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4350 Predictors of Response to Venetoclax Plus Hypomethylating Agent Therapy and Survival in Blast-Phase Myeloproliferative Neoplasm

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
MPN, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Naseema Gangat, MBBS1, Rimal Ilyas, MBBS2*, Kristen McCullough, PharmD3, Kebede H. Begna, MD4, Aref Al-Kali, MD1, Mrinal M. M. Patnaik, MD, MBBS1, Mark R. Litzow, MD1, William J. Hogan, MB, BCh1, Abhishek A. Mangaonkar, MBBS1, Hassan B. Alkhateeb, MD1*, Mithun V. Shah, MD, PhD1, Michelle A Elliott, MD1, James M. Foran, MD5, Talha Badar, MD6, Jeanne M. Palmer, MD7, Curtis A. Hanson, MD8, Animesh Pardanani, MBBS, PhD 1 and Ayalew Tefferi, MD1

1Division of Hematology, Mayo Clinic, Rochester, MN
2Mayo Clinic, Rochester, MN
3Division of Pharmacology, Mayo Clinic, Rochester, MN
4Divison of Hematology, Mayo Clinic, Rochester, MN
5Division of Hematology/Oncology and Blood and Marrow Transplanation and Cellular Therapy, Mayo Clinic, Jacksonville, FL
6Division of Hematology and Oncology, Mayo Clinic Florida, Jacksonville, FL
7Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ
8Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN


Myeloproliferative neoplasms (MPN) with blast phase (BP) transformation (MPN-BP) are associated with shortened survival since most patients are elderly and unfit for intensive chemotherapy. Venetoclax (Ven) plus hypomethylating agent (HMA) is FDA approved for elderly/unfit acute myeloid leukemia, however MPN-BP patients were excluded from Ven+HMA clinical trials. Accordingly, in the current study, our main objective was to examine Ven+HMA treatment outcomes including the impact of karyotype and mutations on response and survival in MPN-BP.


Patients with MPN-BP that received Ven+HMA outside clinical trials at the Mayo Clinic between July 2018 and May 2022 were retrospectively recruited after institutional review board approval. Diagnosis of MPN-BP required the presence of ≥20% blasts in either the peripheral blood or bone marrow. Cytogenetic and molecular studies were performed by conventional karyotype, and next-generation sequencing, respectively. All patients received at least one cycle of Ven+HMA which included either azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5. Response was assessed according to the 2017 European Leukemia Net (ELN) criteria.


Patient characteristics

47 patients with MPN-BP (median age 71 years, range 46-84; 60% males) received Ven+HMA either upfront (n=32) or following relapse (n=15). Antecedent MPN included ET/post-ET MF in 18 (38%), PV/post-PV MF in 16 (34%), and PMF in 13 (28%) patients. Driver mutation profile included JAK2 in 76% of the patients and CALR in 18%; other mutations included TP53 in 17 patients (39%), TET2 in 10 (23%), ASXL1 in 15 (34%), IDH1/2 in 12 (27%), EZH2 in 6 (14%), RUNX1 in 6 (14%), N/KRAS, SRSF2 and U2AF1 in 5 (11%) each. ELN cytogenetic risk was favorable (2%), intermediate (34%) or adverse (64%); among the latter, 55% were classified as complex.


Thirty-one (66%) patients received decitabine and the remainder azacitidine with median Ven dose of 200 mg for a median of 3 cycles (range, 1-9 cycles). 21 (45%) patients experienced cycle delays/interruptions and treatment was complicated by neutropenic fever in 22 (47%) cases.

CR or CRi was documented in 20 (43%) patients; 12 (26%) patients with CR and 8 (17%) with CRi, and residual morphological features of MPN were present in 10 patients. Among complete responders, median time to response was 1.7 months (range; 1-7 months), with median response duration of 5 months (range, 0.4-35 months). Relapse was documented in 9 (45%) of responding patients. Importantly, 7 of 13 (54%) transplant-eligible patients in CR/CRi, were bridged to transplant.

CR/CRi rates were similar with upfront therapy or in the relapsed setting (47% vs 33%; p=0.38), azacitidine or decitabine (50% vs 39%; p=0.46), presence or absence of TP53 (41% vs 44%; p=0.83), ASXL1 (47% vs 41%, p=0.74), IDH1/2 (50% vs 41%; p=0.58), and K/NRAS mutations (20% vs 46%; p=0.25). CR/CRi was superior without vs with antecedent PV (55% vs 19%, p=0.01), presence vs absence of TET2 mutation (70% vs 35%, p=0.05), and absence of complex karyotype (60%, vs 29%, p=0.04). Multivariable analysis confirmed the favorable impact of TET2 mutation (p=0.02), and absence of antecedent PV (p=0.009) on CR/CRi. Moreover, CR/CRi was significantly higher in TET2 mutated vs unmutated patients without antecedent PV (83% vs 48%) and with antecedent PV (50% vs 9%) (p=0.01).


After a median follow up of 6 months (range, 1-37 months) from initiation of Ven+HMA, 31 (66%) patients have died. Median overall survival was 7 months (range; 1-37 months) and longer in transplanted patients (11 vs 6 months; p=0.04) (Figure). On univariate analysis, survival was superior in the absence of complex karyotype (10 vs 5 months, p=0.003), N/KRAS mutations (8 vs 4 months; p=0.02), with achievement of CR/CRi (10 vs 6 months; p=0.02), and transplant (11 vs 6 months, p=0.04). Multivariable analysis confirmed the favorable prognostic impact of absence of complex karyotype and N/KRAS mutations (p=0.003 and 0.03) (Figure).


The current study identifies MPN-BP patients with a higher likelihood of response (TET2 mutated without antecedent PV) and prolonged survival (absence of complex karyotype and N/RAS mutations) following treatment with Ven+HMA.

Disclosures: Begna: ImmunoGen: Research Funding; Novartis: Honoraria. Al-Kali: Astex: Other: research support to institution. Patnaik: Kura Oncology, Stemline Therapeutics: Research Funding. Litzow: Amgen: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Syndax: Research Funding; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Research Funding; Pluristem: Research Funding; Biosight: Consultancy, Other: Data Monitoring Board; Abbvie: Research Funding. Mangaonkar: Bristol Myers Squibb: Research Funding. Shah: Astellas: Research Funding; Celgene: Research Funding; Marker Therapeutics: Research Funding. Foran: Daichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; DISC Medicine: Research Funding; Roivant: Research Funding; Actinium Pharmaceuticals: Research Funding; Astellas: Research Funding; Astex: Research Funding; Sellas: Research Funding; Pfizer: Research Funding. Palmer: Protagonist: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Research Funding.

*signifies non-member of ASH