Venetoclax chemo combo active and well-tolerated in children with r/r AML
Dr Seth Karol - St. Jude Children’s Research Hospital, Memphis, USA
We described the results of a phase I/II study of venetoclax in combination with intensive chemotherapy in children with relapsed or refractory acute myeloid leukaemia, or AML. The background to the study is that venetoclax is a novel BCL2 inhibitor that has shown effectiveness in combination with hypomethylating agents in older adults with AML who were thought to be unfit for more intensive chemotherapy. Unfortunately that combination was not quite as effective in older adults or in adults with relapsed or refractory disease and hypomethylating agents are not typically used in relapsed paediatric AML due to lower levels of efficacy. So we hypothesised that venetoclax may improve the efficacy of more intensive chemotherapy that is classically given to children with relapsed or refractory AML.
We designed a phase I/II study where we escalated doses of venetoclax and intensive chemotherapy, including cytarabine and idarubicin separately, and then evaluated the safety of that therapy as well as the efficacy of the therapy in this population.
Would you be able to tell us about the results of the trial?
We were happy to see that the combination was well tolerated. We escalated venetoclax from an initial dose of 240mg/m2 up to 360mg/m2 which is an adult equivalent dose of 600mg. That was well tolerated, as was escalating doses of cytarabine from 100mg/m2 for 20 doses to 1g/m2 for eight doses which is a classic high dose cytarabine regimen that we give to children with relapsed disease. So that combination was well tolerated and count recovery was as expected given the intensive chemotherapy backbone. We were also able to add idarubicin to patients who had had limited prior anthracycline exposure which enabled good combination therapy and demonstrated that venetoclax could be given safety with combinations of both anthracycline and intensive cytarabine dose.
Were there any toxicities at all observed?
The most common toxicities were infectious and included febrile neutropenia in approximately two-thirds of patients. Sepsis occurred in approximately 5% of patients and there was one therapy related death that was related to colitis.
Did you identify any other potential targets throughout your study?
We haven’t identified additional potential targets yet. We have identified a population of patients that did not respond. Overall the population responded quite well and 57% of this very heavily pre-treated population was able to achieve a complete remission or a complete remission with incomplete recovery. Many of these were MRD negative. As a result, most of the patients that responded were able to proceed to transplantation which is the definitive therapy for children with relapsed AML. We identified the recommended phase II dose which is, again, that high dose cytarabine of 1g for eight doses as well as the venetoclax at 600mg. 70% of that population that received that dose or received that dose in combination with idarubicin achieved a complete response. So, as a result, we’ve got this very high response rate at the recommended phase II dose.
But we also know that there’s this 30% of patients that don’t respond to that combination and we think that future work really needs to identify novel combinations or novel therapies that will be effective for that group.
In general, what are the main challenges for treating AML in this patient population?
The greatest challenges in this population are the identification of novel targets for a population that is quite refractory to existing therapies. The other challenge is identifying markers for these populations that best identify the appropriate therapies. So some of the work identifying novel targets in adult AML have identified targets that don’t exist in paediatric AML or exist at very low frequencies. So additional work is needed to best identify optimal targeting for relapsed paediatric patients.
And finally what’s next for the study?
We’ll complete enrolment on the phase II dose levels and that is continuing and should occur relatively shortly. Then additional work will be done to identify reasons that we had good response and poor response in different patient subsets and to try to identify novel combinations for those patients that aren’t yet responding.