Venetoclax in the treatment of acute myeloid leukemia: Beyond VIALE‐A

Venetoclax and hypomethylating agent therapy in acute myeloid leukemia. Current management in acute myeloid leukemia (AML) patients that are elderly or with comorbidities which preclude use of intensive induction chemotherapy, includes a combination of venetoclax (Ven) and hypomethylating agent (HMA) therapy.1, 2 In November 2018, the United States Food and Drug Adminstration (FDA) granted accelerated approval to Ven in combination with HMA for newly-diagnosed elderly and/or unfit AML patients based on phase 1b study results which showed a complete remission (CR) with or without count recovery (CRi) rate of 67%.3, 4 Subsequently, in October 2020, Ven received full FDA approval after the VIALE-A study confirmed an overall survival benefit with Ven-azacitidine therapy.5 In the article that accompanies this commentary, Pratz et al report on long-term outcomes from the VIALE-A study; a phase 3 trial which compared Ven-azacitidine with placebo-azacitidine in newly-diagnosed elderly/unfit AML.6 Since then, additional studies including those conducted in the real-world setting, have underscored the value of Ven-HMA in securing complete remission, improving survival, and most importantly, preserving quality of life in patients with AML.7-11 In the current commentary, we share our insights on the therapeutic value of Ven-HMA, underline salient predictors of treatment response and survival, and provide our perspectives on the emerging Ven-based treatment landscape in AML. The VIALE-A study was a phase 3 study of Ven-azacitidine (n = 286) versus placebo-azacitidine (n = 145) in newly-diagnosed AML patients who were ineligible for intensive chemotherapy.5 The recently published VIALE-A long-term follow-up study (median follow-up: 43.2 months, range: 2 years and >3 years, respectively. Furthermore, survival was favorably impacted by MRD response (median survival; 34.2 months vs. 19 months in MRD-negative vs. positive). Collectively, over half of responders and long-term survivors (>2 years) harbored either IDH1/2 (35%) or NPM1 mutations (20%), on the other hand, only a minority displayed FLT3 (11%) or TP53 mutations (8%).6 Notably, 52% of patients in CR/CRi experienced disease progression/relapse, which resulted in a shortened median survival of 6.8 months, despite the use of salvage therapy in 42% of patients.6 This is in contrast to a prior study which reported median survival of ~3 months in patients relapsed/refractory to front-line Ven-HMA; however, in the particular study, only 15% of patients received subsequent chemotherapy.12 The long-term results from the VIALE-A trial confirm the authors' initial observations,5, 13, 14 and are also consistent with recent information on the genotype signatures associated with treatment response and survival in patients treated with Ven-HMA outside of the clinical trial setting.9 In a Mayo Clinic study of 301 patients with newly-diagnosed AML treated with Ven-HMA (median age; 73 years), CR/CRi rate was 60%; response rates were higher with NPM1, IDH2, and DDX41 mutations (favorable) with corresponding CR/CRi rates of 86%, 80% and 100%; on the other hand, presence of TP53, FLT3-ITD and RUNX1 mutations (unfavorable) resulted in lower CR/CRi rates of 40%, 36% and 44%, respectively.9 Taken together, CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutations, to 91%, in the presence of favorable and absence of unfavorable mutations. Akin to the VIALE-A trial, in the aforementioned study, median overall survival was 12.9 months (2-year survival; 32%), and was longer in patients who achieved CR/CRi, and those with IDH2 mutations, and inferior in patients with adverse karyotype and TP53 mutations.9 Furthermore, given the limited applicability of the European LeukemiaNet (ELN) genetic risk stratification in Ven-HMA treated patients,15 a response-based, genetics-enhanced survival model, based on achievement or not of CR/CRi, adverse karyotype, absence of IDH2, and presence of TP53 mutations was proposed in the Mayo Clinic study.9 The foremost determinant of the value of chemotherapy in elderly AML patients, which takes precedence over survival, is the impact of treatment on quality of life. In regard to the latter, a previously published health-related quality of life analysis from the VIALE-A study, showed a significantly longer time to functional deterioration in patients receiving Ven-azacitidine; importantly, treatment did not negatively impact older patients >75 years of age.10 In the VIALE-A study, treatment-emergent, grade ≥3 thrombocytopenia and febrile neutropenia was reported in 46% and 43% of patients, respectively.6 Notably, six patients in CR/CRi succumbed to complications which included infections in 4 cases.6 Although no new safety signals were reported, it should be brought to attention that major cardiac complications including cardiomyopathy, myocardial infarction, and/or pericarditis/effusions