Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia

Winters, Amanda; Gutman, Jonathan A.; Purev, Enkhtsetseg; Nakic, Molly; Tobin, Jennifer; Chase, Stephanie; Kaiser, Jeff; Lyle, Lindsey; Boggs, Chelsey; Halsema, Keri; Schowinsky, Jeffrey; Rosser, Julie; Ewalt, Mark D.; Siegele, Bradford; Rana, Vishal; Schuster, Steven R.; Abbott, Diana; Stevens, Brett M.; Jordan, Craig T.; Smith, Clayton A.

doi:10.1182/bloodadvances.2019000243

Cited by 120 publications

(103 citation statements)

References 21 publications

(37 reference statements)

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“…25 On the other hand, an analysis of 33 AML patients treated upfront with azacitidine and venetoclax found ASXL1 mutation to be predictive of response. 24 In the current report, we report for the first time that biallelic CEPBA mutations predict CR which is in line with the favorable prognostic impact of CEPBA biallelic mutations in AML. 26 benefit with the addition of venetoclax (median survival of 14.7 vs 9.6 months respectively; P < .001).…”

Section: Discussionsupporting

confidence: 82%

“…21 Our observations are reflective of both published clinical trial and "real world" reports with a comprehensive comparison provided in Table S3. 10,24 Low early mortality and infection rates including invasive fungal infections were similar to published clinical trial data. 10 Importantly, treatment cycle delays were frequently encountered in roughly half of patients necessitating venetoclax dose reduction in 70% of patients.…”

Section: Discussionsupporting

confidence: 74%

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Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients

et al. 2020

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Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment-naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment-naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation. 1 | INTRODUCTION Venetoclax in combination with either a hypomethylating agent (HMA) or low dose cytarabine (LDAC) gained FDA approval in November 2018 for newly diagnosed AML patients that are elderly >75 years or unfit for intensive induction regimens. 1,2 The above regimen is being increasingly utilized over the last 2 years, since the vast majority of AML patients are elderly with median age at diagnosis of 68 years. 3-7 Mechanistically venetoclax functions as a selective inhibitor of B-cell leukemia/lymphoma-2 (BCL-2), an anti-apoptotic protein which is overexpressed in leukemia stem cells (LSCs). 8 Functional studies have demonstrated that venetoclax in concert with azacitidine impacts the tricarboxylic acid cycle (TCA) cycle with reduction in α-ketoglutarate and increased succinate levels resulting in inhibition

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 74%

Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients

et al. 2020

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“…A Phase Ib trial of a combination of venetoclax with HMA in treatment-naïve elderly patients not eligible for intensive induction therapy showed a CR+ CRi rate of 67% after a median follow-up of 8.9 months ( 20 ). Similar data were confirmed outside of clinical trials ( 21 ).…”

Section: Discussionsupporting

confidence: 80%

Case Report: Allogeneic Stem Cell Transplantation Following Induction With CPX-351 in Patients With Acute Myeloid Leukemia Is Feasible

Vučinić¹,

Jentzsch²,

Schwind³

et al. 2020

Front. Oncol.

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Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and treatment-related acute myeloid leukemia (tAML) after chemotherapy or radiation therapy for other neoplasms are associated with poor outcomes. CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, has been shown to improve outcomes in AML-MRC and tAML compared with standard 7+3 regimens. Here we report the cases of four consecutive patients with AML-MRC or tAML who received CPX-351 as outpatient induction therapy immediately followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two patients received allo-HSCT in remission (one in complete remission and one in partial remission) and two patients received allo-HSCT in aplasia (one at 11 days and one at 52 days after the start of induction therapy with CPX-351). With a median follow-up of 188 days after allo-HSCT, all but one patient are alive and two are in remission. Further studies will help define and expand the role of CPX-351 in the treatment of AML-MRC and tAML, especially in patients expected to undergo allo-HSCT.

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“…In addition, a “real-world” report of venetoclax combined with azacitidine for the same patient populations at the same institution has been published ( 91 ). Thirty-three patients who received venetoclax + azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial.…”

Section: Clinical Uses Of Venetoclaxmentioning

confidence: 99%

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

et al. 2020

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B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.

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Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia

Cited by 120 publications

References 21 publications

Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients

Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients

Case Report: Allogeneic Stem Cell Transplantation Following Induction With CPX-351 in Patients With Acute Myeloid Leukemia Is Feasible

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

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