Venetoclax plus hypomethylating agent in blast‐phase myeloproliferative neoplasm: preliminary experience with 12 patients

• DOI: 10.1111/bjh.17084
• Publication Date: 2020-09-18T11:56:04Z
• Authors: Naseema Gangat; Erika Morsia; James M. Foran; Jeanne M. Palmer; Michelle A. Elliott; Ayalew Tefferi
• Keywords: Venetoclax; Myeloproliferative neoplasm; Hypomethylating agent

Blast-phase myeloproliferative neoplasm (BP-MPN) is the most dreaded disease complication in primary myelofibrosis (PMF), essential thrombocythaemia (ET) and polycythaemia vera (PV), with a 20-year incidence rate of 9·3 %, 3·9% 2·6% respectively.1 A recently published large collaborative study BP-MPN included 248 Mayo Clinic patients depressing median survival only 3·6 months 5-year <5%.2 In this particular cohort, 69 received intensive chemotherapy complete remission (CR) CR incomplete count recovery (CRi) rates 35% 24% respectively. contrast, corresponding CR/CRi among 26 receiving hypomethylating agent (HMA) alone were markedly inferior at 4%/0%.2 Recent studies acute myeloid leukaemia (AML) have indicated higher response addition venetoclax to HMA, both relapsed/refractory newly diagnosed unfit patients.3 Venetoclax small molecule inhibitor B-cell leukaemia/lymphoma-2 (BCL-2), an anti-apoptotic protein that overexpressed stem cells. Considering above-mentioned dismal HMA alone,2 as well fact + therapy now United States Food Drug Administration (FDA) approved for elderly or AML, we extended such combination BP-MPN. The present report constitutes retrospective review 12 consecutive [median (range) age 71 (48–81) years, 50% males] who one three major campuses (seven from Rochester, MN; Jacksonville, FL; two Scottsdale, AZ). Diagnostic, risk assignments according 2017 European LeukemiaNet (ELN) criteria.4 Table I lists patient characteristics time leukaemic transformation, treatment details, overall outcome. Driver mutation profile Janus kinase 2 (JAK2) 75% calreticulin (CALR) 17%, other mutations tumour p53 (TP53) six (50%), ten–eleven translocation methylcytosine dioxygenase (TET2) four (33%), isocitrate dehydrogenase 1 (IDH1/2) (25%), KRAS proto-oncogene, GTPase (KRAS) (17%) additional sex combs like-1 (ASXL1) (17%). Cytogenetic abnormalities 67% all classified poor risk. Eight (67%) previously untreated their which seven aged >65 while younger was deemed induction chemotherapy. Prior documented allogeneic haematopoietic cell transplantation (AHSCT) another patient. addition, each had prior cytarabine anthracycline, vyxeos cladribine. All hospitalised during cycle 3-day ramp-up lysis syndrome prophylaxis. dose adjusted based on drug interactions particularly azole anti-fungal azacitidine 75 mg/m2 days 1–7 (five patients) decitabine 20 1–5 (nine patients). Bone marrow biopsy obtained after treating physician discretion. Overall (OR) five (42%) (25%) partial (PR) two. Moreover, displayed residual morphological features MPN. Supplementary S1 details achieving PR. Among CR, started complex karyotype remained unchanged despite achievement CR. multiple mutations, initiation, including TP53, FMS-like tyrosine kinase-3 (FLT3) IDH2 each, truncated four-gene follow-up next-generation sequencing disclosed disappearance FLT3 persistence TP53 third (Table II). At 5 (3–15) months, responders alive successfully transitioned AHSCT PR subsequently relapsed salvage followed by AHSCT. Outcome treated compared historical controls same database (n = 26) 69),2 those (4%, P 0·048) (35%, < 0·0001); furthermore, achieved CRi, whereas not seen venetoclax. We acknowledge selection bias either ineligible 45,XY,add(2)(p25), der(2)t(1;2)(p22; q21), add(5)(q13),-13,-17, +mar[20] 46-49,XY,+1, der(1;7)(q10; p10),-6, +8, add(12)(p11·2),-20, +2-4mar [cp4]/46, XY[16] BCOR DNMT3A FLT3-ITD TET2 U2AF1 PTPN11 ASXL1 EZH2 NPM1 SETBP1 STAG2 JAK2 Alive, underwent An presented extramedullary transformation (myeloid sarcoma) without bone involvement; these resolution tumour, imaging studies, HMA. our similar reported pivotal AML up-front OR 68%.5 Similarly, 77% 56% 44 naïve high-risk adverse related AML.6 latter study, amongst 42 cases 36%. experience AML,6 presence did appear compromise ability achieve CR/CRi. Taken together, observations are encouraging terms potential value BP-MPN, bridge For purposes information only, comparison data versus (Figure S1). However, sample size too short comment impact authors declare no conflict interest regarding matters pertinent current manuscript. Naseema Gangat Erika Morsia collected analysed data. James M. Foran, Jeanne Palmer Michelle A. Elliott contributed patients. Ayalew Tefferi wrote paper. reviewed Please note: publisher responsible content functionality any supporting supplied authors. Any queries (other than missing content) should be directed author article.