New Tricks and Old Dogs: Will the Addition of Venetoclax to Conventional Multidrug Chemotherapy Decrease Relapse Risk for Younger Adults With Newly Diagnosed AML?

Intensive cytarabine/anthracycline–based chemotherapy regimens induce remission in more than 80 percent of younger adults with acute myeloid leukemia (AML).^1,2  However, many patients subsequently relapse and are difficult to salvage. Appreciable interest exists in developing more optimal frontline regimens that may mitigate relapse risk and improve long-term survival.

Two early-phase clinical trials from investigators at the MD Anderson Cancer Center explored the addition of the BCL-2 inhibitor venetoclax to intensive multiagent chemotherapy induction and recently reported promising response rates, exceeding those of historic control patients with AML treated with the chemotherapy backbones alone. In a single-arm phase II study, Dr. Tapan Kadia and colleagues assessed the tolerability and efficacy of venetoclax (400 mg daily on days 2-8 of each cycle) in combination with the cladribine, idarubicin, and cytarabine (CLIA) regimen.³  Decreased frequency and dosing of venetoclax was chosen to reduce excessive myelosuppression. FLT3 inhibitors were also added for patients with FLT3-mutant disease. The primary outcome was composite complete response rate (CCR; defined as complete response + complete response with incomplete count recovery). Forty-seven (95%) of 50 enrolled patients with AML, high-risk myelodysplastic syndrome (MDS), or mixed phenotype acute leukemia experienced CCR, with 33 of these (71%) achieving end-induction minimal residual disease (MRD) negativity. Febrile neutropenia was common (42/50 patients, 84%). Three patients treated with CLIA/venetoclax and FLT3 inhibitors died of infectious complications in induction (n=1) or consolidation (n=2, both in remission), and all patients receiving concurrent FLT3 inhibitors had delayed count recovery. Median duration of response, event-free survival (EFS), and overall survival (OS) were not reached. An estimated 12-month EFS was 68 percent for all patients (78% for the European LeukemiaNet [ELN] favorable-risk, 93% for intermediate-risk, and 81% for adverse-risk groups). Of note, patients in the intermediate- and adverse-risk groups were referred for allogeneic hematopoietic stem cell transplantation (HSCT) after remission induction.

A concurrent phase Ib/II clinical trial led by Dr. Courtney DiNardo and colleagues investigated the addition of venetoclax to the fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-ida) regimen in 29 adults with newly diagnosed, and 38 adults with relapsed/refractory (R/R) MDS or AML, including therapy-associated AML.⁴  Primary outcome measures were safety and tolerability of the combination regimen and overall response rate. In the phase Ib component, 21-day dosing of venetoclax (400 mg daily) per cycle resulted in intolerable toxicity, and the study was amended to use 14 days and seven days in induction and consolidation, respectively. As in the venetoclax/CLIA study, infectious complications were common, including febrile neutropenia (50%), bacteremia (35%), and pneumonia (25%), all occurring at similar frequencies in newly diagnosed patients and those with R/R disease. Delayed count recovery was also observed in most patients, particularly after cycle 2. However, the combination regimen was highly effective, with 96 percent of newly diagnosed patients and 69 percent of patients with R/R disease achieving MRD-negative CCR. Sixty-nine percent of newly diagnosed patients and 46 percent of patients with R/R AML/MDS proceeded to allogeneic HSCT. Twelve-month EFS rates for newly diagnosed patients and patients with R/R disease were 85 percent and 31 or 41 percent in phase Ib or phase IIb, respectively. All deaths on study occurred in subjects with R/R MDS/AML (n=6) and were often attributable to infectious complications. Amongst the R/R cohort, patients with complex or adverse-risk cytomolecular genetics (n=16) fared expectedly poorly, with a median EFS of seven months, and those with mutations in tumor suppressor (TP53, WT1, FBXW7, and PHF) and signaling pathway (RAS, FLT3, PTPN11, CBL, and KIT) genes also had inferior survival compared to patients without these molecular aberrations. Conversely, subjects with NPM1-, IDH1-, or IDH2-mutant R/R MDS/AML (n=7) had excellent outcomes with 100 percent CCR. Surprisingly, the six patients with favorable cytogenetics fared unexpectedly poorly with a median EFS of six months.