Outcome of elderly patients after failure to hypomethylating agents given as frontline therapy for acute myeloid leukemia: Single institution experience*

Nanah, Rama; McCullough, Kristen; Begna, Kebede H.; Patnaik, Mrinal M.; Elliott, Michelle A.; Al‐Kali, Aref

doi:10.1002/ajh.24780

Cited by 20 publications

(23 citation statements)

References 34 publications

(42 reference statements)

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“…Another noteworthy observation from our study was the association of CEPBA biallelic mutations with a favorable response, with all four patients harboring CEPBA biallelic mutations responding to therapy vs 18 of 35 (51%) CEBPA wild-type patients. Even though CR/CRi rates in our series were superior with HMA plus venetoclax in comparison to a historical cohort of elderly AML patients treated with HMA alone (50% vs 23%), a substantial improvement in median overall survival was not detected; median overall survival of 11 months with HMA plus venetoclax vs 9.5 months with HMA alone 20,21 .…”

Section: Venetoclax As Upfront Therapy In Amlcontrasting

confidence: 79%

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 As Upfront Therapy In Amlcontrasting

confidence: 79%

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

Gangat

Tefferi

2020

Blood Cancer J.

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“…In order to ascertain the additive benefit of venetoclax in comparison with HMA monotherapy, we went on to compare response rates with a previously published matched cohort of 56 elderly AML patients treated with upfront HMA alone at our institution, 20 and found a statistically significant difference between CR/CRi of 23% with HMA alone vs 50% with the combination of venetoclax and HMA ( P < .001). Not surprisingly, relapses occurred frequently (81%) with HMA alone as opposed to 23% with combination therapy ( P < .001) (Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…Response outcomes were found to be superior with venetoclax and HMA combination with CR/CRi rate of 50% compared to 23% with HMA monotherapy 20 . Consequently, patients attaining CR/CRi have markedly improved survival (median survival; 17 months) but survival continues to be dismal for those not achieving CR/CRi (3 months).…”

Section: Discussionmentioning

confidence: 99%

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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“… 30 Importantly, in this setting, salvage therapy seems to be ineffective as patients who receive salvage therapy after HMA and venetoclax failure showed a median OS of only 2.9 months 30 as compared to 9.5 months when being r/r to HMA alone as previously reported. 31 This suggests a very aggressive disease biology arising after HMA/venetoclax failure. This is supported by the observation that patients with favorable predictive markers (eg, mutations in IDH1/2 or NPM1 ) at the initiation of treatment developed high-risk cytogenetic and molecular features (eg, mutations in TP53 , N/KRAS , and/or KIT ) when being r/r to HMA/venetoclax.…”

Section: Nonintensive Therapymentioning

confidence: 99%

Treatment for Relapsed/Refractory Acute Myeloid Leukemia

Thol

Heuser

2021

HemaSphere

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Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high-dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms-related tyrosine kinase 3 (FLT3), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have received approval for IDH1/IDH2 mutated r/r AML by the FDA (not EMA). APR-246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural-precursor-cell-expressed developmentally down-regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.

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Outcome of elderly patients after failure to hypomethylating agents given as frontline therapy for acute myeloid leukemia: Single institution experience*

Cited by 20 publications

References 34 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

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

Treatment for Relapsed/Refractory Acute Myeloid Leukemia

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