Venetoclax is safe and efficacious in relapsed/refractory AML

Ganzel, Chezi; Ram, Ron; Gural, Alexander; Wolach, Ofir; Gino‐Moor, Sharon; Vainstein, Vladimir; Nachmias, Boaz; Apel, Arie; Koren‐Michowitz, Maya; Pasvolsky, Oren; Yerushalmi, Ronit; Danylesko, Ivetta; Cohen, Yosef; Peretz, Galit; Moshe, Yakir; Zektser, Miri; Yeganeh, Shay; Rowe, Jacob M.; Ofran, Yishai

doi:10.1080/10428194.2020.1761964

Cited by 32 publications

(22 citation statements)

References 15 publications

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“…Such as, in a patient group of relapsed and refractory AML patients and other myeloid malignancies (more than 90% cases being AML), the treatment of venetoclax with other therapies (hypomethylating agents or low-dose cytarabine) achieves an objective response of 21% and a median survival time of 3.0 months (range: 0.5–8.0 months) [ 18 ]. Another study retrospectively analyzes the data from 11 centers and finds that in AML patients who are relapsed/refractory post intensive chemotherapy, treatment with venetoclax combined with hypomethylating agents leads to 76% neutrophil recovery and 59% platelet count recovery in patients who survive for over two cycles of treatments [ 19 ]. A single-arm study using azacitidine plus nivolumab for relapsed/refractory AML patients elucidates that post treatment, the overall response rate is 33% and the CR rate is 22%; in addition, SD rate is 9% [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

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This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71–610) days and 284.5 (95% CI: 81–610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients.

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Section: Discussionmentioning

confidence: 99%

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

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“…Since approval of venetoclax in 2018 for upfront use in AML, it has gained popularity as a salvage regimen with a handful of published retrospective reports that are delineated in Table 2 (refs. 20,[25][26][27][28][29][30][31][32][33][34] ). We recommend exercising caution while interpreting findings from these reports due to immense heterogeneity in patient population studied (inclusion of relapsed MDS, other myeloid malignancies, prior HMA exposure, post AHSCT), in addition to variations in dose and schedule of treatment regimens utilized either as monotherapy, combination with HMA or low-dose cytarabine.…”

Section: Venetoclax As Salvage Therapy In Amlmentioning

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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“…Further, analysis of Bcl‐xL revealed that this anti‐apoptotic factor is not differently expressed in sbBSCs compared with bBSCs and non‐BSCs, suggesting that Bcl‐xL does play a major role in this context (Appendix Fig S1A ). Moreover, a number of previous studies already excluded a relevant alteration in platelets, shown to be dependent on Bcl‐xL, both in patient and in mice after exposure to ABT‐199 (Mason et al , 2007 ; Souers et al , 2013 ; Vandenberg & Cory, 2013 ; Vogler et al , 2013 ; Debrincat et al , 2015 ; Ganzel et al , 2020 ). We thus conclude that the intrinsically high level of Bcl‐2 in CD34 + /Itga6 low sbBSCs may underlie their specific ABT‐199 susceptibility.…”

Section: Resultsmentioning

confidence: 99%

The anti‐apoptotic Bcl‐2 protein regulates hair follicle stem cell function

et al. 2021

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Maintaining the architecture, size and composition of an intact stem cell (SC) compartment is crucial for tissue homeostasis and regeneration throughout life. In mammalian skin, elevated expression of the anti-apoptotic Bcl-2 protein has been reported in hair follicle (HF) bulge SCs (BSCs), but its impact on SC function is unknown. Here, we show that systemic exposure of mice to the Bcl-2 antagonist ABT-199/venetoclax leads to the selective loss of suprabasal BSCs (sbBSCs), thereby disrupting cyclic HF regeneration. RNAseq analysis shows that the pro-apoptotic BH3-only proteins BIM and Bmf are upregulated in sbBSCs, explaining their addiction to Bcl-2 and the marked susceptibility to Bcl-2 antagonism. In line with these observations, conditional knockout of Bcl-2 in mouse epidermis elevates apoptosis in BSCs. In contrast, ectopic Bcl-2 expression blocks apoptosis during HF regression, resulting in the accumulation of quiescent SCs and delaying HF growth in mice. Strikingly, Bcl-2-induced changes in size and composition of the HF bulge accelerate tumour formation. Our study identifies a niche-instructive mechanism of Bcl-2-regulated apoptosis response that is required for SC homeostasis and tissue regeneration, and may suppress carcinogenesis.

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Venetoclax is safe and efficacious in relapsed/refractory AML

Cited by 32 publications

References 15 publications

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

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

The anti‐apoptotic Bcl‐2 protein regulates hair follicle stem cell function

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