bone marrow (BM) involvement by chronic phase myeloid disease or blast phase (BP) myeloid, lymphoid, or mixed lineage disease, which may be accompanied by extramedullary BP disease; patients (pts) may also have extramedullary involvement only. 8p11 translocations are usually detected by karyotyping, and FGFR1 rearrangement is confirmed with fluorescent in situ hybridization (FISH) using break-apart probes for FGFR1. FGFR1 rearrangements may also be detected with next-generation sequencing (NGS) or real-time polymerase chain reaction (RT-PCR). Eosinophilia is not required for diagnosis, but its presence can be a diagnostic clue. MLN^FGFR1 is associated with poor clinical outcomes, with allogeneic stem cell transplant (ASCT) the only potential cure. This real-world study describes baseline characteristics, treatment patterns, and clinical outcomes of 33 confirmed cases in US community practices.

Methods: This was a retrospective, multisite, physician-abstracted chart review conducted in 2 phases within the Cardinal Health Oncology Provider Extended Network (OPEN; data collection: phase 1, 5/29/2020-6/23/2020; phase 2, 12/29/2020-3/4/2021). Eligible pts had to be ≥18 y old at diagnosis; diagnosed with myeloproliferative neoplasm (MPN) unclassified, myelodysplastic syndrome (MDS)/MPN, precursor T- or B-cell lymphoblastic leukemia/lymphoma, post-MPN acute myeloid leukemia (AML), or mixed-phenotype acute leukemia; had BM results available and cytogenetic testing performed. In phase 1, physicians abstracted medical records from eligible pts. Cases were considered probable MLN^FGFR1 if physicians reported detection of an FGFR1-associated translocation and/or FGFR1 rearrangement. In phase 2, demographic/clinical characteristics, treatment, outcomes, and diagnostic/genetic testing results of probable cases were collected. Based on data abstracted from karyotyping, break-apart FISH testing, NGS, and/or RT-PCR testing reports, a subset of probable cases was confirmed as MLN^FGFR1. Cases with inconclusive tests and/or without detection of an 8p11 translocation or FGFR1 rearrangement were excluded.

Results: 560 cases with myeloid/lymphoid malignancies were reviewed and 51 probable cases were identified in phase 1. Among probable cases, 33 pts managed by 12 physicians were confirmed as MLN^FGFR1 in phase 2.

Among the 33 confirmed cases, mean (SD) age at initial MLN diagnosis was 65.9 (13.5) y; 60.6% were male; 63.6% were White, 18.2% Asian, and 15.2% Black. FGFR1-associated translocations were detected by karyotyping in 72.7% of pts and FGFR1 rearrangement was detected by break-apart FISH, NGS, and/or RT-PCR in 66.7%, 21.2%, and 6.1% of pts, respectively. Rearrangement was detected in BM aspirate in 90.9% of pts and in peripheral blood in 9.1%. The most commonly reported partner fusion gene was ZMYM2, observed in 18.2% of pts.

Median (IQR) follow-up since MLN diagnosis was 11.7 (7.9-26.6) mo. Overall, 97.0% of pts initiated therapy, 96.9% of whom received a total of 1 line of therapy at last encounter. Median (IQR) time from initial diagnosis to treatment initiation was 1.9 (1.0-3.0) wk; median (IQR) duration of first-line therapy was 33.4 (23.5-42.1) wk. Only 3 pts underwent ASCT; one had disease relapse after 54.4 wk. Disease progression/transformation to AML was reported in 1 of 18 pts with initial MPN unclassified or MDS/MPN diagnoses. Among 23 pts alive at last encounter, 69.6% remained on active therapy, 17.4% had received palliative treatment, and 8.7% were in remission. Among 10 pts who were deceased at end of study, median (IQR) survival from initial MLN diagnosis was 8.3 (5.4-9.2) mo.

Conclusions: This retrospective chart review demonstrated that, although MLN^FGFR1 is rare, pts with this malignancy will present in US community practice settings. As effective targeted therapies become available, this diagnosis should be considered in pts with congruent presentations and 8p11 translocations on conventional cytogenetics and/or evidence of FGFR1 rearrangement on other molecular testing.

Parasuraman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Teschemaker:Incyte Corporation: Ended employment in the past 24 months. Kish:Cardinal Health Specialty Solutions: Ended employment in the past 24 months. Savill:Daiichi Sankyo: Consultancy; Janssen: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; Incyte: Consultancy; Morphosys: Consultancy; Cardinal Health: Current Employment, Current holder of stock options in a privately-held company; Genentech: Ended employment in the past 24 months; Pfizer: Consultancy. Colucci:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company.