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

Abstract

We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1‐JAK2, n = 8; BCR‐JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6‐ABL1, n = 9). On ruxolitinib (median 24 months, range 2‐36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4‐78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6‐ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3‐60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6‐ABL1 positive patients.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes

“…JAK2 rearrangements (including PCM1::JAK2 due to t(8;9)(p22;p24) and BCR::JAK2 due to t(9;22)(p24;q11)) are sensitive to JAK2 inhibitors, including ruxolitinib (off label). However, response to treatment may be transient and this therapeutic approach is usually a bridge to allogeneic bone marrow transplantation, which should be considered (depending on the patients’ age and comorbidities) [ 91 , 96 ].…”

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

“…As a result of the t(9; 22) (p24.1; q11.2), a fusion gene is formed in which the oligodimerization domain of BCR is juxtaposed to the JAK2 tyrosine kinase domain resulting in constitutive activation of the JAK/STAT signaling pathway, which promotes cellular proliferation, differentiation, and growth [ 4 , 22 ]. JAK inhibitors such as ruxolitinib (JAK1/2) have been used successfully in patients with JAK2 -mutated MPN and, as such, have been proposed as a possible treatment for patients with a BCR-JAK2 + myeloid malignancy [ 10 , 11 ]. Unfortunately, responses seen in the handful of patients treated to date have been mixed with some progressing rapidly and others obtaining a complete cytogenetic response.…”

“…Although combined treatment might be able to control disease for a significant period of time, even when monotherapy with a JAK2 inhibitor fails, only allo-SCT results in long-term disease control, affirming the need for early referral. It needs to be emphasized that TKIs used for the treatment of BCR-ABL1 + CML have not shown to be of any benefit and should be avoided in the treatment of these patients [ 11 ]. Considering the rarity of hematological malignancies with a BCR-JAK2 translocation, it remains important to report cases to disseminate clinical experience, which may allow better characterization of the clinical phenotype and provide beneficial insights regarding targeted therapy regimens for patients who are not eligible for allo-SCT.…”

“…Bone marrow (BM) biopsy demonstrated a hypercellular BM with left-shifted myeloid hyperplasia but less than 1% blasts ( Figure 1(a) ), an increased myeloid to erythroid ratio (>5 : 1) and diffuse grade 3 reticulin fibrosis ( Figure 1(b) ). Cytogenetics revealed a 46XY, del(6) (p21.2p24), t(22; 9; 11) (q11.2, p24, p11.2) [ 11 ]/46XY, del(9) [ 9 ] karyotype with fluorescent in situ hybridization (FISH) analysis showing absence of a BCR-ABL1 rearrangement, but three copies of BCR ( Figure 2 ). The third copy of BCR was identified to be on the short arm terminus of chromosome 9 resulting in a BCR-JAK2 fusion as suggested with an additional JAK2 (9p24.1) probe (not shown).…”

“…In most patients, the disease is highly therapy-resistant with rapid progression occurring within the first couple of months after diagnosis [ 9 ]. While JAK2 inhibitors have been suggested to be of some benefit in controlling disease, so far, long-term remissions have only been achieved after allogeneic stem cell transplantation (allo-SCT) [ 10 , 11 ]. Here, we describe a case of a patient suffering from a therapy-related BCR-JAK2 + myeloid neoplasm with significant disease localized in his lymph nodes.…”