Targeted FGFR inhibition results in a durable remission in an FGFR1-driven myeloid neoplasm with eosinophilia

Abstract

<jats:title>Key Points</jats:title> <jats:p>A novel PCM1-FGFR1 gene rearrangement was identified in a patient with a myeloid neoplasm with eosinophilia. Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, resulted in a durable complete hematologic and cytogenetic remission.</jats:p>

Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells

“…Significant amount of this receptor is expressed on the plasma membrane of three different t(4;11) leukemia cell lines, i.e., RS4;11, MV4-11, and SEM ( Figure 1 A). FGFRs are involved in multiple myeloma, in myeloproliferative disorder, and, importantly, in B-cell precursor (BCP) ALL, the latter including the MLL-rearranged leukemias, thereby supporting their crucial role in hematologic malignancies [ 40 , 41 , 42 ]. Interestingly, FGFR signaling can contribute to prednisolone resistance in BCP ALL cells; however, as activating mutations in this RTK family are very rare, information concerning their role in ALL is limited [ 41 ].…”

Mechanisms of resistance to FGFR1 inhibitors in FGFR1-driven leukemias and lymphomas: implications for optimized treatment

“…The next generation of more specific drugs, largely only targeting the FGFR family, included ponatinib, which was originally developed to target the mutant BCR-ABL rearrangement in CML [46] but showed a reasonable specificity for FGFR1 at lower concentrations. In one case, after showing chemotherapy resistance, partial remission was achieved using ponatinib [32] , although other studies suggested it was less effective [6] . Recently more successful remission was achieved using pemigatinib on a single patient with a t(8;9) rearrangement, although the patient died of unrelated complications [7] .…”

“…As a result, our understanding of its pathobiology has been limited and conducting clinical trials has been challenging. Consequently, the majority of case reports describe only a single patient with limited molecular analysis and, where drug treatments were reported only single cases were involved [ 7 , 22 , 31 – 33 ] . To overcome these limitations, several groups have developed murine models of the disease to study the genetic changes responsible for transformation of the hematopoietic stem cell and to investigate the use of molecularly targeted therapies in suppressing the disease without the limitations of incidence and variable diagnosis imposed in human populations.…”

“…This syndrome is characterized cytogenetically by the presence of reciprocal chromosome translocations that invariably involve 8p11, often as the only cytogenetic abnormality [4] , and is the only example of a malignancy that always involves abnormalities of FGFR1. At least 15 different chromosome translocations have been associated with this syndrome [5][6][7] but the invariant features are the translocation breakpoints occurring in intron 8 of FGFR1, just upstream of the kinase domain, and the presence of a dimerization/oligomerization domain in the partner translocated gene [Figure 1]. The most common rearrangements are t(8;13)(p11;q12), t(8;22)(p11;q11) and t(8;9)(p12;q33) giving rise to ZMYM2-FGFR1, BCR-FGFR1 and CNTRL-FGFR1 fusion kinases respectively.…”

“…This syndrome has since been classified by the WHO [10] as myeloid and lymphoid malignancies associated with eosinophilia and FGFR1 rearrangement (MLN-eo FGFR1). Because of phenotypic overlap in clinical presentation, rearrangements involving PDGFRA and PDGFRB were added to the sub-classification [10,11] , although there are still important clinical differences between each subgroup [6] .…”