have been described in Ven-HMA treated patients.16 Therefore, given the potential for treatment-emergent toxicity, it might be reasonable to consider an abbreviated course (<28 days) of Ven in cycle 1, particularly, since a shorter Ven duration of 14 or 21 days has not been shown to negatively impact remission rates or survival.17 Over the last 5 years, treatment progress in elderly AML is credited to Ven-HMA combination therapy, which coupled with advances in genetic risk stratification and MRD assessment tools has enabled accurate identification of treatment responders and long-term survivors as outlined in Table 1. How do we incorporate the above-discussed information into routine practice and optimize Ven-HMA therapy? First, the prospect of an all oral chemotherapy regimen with Ven-decitabine/cedazuridine is currently under investigation; among 42 newly-diagnosed older/unfit AML patients, CR/CRi rate was 62% with median overall survival of 12.7 months.18 Second, it is becoming increasingly evident that Ven-HMA may not be enough to secure long-term remission and improve survival in patients with adverse cytogenetics, FLT3-ITD and TP53 mutations. In this regard, current efforts in FLT3 mutated AML are focused on incorporating FLT3 inhibitors into triplet (Ven-HMA-FLT3 inhibitor) combinations. In a phase 1/2 study of Ven-azactidine-giltertinib in elderly patients with newly-diagnosed FLT3-ITD mutated AML (n = 30), CR/CRi was 96%, with 93% and 65% achieving MRD negativity by flow cytometry and FLT3-PCR, respectively; moreover 18-month overall survival was 72%.19 In addition, in a preliminary communication from a phase 1/2 study of Ven-decitabine-quizartinib in newly-diagnosed FLT3-ITD mutated AML (n = 10), all patients achieved CR/CRi, with 90% and 78% of evaluable responders being FLT3-PCR and MRD-flow negative; median time to count recovery was 40 days without treatment-related mortality.20 Likewise, "triplet therapy" with IDH1 inhibitor (ivosidenib) + Ven +/− azacitidine has also been shown to induce higher response rates in patients with IDH1-mutated myeloid malignancies (n = 31) with a composite CR rate of 83%–90%; MRD-negative remission in 63% and IDH1 mutation clearance in 64%.21 Finally, the addition of a menin-inhibitor (revumenib) to Ven-HMA is under investigation, and preliminary results with revumenib-decitabine/cedazuridine-Ven showed CR/CRi in 44% (CR 33%) of nine patients with relapsed/refractory KMT2A/NUP98 rearranged or NPM1 mutated AML.22 IDH1/2 mutations NPM1 mutation IDH2 mutation NPM1 mutation DDX41 mutation FLT3-ITD mutation TP53 mutation RUNX1 mutation 14.7 months IDH2 mutated 27.5 months MRD negative (<10−3) 34.2 months MRD negative Adverse cytogenetics CR/CRi IDH2 mutation Adverse cytogenetics TP53 mutation An important question, in the setting of younger and fit patients conventionally treated with intensive induction chemotherapy, is whether or not Ven-HMA is able to overcome the inferior prognosis associated with high risk disease. In a phase 2 trial of Ven-decitabine in younger AML patients with ELN adverse risk (n = 42; median age 39 years), composite CR rate was 93%, and 86% of patients received allogeneic stem cell transplantation.23 However, these findings are hard to interpret since triplet therapy was used for FLT3-mutated patients and only a limited number of patients with complex karyotpe and TP53 mutations were included in the aforementioned study.23 Importantly, in a separate phase 2 study which compared Ven-decitabine with intensive chemotherapy (cytarabine-idarubicin) in younger patients (<60 years) (n = 116), similar composite CR rates were documented in 86% and 79%, respectively, moreover, the incidence of infectious complications was considerably lower with Ven-HMA therapy.24 Lastly, does the addition of Ven to intensive chemotherapy improve outcomes in young patients with newly-diagnosed AML? In this regard, the addition of Ven to fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA-Ven) in young AML patients (median age; 44 years), yielded composite CR in 89%, including 93% who were MRD negative and 60% transitioned to allogeneic transplant.25 Similar results were obtained with Ven plus cladribine, idarubicin, and cytarabine (CLIA-Ven), however, strikingly high rates of neutropenic fever/infections were reported in 96% of patients, which resulted in death in two patients.26 Taken together, the off-label use of Ven-based intensive combination therapies in newly-diagnosed young/fit AML patients warrants careful consideration. The discovery of genotype signatures of response and survival following treatment with Ven-HMA has unveiled the ongoing unmet needs in AML. Whether or not Ven-HMA based triplet regimens will add incremental value remains to be determined. Finally, radical changes in treatment approach might be required to improve the outcome of biologically high risk AML. No conflicts of interest to disclose. No new data was generated.