Finding a Quick, Durable Therapy for Elderly Patients With AML is the Holy Grail, Expert Says

Andrew Wei, MBBS, PhD, discusses a study which explored the safety and efficacy of the novel BCL-2 inhibitor venetoclax in combination with low-dose cytarabine chemotherapy for treatment-naïve patients over the age of 65 with AML.

Andrew Wei, MBBS, PhD

Treating patients with acute myeloid leukemia (AML) who are over the age of 65 can be especially difficult, as many of these patients have treatment-resistant infections which can ultimately cause them to succumb to the disease. Therefore, identifying a new treatment option that can provide a quick and durable effect for these patients is the “holy grail of AML therapy,” says Andrew Wei, MBBS, PhD.

In an interview withTargeted Oncology, Wei, clinical hematologist, head of Leukemia Research Group, Alfred Hospital, and adjunct senior lecturer, Monash University, discusses a study which explored the safety and efficacy of the novel BCL-2 inhibitor venetoclax (Venclexta) in combination with low-dose cytarabine (Ara-C) chemotherapy for treatment-naïve patients over the age of 65 with AML.

TARGETED ONCOLOGY:What was the objective of this study?


The treatment for AML has been extremely difficult for many decades. It’s a condition which effects 20,000 Americans each year. Each year, 10,000 people with AML unfortunately die. This is because half of the population is over the age of 65.

In this group of patients, intensive chemotherapy has been extremely difficult to deliver. One of the reasons why AML is so devastating is that it paralyzes the blood system and people rapidly succumb to treatment-resistant infections, so identifying a new therapy which can induce remissions quickly and durably has been the holy grail of AML therapy.

BCL-2 and other pro-survival proteins are known to be important for control of survival in various cancers, and so the question was asked whether targeted BCL-2 could be effective in AML.

TARGETED ONCOLOGY:How was this study designed?


In a phase I study that was done in relapsed and refractory patients, modest activity was observed, with clinical responses in 19%. To improve upon these responses, the trial was designed to combine venetoclax with low doses of chemotherapy. Low-dose cytarabine, for instance, which has frequently been used in the elderly population over the past few decades, traditionally gives response rates of less than 20% and survival durations of less than 6 months, so not particularly as good outcomes as expected.

This phase I trial examined 61 patients who had low-dose cytarabine combined with venetoclax at a dose of 600 mg. The treatment was started at a low dose on day 2, 50 mg, and increased rapidly over the next 4 days to a peak dose of 600 mg. The reason for this was to reduce the risk of tumor lysis syndrome (TLS), but, fortunately, in this trial, there were no instances of clinical TLS observed, and the venetoclax in combination with low-dose cytarabine was extremely well tolerated with very few severe side effects.

TARGETED ONCOLOGY:What were the findings of the study?


The initial clinical responses to this combination have been very exciting. Traditionally, response rates to low-dose cytarabine in elderly patients has been less than 20%. In this study, the overall response rate was 61%, which is more than 3 times what we have seen historically. Complete remissions amounted to 54% of patients, and there was another 7% of patients that had a partial remission, giving a total response rate of 61%.

Furthermore, responses were observed in quite a diverse range of AML subgroups, including patients over the age of 75, where they had a 70% response rate, secondary AML with a 52% response rate. Even patients that had prior exposure to hypomethylating agents, the response rate was 53%, and this is a difficult patient population for which we don’t have particularly effective therapies.

Furthermore, in patients with adverse karyotypes, which is generally considered untreatable with low-dose cytarabine, there was a clinical response rate of 47% observed. In terms of survival with low-dose cytarabine, survival durations have generally been very short. So far in this study, with 8 months of follow-up, the survival rate is currently sitting at 64%, which is certainly a very encouraging early sign.

Among the patient population that had a response to venetoclax, the survival rate is currently above 80% with 8 months of follow-up. We hope that with longer follow-up, these types of survival durations can be sustained, and if so, this would indicate that we have a particularly exciting drug for the future treatment of AML. Because of this study, a phase III randomized trial is currently being planned. It’s commencing sometime in 2017.

One important aspect of this therapy is that the patients achieved remission very quickly, so 70% of patients achieved a complete remission within 2 cycles of therapy. This is extremely important because the biggest impact on the patients’ quality of life is having low blood counts, low neutrophils causing infection, low platelets putting patients at risk of bleeding complications. So, to achieve a remission means their blood counts have been normalized very quickly, and this is something that has been extremely exciting about this new combination therapy.


Wei A, Strickland S A, Roboz G, et al. Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naïve Patients Aged ≥ 65 Years With Acute Myeloid Leukemia. Abstract presented at: 2016 ASH Annual Meeting; December 3, 2016; San Diego, CA. Abstract 102.