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

Gangat, Naseema; Morsia, Erika; Foran, James M.; Palmer, Jeanne; Elliott, Michelle A.; Tefferi, Ayalew

doi:10.1111/bjh.17084

Cited by 18 publications

(18 citation statements)

References 8 publications

(24 reference statements)

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“…The ORR in CMML-BT (42.9% in the BT subgroup and 42.9% in patients previously treated wih HMA) was also similar to those seen in blast phase MPN (42.0%), where OS was similar with HMA monotherapy versus the combination of HMA and venetoclax. 13,14 This mutation can result in polymerization of the Hb α 2 β s 2 tetramer, causing red cell sickling, erythrocyte membrane damage and red cell destruction. 1,2 Until recently, there were few therapies which directly targeted red cell sickling.…”

Section: Outcomes Of Venetoclaxbased Therapy In Chronic Phase and Blast Transformed Chronic Myelomonocytic Leukemiamentioning

confidence: 99%

Outcomes of venetoclax‐based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia

et al. 2021

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Section: Outcomes Of Venetoclaxbased Therapy In Chronic Phase and Blast Transformed Chronic Myelomonocytic Leukemiamentioning

confidence: 99%

Outcomes of venetoclax‐based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia

et al. 2021

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“…We recently reported outcomes with venetoclax and HMA combination therapy in 12 patients with blast-phase MPN, with an overall response rate of 42%, comprising of three patients achieving CR (25%) and two with partial response (PR). Impressively, three of five responding patients transitioned to AHSCT 45 . In comparison to historical controls from the Mayo Clinic database of patients with blastphase-MPN treated with HMA alone (n = 26) or intensive chemotherapy (n = 69), CR rate of 25% with HMA plus venetoclax was higher 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 but none among patients receiving HMA alone or HMA with venetoclax 46 .…”

Section: Venetoclax In Mds and Other Chronic Myeloid Malignanciesmentioning

confidence: 99%

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points

Gangat

Tefferi

2020

Blood Cancer J.

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Venetoclax (VEN), a small-molecule inhibitor of B cell leukemia/lymphoma-2, is now FDA approved (November 2018) for use in acute myeloid leukemia (AML), specific to newly diagnosed elderly or unfit patients, in combination with a hypomethylating agent (HMA; including azacitidine or decitabine) or low-dose cytarabine. A recent phase-3 study compared VEN combined with either azacitidine or placebo, in the aforementioned study population; the complete remission (CR) and CR with incomplete count recovery (CRi) rates were 28.3% and 66.4%, respectively, and an improvement in overall survival was also demonstrated. VEN-based chemotherapy has also shown activity in relapsed/refractory AML (CR/CRi rates of 33–46%), high-risk myelodysplastic syndromes (CR 39% in treatment naïve, 5–14% in HMA failure), and blast-phase myeloproliferative neoplasm (CR 25%); in all instances, an additional fraction of patients met less stringent criteria for overall response. Regardless, venetoclax-induced remissions were often short-lived (less than a year) but long enough to allow some patients transition to allogeneic stem cell transplant. Herein, we review the current literature on the use of VEN-based combination therapy in both acute and chronic myeloid malignancies and also provide an outline of procedures we follow at our institution for drug administration, monitoring of adverse events and dose adjustments.

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“…However, recent publications in a small number of patients indicate that venetoclax may not be an effective treatment in MPN-AP/BP patients (because Bcl-xl is elevated in MPN-BP cells [129] and sensitivity to venetoclax correlates negatively with Bcl-xl levels [130]) except for patients harboring IDH1/2 mutations due to the production of R-2-hydroxyglutarate. Tremblay et al [131] and Gangat et al [132] conducted retrospective studies on small cohorts of MPN-BP patients treated with the combination of venetoclax and hypomethylating agents (decitabine or azacitidine): the median OSs were not extended compared to the historically poor survivals reported for MPN-BP. Notwithstanding the short OSs in both studies, a few patients achieved CR and CR i ; and underwent allo-HSCT.…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

“…Notably, in a few recent preclinical and clinical studies, the investigators reported an increased sensitivity of IDH1/2 -mutated human AML cells and prolonged survival in IDH1/2 -mutated AML patients with venetoclax [133-136]. In the report by Gangat and colleagues [132], the responses of 2 patients with IDH2 -mutated BP-MPN revealed an analogous sensitivity to venetoclax-based combination treatment. In another recent report, a patient with IDH2 -mutated MPN-BP responded to venetoclax monotherapy [137].…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

Accelerated Phase of Myeloproliferative Neoplasms

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Background: Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20–25% of the cases. MPN-AP and MPN-BP are characterized by 10–19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival. Summary: MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3–5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.

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

Cited by 18 publications

References 8 publications

Outcomes of venetoclax‐based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia

Outcomes of venetoclax‐based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points

Accelerated Phase of Myeloproliferative Neoplasms

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