Long-term efficacy and safety of nilotinib therapy after imatinib failure in eosinophilic myeloproliferative neoplasm and ETV6-ABL rearrangement

Abstract

Dear Editor, The ETV6 gene, previously known as TEL, is a member of the ETS family of transcription factors located at 12p13. Its role in leukemogenesis was initially estabilished as a fusion partner to the PDGFR-beta gene in a case of chronic myelomonocytic leukemia with t (5;12)(q33;p13) [1]. The ETV6-ABL gene product has been demonstrated to have tyrosine kinase activity remarkably similar to that of BCR-ABL, despite the fusion partners for ABL being completely different [2]. Several studies proved the efficacy of imatinib for patients with hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL), especially in those who express the FIP1L1-PDGFRα fusion gene [3][4][5]. As development of resistance or intollerance to Imatinib in these patients may parallel that seen in chronic myeloid leukemia (CML), the evaluation of second-generation tyrosine kinase inhibitors (TKIs), such as nilotinib, has been reported [6]. However, to date, little is known on long-term efficacy and safety of secondgeneration TKIs after imatinib failure in patients with eosinophilic neoplasms.A 65-year-old male was found to have hemoglobin 13.0 g/dL, platelets 302×10 3 /μL, leukocytes 16.7×10 3 /μL, with 65 % neutrophilis, 3 % metamyelocytes, 3 % myelocytes, 10 % eosinophils, 8 % basophils, 8 % lymphocytes, and 3 % monocytes. The physical exam was negative. Bone marrow biopsy and aspirate were consistent with a chronic phase myeloproliferative neoplasm (MPN). Karyotype was 46,XY,t(9;12)(q34;p12); molecular analysis was negative for BCR/ABL and for rearrangements involving PDGFRα and β and FIP1L1 gene, while showing a fusion between ETV6 and ABL genes.

Myeloproliferative Neoplasm Driven by ETV6-ABL1 in an Adolescent with Recent History of Burkitt Leukemia

“…Definitive evidence of the prognostic influence of the ETV6-ABL1 fusion in haematological neoplasms is lacking; however, overall data suggests that it is a poor prognostic factor, particularly in patients with ALL and AML [1,12]. There also are no definitive data to standardize the treatment for ETV6-ABL1 MPNs, although multiple reports advocate for the early introduction of first and/or second generation TKIs [13][14][15]. Recently, Zhang et al published a retrospective series of 42 adult patients with a confirmed myeloproliferative neoplasm associated with eosinophilia and a tyrosine kinase gene fusion.…”

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

“…We identified an additional 14 cases in the literature [16–27,53,54] with adequate data on response on TKI and follow‐up. In concordance with our findings, imatinib can induce but not maintain long‐term remissions 25 . Unfortunately, only limited data on TK‐domain mutations are available which might explain the lack of response to and early progression on imatinib.…”

“…Beside ALL, the phenotype may resemble in adults a myeloid neoplasm such as atypical chronic myeloid leukemia (aCML), chronic eosinophilic leukemia (CEL), myelodysplastic/myeloproliferative neoplasm unclassified (MDS/MPN‐U) or MPN‐U which are diagnosed in CP or BP. However, data on treatment and response to ABL1 inhibitors such as imatinib, nilotinib or dasatinib are limited to case reports or small cases series 16‐27 …”

“…We therefore sought to evaluate the clinical characteristics and response to various TKI in 18 patients with myeloid neoplasms and associated PCM1‐JAK2 , BCR‐JAK2 or ETV6‐ABL1 fusion genes. In an extended analysis, we integrated our data into the reports of 40 patients with JAK2 fusion genes ( PCM1‐JAK2 , n = 28) 8,9,12‐15,28‐40 or BCR‐JAK2 (n = 12) 41‐52 and 14 patients with TKI‐treated ETV6‐ABL1 positive chronic myeloid neoplasms 16‐27,53,54 . This analysis provides a comprehensive overview of responses to TKIs in patients with these rare fusions.…”