More than half of children with relapsed or refractory AML achieved remission with venetoclax-based intensive chemotherapy in a phase 1 study.
Venetoclax combined with intensive cytarabine-based chemotherapy has produced encouraging remission rates in children and young adults with relapsed or refractory acute myeloid leukaemia, adding to growing evidence that the BCL-2 inhibitor could become part of standard salvage treatment in paediatric disease.
Final results from the multicentre phase 1 VENAML study, published in The Lancet Haematology, showed that 57% of patients achieved a complete response with or without haematological recovery after just one cycle of therapy.
Nineteen of the 25 complete responders were measurable residual disease (MRD) negative, giving an MRD-negative remission rate of 43% across the entire study population.
“Our results further show that venetoclax combined with high-dose cytarabine-based regimens is active and tolerable in children with relapsed AML,” the researchers wrote.
“These data also show activity across genomic subgroups commonly observed at relapse.
“To our knowledge, this study represents the largest report of children treated with venetoclax and intensive chemotherapy for relapsed AML and provides a comprehensive activity analysis of patients treated at the recommended phase 2 dose, including those enrolled in a newly introduced expansion cohort. This study further supports use of this regimen in this population.”
For clinicians treating relapsed paediatric AML, where outcomes remain poor despite advances in frontline therapy, the results offer further reassurance that venetoclax can be safely incorporated into intensive chemotherapy regimens while providing the disease control needed to bridge patients to allogeneic stem cell transplantation.
Despite overall survival for newly diagnosed paediatric AML approaching 70%, between 20% and 40% of children relapse, and long-term survival after relapse remains only around one in three patients.
While venetoclax has transformed treatment for older adults with AML who are unfit for intensive chemotherapy, evidence supporting its use in children has been limited, particularly in combination with intensive salvage regimens.
The VENAML expansion study enrolled 44 patients aged between two and 24 years across three US centres.
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All had relapsed or refractory disease and many had particularly adverse clinical features. More than one-third had previously undergone haematopoietic stem cell transplantation, almost one-third had disease that had already failed salvage therapy and four patients had primary refractory AML.
Patients received venetoclax with high-dose cytarabine either alone, with idarubicin or with azacitidine. Although the study was not designed to compare the three regimens directly, activity was seen across all treatment groups.
Complete response rates were 55% with venetoclax and cytarabine alone, 53% when idarubicin was added and 71% in the small cohort receiving azacitidine. Including partial responses, the overall response rate reached 66%, suggesting meaningful anti-leukaemic activity regardless of the chemotherapy backbone used.
The remissions translated into opportunities for potentially curative treatment, the researchers found. Twenty two of the 25 patients who achieved complete remission proceeded to allogeneic stem cell transplantation.
All patients who entered transplantation with MRD-negative disease remained MRD negative at the time of transplant, underscoring the ability of the regimen to achieve deep remissions before definitive therapy.
The researchers also reported responses across a range of molecular subtypes, including patients with KMT2A rearrangements, FLT3 alterations and favourable-risk genetic lesions.
Although patient numbers within individual genomic groups were too small to draw firm conclusions, they said the breadth of activity was encouraging given the biological heterogeneity that characterises relapsed AML.
They said one of the more intriguing findings came before combination chemotherapy had even started.
Patients initially received a seven-day window of venetoclax monotherapy, allowing investigators to assess early biological response.
Among patients whose circulating blast count fell by at least 50% during this period, 78% subsequently achieved complete remission after combination therapy. By comparison, only one-quarter of patients with a poor early response went on to achieve remission.
While the researchers cautioned that the strategy required prospective validation, the findings raised the possibility that an early response to venetoclax could help identify patients most likely to benefit from venetoclax-based salvage regimens or prompt earlier consideration of alternative approaches in non-responders.
The safety profile was consistent with expectations for intensive chemotherapy in this setting. Grade 3 or 4 febrile neutropenia occurred in 52% of patients, gastrointestinal toxicities in 32% and serious infections in 25%.
There were two grade 5 adverse events, including one death from sepsis and colitis considered possibly treatment related. No dose-limiting toxicities were observed in the cohort receiving azacitidine, allowing that regimen to move forward at the recommended phase 2 dose.
With a median follow-up of just over five years, estimated three-year overall survival for the entire cohort was 40%.
Survival differed between treatment cohorts, but the investigators emphasised that these comparisons are difficult to interpret because patients entered the different cohorts with varying prior therapies, anthracycline exposure and genomic risk profiles.
The study was not powered to compare chemotherapy partners and could not establish whether adding idarubicin or azacitidine improved outcomes compared with venetoclax and cytarabine alone.
“Although the durability of these responses is not well assessed in this trial due to most responding patients proceeding to stem cell transplantation, our results suggest this therapy is able to reach disease control while avoiding toxicities that preclude subsequent transplantation,” the researchers wrote.
Other limitations of the study included the absence of randomisation and the modest populations of rare genetic subgroups to precisely assess responses in these groups.
However, the researchers said their findings aligned with growing experience in adult AML, where venetoclax-containing regimens had become established in older or medically unfit patients and were increasingly being investigated alongside intensive induction chemotherapy in fitter populations.
Whether similar benefits can be translated into frontline paediatric AML is now the subject of ongoing clinical trials.
“Overall, these results support the ongoing investigation of venetoclax in combination with intensive chemotherapy in both children with newly diagnosed and relapsed paediatric AML,” the researchers concluded.
