Myeloid/lymphoid neoplasm with ZMYM2::FGFR1 rearrangement: A complex trilineage phenotypic and clonal evolution with associated genomic alterations.

We report a case of myeloid/lymphoid neoplasm with ZMYM2::FGFR1 rearrangement (MLNZMYM2::FGFR1) exhibiting a complex disease evolution. This neoplasm initially presented as T-lymphoblastic lymphoma (T-LBL) in lymph node and myeloproliferative neoplasm (MPN) with eosinophilia in bone marrow, then transitioned to systemic mastocytosis (SM) likely accompanied by additional JAK3 and other mutations and finally transformed to acute myeloid leukemia (AML) accompanied by additional/secondary genetic abnormality (gain of chromosome 21, der(13)t(8;13), and RUNX1 mutation). To our knowledge, this is the first case of MLNZMYM2::FGFR1 with a complex trilineage/phenotypic [T-cell (T-LBL), mast cell (SM), and myeloid (MPN and AML)] lineage evolution.

Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement.

INTRODUCTION: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangements (MLNFGFR1) are rare entities with aggressive features and poor prognosis. Presentation is heterogeneous, ranging from myeloproliferative neoplasms (with or without eosinophilia) to T-cell lymphoma and acute leukemia. Historical treatments have been guided by the presenting phenotype with induction chemotherapy frequently used. Pemigatinib is a FGFR1-3 tyrosine kinase inhibitor that has demonstrated high complete hematologic and cytogenetic response rates in MLNFGFR1. AREAS COVERED: We discuss the pathogenesis, presentation, and historical treatments for MLNFGFR1, in addition to clinical data using pemigatinib and other targeted therapies. Discussion of the mechanism of action and adverse events is also included. EXPERT OPINION: Pemigatinib represents a significant advance in the management of MLNFGFR1. High rates of complete hematologic and cytogenetic response have been observed. While direct comparative data are unavailable, outcomes appear favorable compared to conventional approaches. Long-term efficacy and tolerability are not yet known, and allogeneic hematopoietic stem cell transplant (alloHSCT) continues to be the treatment with the highest chance of long-term disease free survival in responding patients. Combinations of pemigatinib and chemotherapy, particularly for more aggressive phenotypes, warrant future investigation as does the use of pemigatinib maintenance following alloHSCT.

Synergetic effect of Azacitidine and Sorafenib in treatment of a case of myeloid neoplasm with sole chromosomal abnormality t(8;22)(p11.2;q11.2)/BCR-FGFR1 rearrangement.

The sole t(8;22)(p11.2;q11.2)/BCR- FGFR1 chromosomal abnormality formerly known as aCML is an extremely rare disease entity with a history of rapid progression. Though patients resemble phenotypically chronic myeloid leukemia, the treatment of patients with sole BCR-FGFR1 rearrangement are still challenging for clinicians due to rapid progressive nature and unavailability of uniform treatment guidelines. In present case study, we describe a case of myeloid neoplasm with sole chromosomal abnormality of t(8;22)(p11.2;q11.2)/BCR-FGFR1 rearrangement which is successfully managed by Sorafenib with Azacitidine. Hence our case report suggests that combination of Sorafenib and Azacitidine treatment is effective in sole BCR-FGFR1 rearrangement, however this combination therapy should be studied in large clinical trials.

Myeloid/lymphoid neoplasm with eosinophilia and BCR/FGFR1 rearrangement with transformation to cortical T-lymphoblastic lymphoma and erythroid precursors: a case report.

BACKGROUND: Myeloproliferative neoplasms are a group of diseases with diverse biological and clinical characteristics. As a provisional separate entity, myeloid/lymphoid neoplasms with eosinophilia and genetic rearrangement have been described, which may present an initial clinical behavior of myeloproliferation and be characterized by varied genetic rearrangements. One of these entities is associated with FGFR1 rearrangements, characterized by its low prevalence and few treatment options. CASE PRESENTATION: We present the case of a 53-year-old Mestizo male patient of Hispanic origin who initially presented weight loss and fatigue, with a complete blood count showing leukocytosis and eosinophilia, with an initial diagnosis of nonspecific myeloproliferative disorder. In a next-generation sequencing study, BCR::FGFR1 rearrangement was documented, a diagnosis of myeloid/lymphoid neoplasia with eosinophilia and BCR::FGFR1 rearrangement was made, and hydroxyurea therapy was initiated. Subsequently, transformation to cortical T-lymphoblastic leukemia/lymphoma and erythroid precursors was documented, requiring management with chemotherapy. CONCLUSIONS: Myeloid/lymphoid neoplasms with eosinophilia and genetic rearrangements constitute a group of deeply heterogeneous diseases with variable clinical and diagnostic characteristics and whose treatment is not clearly defined.

