Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase.

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia,

Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene.

BACKGROUND AND OBJECTIVES: We sought to identify new fusion genes with involvement of the platelet-derived growth factor receptor beta gene (PDGFRB) in three patients presenting with various subtypes of chronic myeloproliferative disorders associated with chromosomal aberrations involving chromosome bands 5q31-33. DESIGN AND METHODS: We performed 5 rapid amplification of cDNA ends (5 -RACE)-polymerase chain reaction (PCR) with RNA/cDNA derived from a patient (case #1) with a t(5;12)(q31-33;q24) and a second patient (case #2) with a complex rearrangement involving chromosomes 1, 5 and 11. A newly developed DNA-based long-distance inverse PCR (LDI-PCR) was performed on a third patient (case #3) with a t(4;5;5)(q23;q31;q33). RESULTS: In cases #1 and #2, we identified mRNA fusions between GIT2 exon 12 and GPIAP1 exon 7, respectively, and PDGFRB exon 11. In case #3, LDI-PCR revealed a fusion between PRKG2 exon 5 and a truncated PDGFRB exon 12. The region encoding the catalytic domain of PDGFRbeta is retained in all three cases, with the partner contributing a coiled-coil domain (GPIAP1, PRKG2) or an ankyrin protein interaction motif (GIT2) that may potentially lead to dimerization and constitutive activation of the fusion proteins. Treatment with imatinib (400 mg/day) has led to sustained complete hematologic remission in all three patients. INTERPRETATION AND CONCLUSIONS: These data provide further evidence that numerous partner genes fuse to PDGFRB in BCR-ABL negative chronic myeloproliferative disorders. Although these fusion genes occur rarely, their identification is essential in order to detect patients in whom targeted treatment with tyrosine kinase inhibitors is likely to be successful.