Venetoclax and Chemo: A 'Step Forward' for Children With r/r AML

Kate Johnson

March 17, 2020

Adding the targeted therapy venetoclax (Venclexta, AbbVie) to high-dose chemotherapy is a "step forward" for pediatric patients with relapsed or refractory acute myeloid leukemia (AML), says an expert commenting on a phase 1 study, both published on March 11 in The Lancet Oncology.  

The safety and activity of this therapy in relapsed or refractory disease suggests it should also be tested in newly diagnosed pediatric patients with high-risk AML, say the study authors, led by Seth E. Karol, MD, from St Jude Children's Research Hospital, Memphis, Tennessee, and colleagues including from the University of North Carolina, Chapel Hill.

In the accompanying commentary, Richard Aplenc, MD, PhD, from the Division of Oncology at the Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, goes further, and says the "study is notable for several reasons."

"Not only is it the first peer-reviewed publication evaluating the efficacy of venetoclax in a pediatric population, but it is also the first evaluation of the combination of venetoclax with intensive acute myeloid leukemia chemotherapy," he writes. "Thus, in addition to their implications for children, these results are also relevant for the much larger group of adults with acute myeloid leukemia who are fit for intensive therapy."

"This study therefore continues the tradition of rigorous pediatric oncology research having an effect that exceeds the proportionally small number of children with cancer," he comments.

Venetoclax is currently approved for use in chronic lymphocytic leukemia or small lymphocytic lymphoma, so AML is a potential new indication.

Study Details

The dose-escalation study, conducted at three research hospitals in the United States, is apparently the first to use venetoclax in children and young adults, the authors note.

"We found that the combination of venetoclax and high-dose cytarabine with or without idarubicin was well-tolerated and active," they report.

Approximately 70% of the 20 patients who were evaluated showed a complete response with or without complete hematological recovery after one cycle of therapy. 

The trial initially enrolled a total of 38 patients aged 3-22 years (median 10 years), including four with primary refractory AML, 33 with relapsed AML, and one with relapsed mixed-phenotypic AML.

All patients had adequate organ function and performance status. 

Two patients who did not receive combination therapy because of either rapid disease progression or infection were excluded from further analyses.

The dose escalation included a complicated regimen involving one of two doses of both venetoclax (240 or 360 mg/m² orally once per day) and cytarabine (100 mg/m² for 20 doses or 1000 mg/m² for eight doses intravenously every 12 hours), with or without idarubicin (12 mg/m² as a single intravenous dose), using a rolling-6 accrual strategy.

The primary endpoint was identification of the recommended phase 2 dose of venetoclax plus chemotherapy. This was defined as the highest dose at which six participants were treated, with at most one experiencing dose-limiting toxicity. 

The secondary endpoint was the proportion of patients treated at the recommended phase 2 dose who achieved complete remission or complete remission with incomplete hematological recovery. 

After a median follow-up of 7.1 months, response to phase 1 of therapy, determined by bone marrow evaluation between days 35 and 49, was evaluable in 35 patients among whom some response was observed in 24 (69%). More specifically, 16 (46%) had a complete response, four (11%) had a complete response with incomplete hematological recovery, four (11%) had a partial response, and 11 (31%) had no response.

"Our data suggest that complete responses might be more frequent when venetoclax is combined with high-dose chemotherapy than with intermediate-dose cytarabine," they note.

Therefore, the recommended phase 2 dose of venetoclax was 360 mg/m2 (maximum 600 mg) combined with cytarabine (1000 mg/m2 per dose for eight doses), with or without idarubicin (12 mg/mas a single dose).

This improved the response rates. Among the 20 evaluable patients treated at the recommended phase 2 dose, 14 (70%) showed complete response with or without complete hematological recovery and two (10%) showed partial response.

"The most common grade 3-4 adverse events were febrile neutropenia (22 [66%]), bloodstream infections (six [16%]), and invasive fungal infections (six [16%])," note the authors. "Treatment-related death occurred in one patient due to colitis and sepsis."

Despite the responses being "encouraging overall, discreet subsets of patients experienced poor responses," the study authors note. Analysis of recurrent genetic lesions in this population revealed that none of the five patients with FLT3 activation responded. "This finding is consistent with previous reports in which FLT3-activated samples were resistant to venetoclax," they write. "Combining venetoclax with FLT3 inhibitors is an attractive therapeutic approach for these patients."

Adding to the objective tolerability of the regimen, survey results from patients and parents were also favorable. Patients and their parents maintained normal Herth Hope Index scores throughout the first cycle, "suggesting that the adverse effects did not diminish either hope or quality of life."

In the commentary, Aplenc writes that the "possibility that venetoclax might improve the efficacy of induction regimens without an anthracycline is also exciting," he added, noting that "the response rate for venetoclax combined with intensive chemotherapy does not seem to be modified by the inclusion of an anthracycline in the chemotherapy regimen."

Specifically, seven (64%) of 11 patients without idarubicin and six (67%) of nine patients receiving idarubicin had a complete response on the same dose levels of venetoclax, he notes. "The replacement of an anthracycline with venetoclax would have an immediate impact because standard chemotherapy for children with acute myeloid leukemia in the Children's Oncology Group exposes patients to a high cumulative exposure of anthracycline that causes both short-term and long-term cardiac morbidity and mortality."

The trial is registered at (NCT03194932) and is now enrolling to address secondary and exploratory objectives.

The study was funded by the US National Institutes of Health, American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research. Karol and several coauthors have reported no relevant financial relationships. Other coauthors have reported receiving travel or research funding from AbbVie (the manufacturer of venetoclax), and three are company employees. Aplenc has reported no relevant financial relationships.

Lancet Oncol. Published online March 11, 2020. Full text, Editorial

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