Clinical Characteristics and Treatment with Various Tyrosine Kinase Inhibitors in Patients with ETV6-ABL1 positive Eosinophilia-Associated Myeloproliferative Neoplasms
Authors: Reiter Andreas , Ahmadova Gunay , Jawhar Mohamad , Virchis Andres , Somervaille Tim , Williams Mark , Schönberger Bernd , Frewin Rebecca , Jost Philipp J. , Maschke Annett , Keller Peter , Haferlach Torsten , Naumann Nicole , Schwaab Juliana , Fabarius Alice , Hofmann Wolf-Karsten , Haferlach Claudia , Cross Nicholas C.P. , Metzgeroth Georgia 
Published: October 2019

Abstract
The ETV6-ABL1 fusion gene, as consequence of a t(9;12)(q34;p13), is a rare but recurrent genetic aberration found in chronic or blast phase of eosinophilia-associated myeloproliferative neoplasms (MPN-eo) and de novo acute B-cell lymphoblastic leukemias (B-ALL) or lymphoblastic T-cell lymphomas (T-LBL). Here, we sought to evaluate a) relevant clinical characteristics, b) treatment options and c) survival in 7 ETV6-ABL1 positive patients (male, n=4; median age 46 years; range 20-61). Cytogenetic analyses revealed a conventional reciprocal translocation t(9;12)(q34;p13) in 3 cases, an ins(12;9)(p13;q34q22) and a normal karyotype in one patient each, and a complex karyotype in 2 patients. In all cases, ETV6-ABL1 was confirmed by FISH analysis and/or RT-PCR. Histopathological diagnoses of the hypercellular bone marrow (BM) included atypical chronic myeloid leukemia (n=3), MPN-eo (n=3, concomitant T-LBL in one patient) or chronic myelomonocytic leukemia (n=1). In peripheral blood, all patients presented with left shifted leukocytosis (median 84 x 109/l, range 21-143) and significant (>1.5 x 109/l) eosinophilia (median 6.1 x 109/l, range 2.0-7.1) but without increased blast cells. Splenomegaly was present in 60% of patients. After a median of 3 months (range 0-6) from diagnosis, all patients were treated with a TKI (imatinib, n=5; dasatinib, n=1; nilotinib, n=1) at standard doses. On dasatinib (#2) or nilotinib (#3), 2 patients achieved a complete hematologic remission (CHR) within 3 months and complete cytogenetic remission (CCR) after 5 months (#3) or complete molecular remission (CMR) after 18 months (#2), respectively (Figure). On imatinib (n=5), 2 of 5 patients (#4 and #5) achieved a CHR within 3 months with loss of CHR after 9 (#4) and 5 months (#5), respectively. Patient #4 developed a myeloid sarcoma. After local radiation, he received an allogeneic stem cell transplant (SCT) but died 8 months later due to GvHD while in CMR. Patient #5 switched to nilotinib and achieved a CCR and CMR after 3 and 10 months, respectively. Patient #1 has not achieved a significant response after 4 months on imatinib. Patient #6 showed progressive disease within 2 months on imatinib, but achieved a rapid CHR and durable CCR and CMR on dasatinib after 13 and 14 months, respectively. Patient #7 presented with a classical myeloid/lymphoid (T-LBL) neoplasm with eosinophilia (MLN-eo) according to the WHO classification. On imatinib, a regression of lymphadenopathy, but persistence of leukocytosis and eosinophilia was observed. With increasing leukocytosis and reappearance of lymphadenopathy, the patient was switched to dasatinib (9 months), followed by nilotinib (2 months). The responses were only partial and transient and the patient died 23 months after diagnosis with myeloid blast phase (secondary acute myeloid leukemia). Overall, after a median treatment time of 22 months (range, 3-58), 4 patients are in CCR (n=1, patient #3) or CMR (n=3; patients #2, #5, #6) while on a second generation TKI and two patients (#4, #7) have died. On imatinib, none of 5 patients achieved a CCR or CMR. We conclude that a) cytogenetic analysis is an important tool for the identification of potential TK fusion genes such as ETV6-ABL1, b) ETV6-ABL1 is a candidate for incorporation into the WHO-defined subcategory ´MLN-eo´, c) patients with MPN-eo can achieve durable CHR, CCR or CMR on TKI with second generation TKI being more effective than imatinib d) close monitoring by cytogenetics, FISH and RT-PCR is recommended for early identification of inadequate response or resistance.
Figure (A) responses and (B) overall survival in 7 patients with ETV6-ABL1 positive MPN-eo treated with various tyrosine kinase inhibitors.Abbreviation, CHR:complete hematologic response; CCR: complete cytogenetic response; CMR: complete molecular response; CP: chronic phase; BP: blast phase; allo SCT: allogeneic stem cell transplantation. Figure. (A) responses and (B) overall survival in 7 patients with ETV6-ABL1 positive MPN-eo treated with various tyrosine kinase inhibitors.Abbreviation, CHR:complete hematologic response; CCR: complete cytogenetic response; CMR: complete molecular response; CP: chronic phase; BP: blast phase; allo SCT: allogeneic stem cell transplantation.

Disclosures
Somervaille: Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.