The 8p11 myeloproliferative syndrome: Genotypic and phenotypic classification and targeted therapy.

EMS(8p11 myeloproliferative syndrome, EMS) is an aggressive hematological neoplasm with/without eosinophilia caused by a rearrangement of the FGFR1 gene at 8p11-12. It was found that all cases carry chromosome abnormalities at the molecular level, not only the previously reported chromosome translocation and insertion but also a chromosome inversion. These abnormalities produced 17 FGFR1 fusion genes, of which the most common partner genes are ZNF198 on 13q11-12 and BCR of 22q11.2. The clinical manifestations can develop into AML (acute myeloid leukemia), T-LBL (T-cell lymphoblastic lymphoma), CML (chronic myeloid leukemia), CMML (chronic monomyelocytic leukemia), or mixed phenotype acute leukemia (MPAL). Most patients are resistant to traditional chemotherapy, and a minority of patients achieve long-term clinical remission after stem cell transplantation. Recently, the therapeutic effect of targeted tyrosine kinase inhibitors (such as pemigatinib and infigratinib) in 8p11 has been confirmed in vitro and clinical trials. The TKIs may become an 8p11 treatment option as an alternative to hematopoietic stem cell transplantation, which is worthy of further study.

Myeloid/lymphoid neoplasms with FGFR1 rearrangement.

Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare entity. We present a multicenter experience of 17 patients with FISH-confirmed FGFR1 rearrangement. The clinical presentation at diagnosis included myeloproliferative neoplasm (MPN) in 4 (24%) patients, acute leukemia (AL) in 7 (41%), and concomitant MPN with AL in 6 (35%). The two most frequently observed cytogenetic abnormalities were t(8;13)(p11.2;q12)(partner gene ZMYM2) and t(8;22)(p11.2; q11.2)(BCR). Seventy-eight percent of tested patients had a RUNX1 mutation, of whom all had AL. Overall response rate to frontline therapy was 69%, and 76% of patients subsequently received allogeneic stem cell transplant (ASCT). After a median follow-up of 11 months, median progression-free survival was 15 months and median overall survival was not reached. In conclusion, FGFR1-rearranged hematologic malignancies present with features of MPN and/or AL. FGFR1 and RUNX1 are therapeutic targets for ongoing and future clinical trials.

Myeloproliferative neoplasms with t(8;22)(p11.2;q11.2)/BCR-FGFR1: a meta-analysis of 20 cases shows cytogenetic progression with B-lymphoid blast phase.

Rearrangements of FGFR1 result in the 8p11 myeloproliferative syndrome, a group of rare diseases that features a myeloproliferative neoplasm (MPN) that commonly progresses to lymphoblastic leukemia/lymphoma or acute myeloid leukemia. The most common partner of FGFR1 is ZMYM2, and patients with the ZMYM2-FGFR1 fusion often present with MPN and T-lymphoblastic lymphoma. There are 14 other partners that can fuse with FGFR1, and of interest is the BCR-FGFR1 fusion that results from t(8;22)(p11.2;q11.2). Patients with t(8;22) often show leukocytosis and present with an MPN resembling chronic myeloid leukemia or very rarely, with B-lymphoblastic leukemia (B-ALL). In this study, we analyzed the clinicopathological, cytogenetic, and molecular features of 2 new patients with the t(8;22)(p11.2;q11.2)/BCR-FGFR1 who presented with B-ALL. An underlying MPN became apparent when a morphologic remission of B-ALL was achieved after chemotherapy. We subsequently reviewed the literature and identified 18 additional cases reported with B-ALL in a background MPN or with the MPN as a chronic phase. Our data suggest that the t(8;22)(p11.2;q11.2)/BCR-FGFR1 may arise from a myeloid/B progenitor cell. It is important to recognize that neoplasms carrying the t(8;22)/BCR-FGFR1, although rare, can commonly with B lymphoblastic leukemia at the initial diagnosis, which could distract one from recognizing a possible underlying 8p11 myeloproliferative syndrome.