Venetoclax Combo Therapy Shows Promise in Pediatric Patients with R/R AML


Early data on the safety and tolerability of combination venetoclax and cytarabine or cytarabine/idarubicin were presented at ASCO 2019.

Combining venetoclax with cytarabine or cytarabine/idarubicin appears to be active and well tolerated in select pediatric patients with relapsed or refractory acute myeloid leukemia (AML), according to new data (abstract 10004) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

An orally administered BCL-2 antagonist, venetoclax has demonstrated activity in adults with newly diagnosed or relapsed AML. However, this investigation, conducted by researchers at St. Jude’s Children’s Research Hospital, is the first to examine the use of venetoclax in combination with high-dose cytarabine and idarubicin in patients aged 2 to 22 years with relapsed AML.

“The side effect profile of patients treated on the trial was very similar to that seen with high-dose chemotherapy alone, suggesting that venetoclax did not alter the tolerance of patients to the chemotherapy. At the same time, response rates were encouraging with this combination, with some patients with heavily pretreated AML responding to this combination and able to proceed to transplantation,” said study investigator Seth Karol, MD, a pediatric hematologist/oncologist at St. Jude Children’s Research Hospital.

In this phase 1 study, patients with relapsed AML or AML refractory to at least two courses of induction therapy were enrolled in a rolling-six design. All patients received venetoclax (240 or 360 mg/m2) on days 1 to 28 and low-dose cytarabine (100 mg/m2 every 12 hours for 20 doses) or high-dose cytarabine (1000 mg/m2 every 12 hours for 8 doses) beginning on day 8. In addition, on day 8, patients who had previously received < 270 mg/m2 of doxorubicin equivalents received idarubicin 12 mg/m2.

A single prolonged hematological suppression beyond day 50 was observed in 18 evaluable patients, and the researchers found no unexpected toxicities. In this study, 14 patients experienced a total of 40 grade 3 toxicities, and 1 patient experienced grade 4 fungal sepsis.

“Common side effects included febrile neutropenia, colitis, and bacteremia. All of these side effects are also common with high-dose cytarabine or cytarabine with idarubicin. The key message of this study is that venetoclax combined with high-dose cytarabine or high-dose cytarabine with idarubicin is tolerable and has a promising efficacy signal in children with relapsed or refractory AML,” Karol told Cancer Network.

The study suggested that the phase 2 dose of venetoclax, which was 360 mg/m2 (maximum of 600 mg), could be safely combined with high-dose cytarabine or high-dose cytarabine/idarubicin. The researchers found that the end-of-cycle marrow responses included 7 complete remissions/complete remissions with incomplete blood count recovery and 3 partial responses among the 12 patients with > 50% reduction in blasts following the 7-day venetoclax window therapy. Minimal residual disease (MRD) negative remissions occurred in 4 patients, according to the authors.

Catherine M. Diefenbach, MD, assistant professor of medicine and clinical director of lymphoma at NYU Langone’s Perlmutter Cancer Center, said the finding that venetoclax combined with high-dose cytarabine and idarubicin appeared to be both safe and active in a pediatric population is significant.

“This is similar to the data seen in the adult population, and it is encouraging to see that there are no new concerning safety findings in the pediatric population and that the efficacy appears quite good,” Diefenbach told Cancer Network. “These are very small numbers, and these data need to be validated in a larger, randomized study. But if validated, this will offer a new treatment strategy for patients with relapsed/refractory AML.”

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