Venetoclax Plus Low-Dose Cytarabine Safe and Effective in Older Patients With Acute Myeloid Leukemia

The combination of the selective BCL-2 inhibitor venetoclax and low-dose cytarabine (LDAC) is a safe, effective option in older patients with acute myeloid leukemia (AML) who are unable to receive intensive, anthracycline-containing chemotherapy, according to the results of a phase II trial presented at the 2016 ASH Annual Meeting by Andrew Wei, MBBS, PhD, from the Australian Centre for Blood Diseases and Monash University in Melbourne, and investigators.

“Older patients with AML who are often unfit for intensive chemotherapy have limited treatment options,” Dr. Wei said during his presentation of the results. “Targeting the pro-survival molecule BCL-2 [with venetoclax] has demonstrated clinical efficacy,” and may enhance the “modest efficacy” of LDAC alone seen in earlier research in this patient population, he added.

This study provides updates about the safety and efficacy of LDAC plus 600 mg of venetoclax in 20 patients enrolled between December 2015 and March 2016. This was the recommended phase II dose of venetoclax determined in a non-randomized, open-label, phase I/II dose-escalation/expansion study of the LDAC plus venetoclax combination in older treatment-naïve patients with AML.

Twenty patients were included in the study (median age = 74 years; range = 66-87 years). Patients were eligible for study inclusion if they were ≥65 years old, considered unfit for intensive chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, and had adequate renal and liver function. Patients treated with cytarabine for a pre-existing myeloid disorder or those with acute promyelocytic leukemia or active central nervous system involvement with AML were excluded from the study.

Following a five-day dose ramp-up schedule to reach the 600 mg dose, venetoclax was administered orally once daily on days two through 28 of cycle one and days one through 28 of subsequent cycles. LDAC 20 mg/m2 was administered subcutaneously once daily on days one through 10 of each 28-day cycle. Because venetoclax has such potent activity, tumor lysis syndrome (TLS) is a concern with this treatment; to mitigate the risk of TLS, all patients were hospitalized and received prophylaxis starting 48 hours before venetoclax administration during cycle one.

The median time on venetoclax was 147.5 days (range = 8-455 days), and during treatment, the most common grade 3/4 adverse events (AEs), excluding cytopenias, were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), followed by decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred.

Three-quarters of patients (n=15/20) achieved an objective response, which included 14 patients with either complete response (CR) or CR with incomplete marrow recovery (CRi) and one patient with a partial response (PR; TABLE). “All 14 of the CR/CRi patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm,” the investigators noted.

The median time to best response was 30 days (range = 23-169). Also, in the 19 patients who had bone marrow (BM) data available, 16 (84%) had their BM blast percentage reduced to >5 percent.

Two patients who achieved CR/CRi died: one from disease progression and the other from acute hepatic failure.

At the time of presentation, the median overall survival (OS) had not been reached, Dr. Wei and investigators wrote, adding that responders experienced a “substantially better survival compared with non-responders.” As seen in the TABLE, the estimated 12-month OS was 74.7 percent (95% CI 49.4-88.6) and 86.7 percent (95% CI 56.4-96.5) for the 15 patients who responded to treatment.

Combined with data presented earlier this year at the 2016 ASCO meeting, venetoclax, which was granted breakthrough therapy designation by the U.S. Food and Drug Administration, appears to be an active, tolerable option in older patients with AML.


Wei A, Strickland S, Roboz G, et al. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naive patients aged ≥65 years with acute myeloid leukemia. Abstract #102. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.

TABLE. Overall Response Rate and 12-Month Overall Survival Estimates
  All Patients


Prior Hypomethylating Agent


No Prior Hypomethylating Agent


Prior Myeloid Neoplasm


No Prior Myeloid Neoplasm


Overall response rate (CR+CRi+PR), n 15






0 15


12-month overall survival estimate 74.7%

(95% CI 49.4-88.6)

N/A 71.8%

(95% CI 44.9-87.2)

N/A 83.3%

(95% CI 56.8-94.3)

CR = complete response; CRi = complete response with incomplete marrow recovery; PR = partial response