VALDAC: A prospective study of venetoclax and low-dose cytarabine for MRD and oligoblastic relapse in AML

Treatment for relapsed/refractory acute myeloid leukemia (AML) remains a challenge due to reduced efficacy and high rates of complications related to disease-associated cytopenia. There have been promising results with venetoclax plus azacitidine or low-dose cytarabine (LDAC) at measurable residual disease (MRD) relapse; however, most studies have been retrospective.

Recently, Tiong et al.¹ published results from the phase II VALDAC study (ACTRN12619000746134) in Journal of Clinical Oncology investigating the outcomes of venetoclax + LDAC in patients with AML and either MRD or oligoblastic relapse. Here we summarize the key findings.

Study design¹

• A phase II multicenter prospective study which stratified patients to an MRD or oligoblastic relapse cohort.
• Venetoclax 600 mg was administered orally, once daily on Days 1–28.
• LDAC 20 mg/m² was administered subcutaneously, once daily on Days 1–10.
• The primary endpoint was MRD/hematologic response within two treatment cycles.
• Secondary endpoints were overall survival (OS), stem cell transplant realization, safety, and use of hospital resources.

Key findings¹

• A total of 48 patients were enrolled in the study
  • 26 had MRD relapse
  • 22 had oligoblastic relapse
• The median follow-up period was 25 and 22 months in the MRD and oligoblastic cohort, respectively.

Efficacy

• The median time to first MRD response and hematologic response was one treatment cycle in the MRD and oligoblastic cohort, respectively.
• Response rates after two treatment cycles were comparable between the two cohorts (Figure 1).

MRD, measurable residual disease.
^*Adapted from Tiong, et al.^1
†Response in the MRD cohort was defined as an MRD response.
^‡Response in the oligoblastic cohort was defined as a hematologic response (complete remission [CR]/CR with partial hematologic recovery/CR with incomplete recovery).

• The median OS was not reached in both cohorts.
• The estimated 2-year OS rate was 67% for the MRD cohort and 53% for the oligoblastic cohort.
• The estimated 2-year event free survival was 53% for the MRD cohort and 36% for the oligoblastic cohort.
• Of the 31 eligible patients, 71% proceeded to stem cell transplantation.
  • The median OS post-transplant was not reached for either cohort.

Safety

• In the oligoblastic cohort, there were more cases of Grade ≥3 anemia and infections compared with the MRD cohort (32% vs 4%; p = 0.02 and 36% vs 8%; p = 0.03, respectively).
• The number of patients experiencing Grade 4 neutropenia (32% vs 23%), thrombocytopenia, (27% vs 15%) and febrile neutropenia (15% vs 5%) were comparable between the oligoblastic and MRD cohorts.
• Unplanned hospital admission was experienced by 35% and 59% of patients in the MRD and oligoblastic cohorts, respectively.
• Three patients in the oligoblastic cohort died during treatment.

Key learnings

The results from this study confirm the safety and promising efficacy of venetoclax + LDAC in patients with AML and either MRD or oligoblastic relapse. This regimen has the advantage of outpatient-based administration, fewer serious complications, and comparable efficacy vs intensive chemotherapy. Future studies should evaluate pretransplant MRD eradication versus directly proceeding to transplant, as well as the ability of MRD-directed therapy to modify disease history compared with treatment at morphological relapse.