Venetoclax combination therapy in relapsed/refractory acute myeloid leukemia: A single institution experience

Gaut, Daria; Burkenroad, Aaron; Duong, Tuyen Van; Feammelli, Jesse; Sasine, Joshua P.; Schiller, Gary J.

doi:10.1016/j.leukres.2020.106314

Cited by 49 publications

(42 citation statements)

References 17 publications

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“…16 In other published series which include post-transplant relapses, response rates were found to be highly variable ranging from 21% to 64%. [12][13][14][15]29 A comparison of our findings with the existing literature is detailed in Table S4. In particular, considerable inconsistency is appreciated in regards to clinical and mutational predictors of response and survival which is likely explained by heterogeneity in disease biology and prior therapies received by relapsed/refractory AML patients.…”

Section: Discussionmentioning

confidence: 72%

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: Discussionmentioning

confidence: 72%

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

et al. 2020

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“…Unfortunately, retrospective results for venetoclax combination therapy in the relapsed/refractory setting have not been as promising, however, prospective studies are ongoing. Overall response rates in these patients, some of whom have been heavily pre-treated, range from 21%-64%[ 50 , 51 ]. Patients with secondary AML and those whose AML harbors a TP53 mutation have the poorest responses[ 52 ].…”

Section: Targeting B-cell Lymphoma-2 In Acute Myeloid Leukemiamentioning

confidence: 99%

B-cell lymphoma-2 inhibition and resistance in acute myeloid leukemia

Wilde¹,

Ramanathan²,

Kasner³

2020

WJCO

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Spurred by better understanding of disease biology, improvements in molecular diagnostics, and the development of targeted therapies, the treatment of acute myeloid leukemia (AML) has undergone significant evolution in recent years. Arguably, the most exciting shift has come from the success of treatment with the B-cell lymphoma-2 inhibitor venetoclax. When given in combination with a hypomethylating agent or low dose cytarabine, venetoclax demonstrates high response rates, some of which are durable. In spite of this, relapses after venetoclax treatment are common, and much interest exists in elucidating the mechanisms of resistance to the drug. Alterations in leukemic stem cell metabolism have been identified as a possible escape route, and clinical trials focusing on targeting metabolism in AML are ongoing. This review article highlights current research regarding venetoclax treatment and resistance in AML with a focus on cellular metabolism.

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“…Gaut et al 11 . recently reported their experience with venetoclax combination therapy in 14 adult patients with relapsed/refractory AML.…”

Section: Medication Total Dose (Mg) Daily Dose Daymentioning

confidence: 99%

Venetoclax and decitabine for relapsed paediatric myelodysplastic syndrome‐related acute myeloid leukaemia with complex aberrant karyotype after second stem cell transplantation

Raedler¹,

Heyde²,

Kolokythas³

et al. 2020

Br J Haematol

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Venetoclax combination therapy in relapsed/refractory acute myeloid leukemia: A single institution experience

Cited by 49 publications

References 17 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

B-cell lymphoma-2 inhibition and resistance in acute myeloid leukemia

Venetoclax and decitabine for relapsed paediatric myelodysplastic syndrome‐related acute myeloid leukaemia with complex aberrant karyotype after second stem cell transplantation

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