Stairway at McCormick Place,
site of ASCO Annual Meeting
© ASCO/Todd Buchanan

CHICAGO—Investigators are pursuing the combination of the selective BCL-2 inhibitor venetoclax plus low-dose cytarabine (LDAC) in older, treatment-naïve patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

These patients have few treatment options, and to date, the combination is achieving significant reduction in bone marrow and peripheral blast counts.

The combination has also achieved some complete responses, including those with incomplete marrow recovery, for a complete response (CR) rate of 54%. By comparison, expected CR rates with LDAC are about 10%.

Tara L. Lin, MD, of the University of Kansas Medical Center in Kansas City, reported the results of the non-randomized, open-label phase 1/2 dose-escalation/expansion study as abstract 7007* at the 2016 ASCO Annual Meeting.

Dr Lin reported on the 18 patients enrolled in the phase 1 portion and on an additional 8 patients treated in the phase 2 portion.

Objectives of the study were safety, efficacy, and exploratory for biomarkers predictive of outcome.

Dr Lin noted that the entire study had almost reached full enrollment early in May, and an additional 50 patients had been treated on the phase 2 portion to date.

Eligibility criteria

Patients 65 years or older with untreated AML were eligible to enroll. They could not be eligible for standard induction therapy, and they had to have ECOG performance status of 0 – 2.

Patients were excluded if they had received cytarabine previously for a pre-existing myeloid disorder, acute promyelocytic leukemia, or active central nervous system involvement with AML.

Dosing schedule

In the phase 1 portion, patients received venetoclax orally once daily on days 2 – 28 of cycle 1 and days 1 – 28 of subsequent cycles, which were 28 days.

They received LDAC at 20 mg/m² subcutaneously on days 1 – 10 of all cycles.

The venetoclax dose escalated from 50 mg to 600 mg in 6 days for dose level 1, and from 100 mg to 800 mg in 6 days for dose level 2.

Every patient was hospitalized prior to the initiation of therapy and aggressive tumor lysis prophylaxis begun at least 48 hours prior to venetoclax administration during cycle 1 and 24 hours prior to start of LDAC.

Once the patients had received prophylaxis and had a white blood cell count <25,000/μL, they were able to begin therapy starting with LDAC on day 1 and continuing through day 10.

No patient received venetoclax on day 1, Dr Lin emphasized.

Instead venetoclax began 24 hours after the LDAC, starting on day 2, and dose escalated each day until patients reached the maximum dose that was designed for their cohort level, which was then continued on days 6 – 28.

“A dose-limiting toxicity of thrombocytopenia was identified in the phase 1 portion,” Dr Lin said, “which led to the phase 2 dose recommendation of 600 mg daily of venetoclax.”

Demographics

Twenty-six patients were evaluable at the time of the presentation, 16 in the venetoclax 600-mg dose group and 10 in the 800-mg dose group.

The patients were a median of 75 years (range 66 – 87).

Sixty-five percent were males, 62% were ECOG status 1, and 19% (5 patients) had received prior hypomethylating treatment for pre-existing myelodysplastic syndromes.

Thirty-eight percent had bone marrow blast counts of 51% or greater.

Safety

Treatment-emergent adverse events (TEAEs), excluding cytopenias, occurring in 30% or more of patients included nausea (77%), fatigue (42%), febrile neutropenia (38%), diarrhea (35%), and vomiting (31%).

Grade 3/4 TEAEs, excluding cytopenias, occurring in 10% or more of patients included febrile neutropenia (38%), hypertension (12%), hyponatremia (12%), and hypophosphatemia (12%).

“In general,” Dr Lin said, “the drug was very well tolerated and patients were not discontinuing therapy because of side effects.”

Pharmacokinetics

At day 10, which coincided with the end day of the co-administration of the 2 drugs, and again, at day 18, when patients were receiving venetoclax alone, no differences were seen in either the C_max per dose or AUC per dose between day 10 and day 18.

So the co-administration of LDAC did not markedly affect venetoclax exposures.

Efficacy

The overall response rate, consisting of CR plus CRi plus partial responses (PR), totaled 58% (15/26) of all patients.

Nine patients (35%) had resistant or progressive disease; 2 had incomplete data due to discontinuation.

Most patients (79%)—19 of 24—had a decrease in bone marrow blast count of over 50%, and 88% (15/17) had a decrease in peripheral blast count of over 50%.

Responses of patients who had received hypomethylating agents did not differ from those who had not.

The investigators also evaluated the impact of a prior myeloproliferative neoplasm (MPN) (n=4) on outcome and found that none of these patients had a response to therapy.

However, patients who did not have a previous MPN had a response rate of 68%.

Survival

At 12 months, overall survival (OS) in all patients was 57.6%. If MPN patients were not included in the analysis, the OS increased to 70.5%.

The 11 non-responders had a median OS of 4 months, while for the 15 responders (CR, Cri, PR) the median OS has not yet been reached.

“This data, in terms of taking into account the safety data, how well it appears to have been tolerated by the patients, and these overall response data,” Dr Lin said, “certainly suggest that venetoclax plus low-dose araC appears to have significant activity in this older patient population and . . . is worth further study for this patient group.”

Venetoclax has demonstrated single-agent activity in heavily pretreated patients with relapsed/refractory AML. It received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL), and has 3 breakthrough therapy designations from the FDA—one in combination with hypomethylating agents for treatment-naïve AML, one in relapsed or refractory CLL, and one in combination with rituximab for relapsed/refractory CLL.

The European Commission also granted venetoclax orphan designation for AML.

Venetoclax is being developed by AbbVie in collaboration with Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis, and interpretation of data.

*Data in the abstract differ from the presentation.

Venetoclax + LDAC has potential in older AML patients