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Examining Venetoclax Combinations in Older Patients with Acute Myeloid Leukemia

December 30, 2021

Older patients with acute myeloid leukemia (AML) who are unable to receive standard 7+3 induction chemotherapy have limited treatment options. Selective targeting of the BCL2 protein has shown promising results in treating other hematologic malignancies. Earlier this year, the U.S. Food and Drug Administration granted venetoclax, an oral, selective BCL2 inhibitor, breakthrough therapy designation in combination with hypomethylating agents for treatment-naïve patients with AML. New research presented at the 2016 ASCO Annual Meeting suggests that BCL2 inhibition is a safe and effective front-line treatment option in older AML patients.

Venetoclax Plus Low-Dose Cytarabine

In the first study, Tara L. Lin, MD, from the University of Kansas Medical Center, and authors presented early results from a non-randomized, open-label, phase I/II dose-escalation/expansion study of venetoclax plus low-dose cytarabine (LDAC) in treatment-naïve AML patients ≥65 years who were not eligible for intensive chemotherapy.1

Though LDAC has been a standard treatment for older patients who are unfit for more intensive treatment for decades, Dr. Lin said in an interview with ASH Clinical News, "The response rates to cytarabine alone are only about 30 percent, and those remissions are short-lived. For many new drugs coming out, cytarabine can be a backbone to build upon [when evaluating] a new way to target the leukemia, because we know its parameters and expected side effects."

The study was conducted in two phases: the first dose-escalation phase followed a 3+3 design to determine the maximum tolerated dose (MTD), while the second phase examined the safety and preliminary efficacy of that recommended dose.

Patients received oral venetoclax once-daily on days two through 28 of the first 28-day treatment cycle (days 1-28 in subsequent cycles) and LDAC 20 mg/m2 administered subcutaneously once daily on days one through 10. Venetoclax was administered 24 hours after LDAC in escalating doses, for a target of 600 mg or 800 mg by day six. The investigators monitored dose-limiting toxicities (DLTs; including grade 4 toxicity, platelet count <25,000/μL, or absolute neutrophil count <500/μL within 14 days of the last venetoclax dose).

Twenty-six patients (median age = 74 years; range = 66-87 years) are enrolled in the trial: 16 in the venetoclax 600 mg group and 10 in the venetoclax 800 mg group.

All-grade treatment-emergent adverse events (AEs; excluding cytopenias) included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%). "The tolerability was much better than I expected, especially for an older patient population," Dr. Lin said. "It was gratifying to see that the most common side effects were those we are used to seeing in the treatment of AML patients."

"We were really concerned, with a drug like venetoclax which can have such potent activity, that we would see tumor lysis syndrome, but, so far, we haven't seen any protocol-specified evidence of this," she added.

In the phase I study portion, the recommended venetoclax dose was determined to be 600 mg. Preliminary results from phase II show an overall response rate (ORR) of 58 percent, including:

  • 6 patients achieving complete remission (CR)
  • 8 patients achieving CR with incomplete marrow recover (CRi)
  • 1 patient achieving partial remission (PR)

Notably, two patients who received venetoclax 800 mg experienced a DLT (grade 4 thrombocytopenia) lasting more than 42 days without evidence of residual leukemia.

Though this is an "early look at the data," Dr. Lin said she is encouraged by the results and hopes to see similar results throughout the study, which has a planned completion date of October 2017. "The ORR of 58 percent was, for this patient population, certainly better than we've seen with the standard therapy like low-dose cytarabine alone."

Venetoclax with Hypomethylating Agents

In the second study, Daniel Pollyea, MD, from the University of Colorado School of Medicine, and authors assessed the safety and preliminary efficacy of venetoclax plus a hypomethylating agent (decitabine or azacitidine) in older, treatment-naïve AML patients.2 Patients were eligible for inclusion in this non-randomized, open-label, dose-escalation, phase Ib study if they:

  • Were ineligible for standard induction therapy
  • Had an Eastern Cooperative Oncology Group performance status of 0-2
  • Had an intermediate- or poor-risk karyotype

Thirty-nine patients (median age = 74 years; range = 65-85 years) were enrolled in the study, and were assigned to one of two treatment cohorts:

  • Cohort A: 20 mg/m2 of decitabine administered intravenously (IV) on days 1-5 of each 28-day cycle plus once-daily continuous oral venetoclax (400 mg or 800 mg; n=20)
  • Cohort B: 75 mg/m2 of azacitidine administered subcutaneous or IV daily on days 1-7 of each 28-day cycle plus once-daily continuous oral venetoclax (400 mg or 800 mg; n=19)

The venetoclax dose escalation followed a 3+3 design, with a final dose level of 1,200 mg. The authors did not observe any dose-limiting toxicity, and the MTD had not been reached, Dr. Pollyea reported.

The median time on the study was 111 days (range = 6-375 days), with 41 percent of patients (n=16) still receiving study treatment as of the data cut-off point of November 28, 2015.

The ORR was 76 percent (n=26):

  • 13 patients achieved a complete response (CR)
  • 11 achieved CR with incomplete marrow recovery (CRi)
  • 2 achieved a partial remission (PR)

The median time to CR or CRi was 29.5 days (range = 24-112 days), and the median duration of response was 8.4 months (range = 6.8 – not reached).

Poor-risk cytogenetics were reported in 24 percent of patients (n=8), and the ORR among these patients was 88 percent (n=7). IDH1/IDH2 mutations were reported in 32 percent of patients (n=11); nine of these patients responded to treatment (ORR=82%).

As in the study by Dr. Lin and colleagues, the most common treatment-related AEs were nausea (54%), febrile neutropenia (41%), and diarrhea (44%). Febrile neutropenia (41%) and neutropenia (33%) were the most common grade 3 or 4 AEs, while the most frequent, serious AE was febrile neutropenia (28%). No clinically meaningful safety differences were observed in either treatment cohort.

Four relapses occurred, all in the treatment cohort receiving decitabine plus venetoclax. Six deaths occurred within 30 days of the last dose of venetoclax: three of these were related to disease progression and the others were related to sepsis, respiratory failure, and bacteremia.

"[Compared with standard induction therapy] this is a better tolerated therapy, [with] less mortality, less complications, and the ability for outpatient treatment," Dr. Pollyea told ASH Clinical News. "The response rates that we are seeing are really promising compared to historical controls and with the backbone of hypomethylating agents alone."


  1. Lin TL, Strickland SA, Fiedler W, et al. Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment-naive patients age ≥ 65 with acute myelogenous leukemia. Abstract #7007. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, June 4, 2016; Chicago, IL.
  2. Pollyea DA, Dinardo CD, Thirman MJ, et al. Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy. Abstract #7009. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, June 6, 2016; Chicago, IL.


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