CHICAGO — Venetoclax in combination with cytarabine alone or with idarubicin demonstrated clinical activity and appeared safe among children with relapsed or refractory acute myeloid leukemia, according to results of a phase 1 study presented at ASCO Annual Meeting.
“The data on venetoclax [Venclexta; AbbVie, Genentech] in adult patients with AML were very promising,” Jeffrey Rubnitz, MD, PhD, pediatric oncologist at St. Jude Children’s Research Hospital, said during his presentation. “About 2 years ago we developed a protocol based on the rationale that venetoclax is an orally available BCL-2 inhibitor that has a very good safety profile. ... Our hypothesis was that venetoclax in combination with chemotherapy would be active and tolerable in pediatric patients with relapsed or refractory AML.”
In this study, Rubnitz and colleagues evaluated the first use of venetoclax in combination with high-dose cytarabine and idarubicin among 18 patients aged 2 to 22 years with relapsed or refractory AML.
The researchers administered 240 mg/m2 or 360 mg/m2 venetoclax on days 1 to 28 with, beginning on day 8, either low-dose (100 mg/m2 every 12 hours for 20 doses) or high-dose (1,000 mg/m2 every 12 hours for eight doses) cytarabine.
Six patients received the combination of low doses (level 1), three received the higher venetoclax dose and low-dose cytarabine (level 2a), three received the lower venetoclax dose and high-dose cytarabine (level 2b) and three received the combined high-dose regimen (level 3). Patients who had previously received more than 270 mg/m2 of doxorubicin equivalents received idarubicin at 12 mg/m2 on day 8 in addition to the high-dose cytarabine and venetoclax regimen (level 4).
End-of-cycle marrow responses among the 12 patients who had greater than 50% reduction in blasts after the 7-day venetoclax window therapy included seven complete responses or complete responses with incomplete count recovery and three partial responses.
Four patients experienced minimal residual disease-negative remissions.
Toxicity appeared consistent with those of the cytotoxic chemotherapy. Fourteen patients experienced grade 3 toxicities, including six infections and 23 instances of febrile neutropenia. One patient developed grade 4 fungal sepsis. Only one intensity-limiting toxicity — prolonged hematological suppression beyond day 50 — occurred.
Researchers established 360 mg/m2 (max 600 mg) as the recommended phase 2 venetoclax dose in combination with high-dose cytarabine with or without idarubicin.
BH3 profiling of samples and a phase 2 expansion of both dose levels 3 and 4 to better characterize this regimen’s effectiveness are already underway.
“We can conclude that venetoclax [in combination with] cytarabine with or without idarubicin is safe and active in pediatric patients with relapsed AML,” Rubnitz said. “This was based on very small numbers, and we are continuing enrollment at dose levels 3 and 4.” – by John DeRosier
Karol SE, et al. Abstract 10004. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Rubnitz reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.