Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure

Ball, Brian; Famulare, Christopher; Stein, Eytan M.; Tallman, Martin S.; Derkach, Andriy; Roshal, Mikhail; Gill, Saar; Manning, Benjamin; Koprivnikar, Jamie; McCloskey, James; Testi, Rebecca; Prébet, Thomas; Ali, Najla H Al; Padron, Eric; Sallman, David A.; Komrokji, Rami; Goldberg, Aaron D

doi:10.1182/bloodadvances.2020001482

Cited by 89 publications

(86 citation statements)

References 14 publications

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“…A recent multi-institutional retrospective analysis of forty-four treatment naïve or relapsed MDS patients (IPSS-R very high risk (41%), poor or very poor-risk cytogenetics (43%), therapy-related MDS (34%), prior treatment with HMA (73%), and >10% marrow blasts (57%)) treated with a combination of venetoclax with either azacitidine or decitabine, yielded an overall response rate of 59% with two-thirds of patients successfully bridged to AHSCT 41 . Response breakdown was as follows: 14% CR, 27% mCR with hematologic improvement, and 18% mCR without hematological improvement.…”

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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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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“…Guadecitabine is a dinucleotide of decitabine and deoxyguanosine linked by a phosphodiester bond, which is gradually cleaved, leading to a slow-release and thus prolonged cellular exposure of its active metabolite decitabine [ 122 , 123 ]. The most promising combinatorial strategies include a combination with the selective BCL-2 inhibitor, venetoclax [ 124 ] and the mutant p53 reactivator, APR-246 [ 125 , 126 ]. The combination with venetoclax and azacitidine has been FDA-approved for the treatment of AML in adults of 75 years or older (21 November 2018, , accessed on 6 April 2021), while the combination with APR-246 has received the breakthrough designation in MDS patients with TP53 mutation (1 April 2020, , accessed on 6 April 2021).…”

Section: Epigenetic Drugsmentioning

confidence: 99%

“…Clinical trials with APR-246 in combination with azacitidine are ongoing and have shown high response rates in high-risk MDS patients, albeit only in those with the deactivating p53 mutation [ 126 ]. Venetoclax in combination with azacitidine increased response and prolonged survival compared to azacitidine treatment alone in MDS patients [ 124 ]. Overall, hypomethylating agents still represent the best treatment strategy for many high-risk MDS patients [ 127 ], and combinatorial treatment schemes hold the promise to improve response and to reduce the onset of primary and secondary resistances.…”

Section: Epigenetic Drugsmentioning

confidence: 99%

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

Maher

Diesch

Pannérer

et al. 2021

Cancers

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Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.

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“…The BCL2-inhibitor, venetoclax, in combination with HMAs or LD-AraC, has shown substantial activity and has advanced to the standard of care in first-line treatment of elderly patients with AML [145]. This combination has showed promising efficacy also in MDS and is currently further investigated in the first-line and HMA relapsed/refractory settings [146][147][148]. Nevertheless, the management of hematological toxicity remains a major challenge and requires careful monitoring of patients, dose adaptations and supportive treatment with growth-factors, antibiotics, and antimycotics.…”

Section: Higher-risk Mdsmentioning

confidence: 99%

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Chanias

Stojkov

Stehle

et al. 2021

Cancers

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Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

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Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure

Cited by 89 publications

References 14 publications

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

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

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

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