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

Abstract

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

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