ASH 2020 | Zella 201: alvocidib-based regimens in MCL-1 dependent high-risk AML

Zella 201 was a randomized Phase II study of alvocidib plus cytarabine and mitoxantrone in a time-sequential therapy regimen versus cytarabine and mitoxantrone in relapsed/refractory AML patients who have MCL-1 dependence by a novel BH3 biomarker profile technique. The results that we’re presenting at ASH is the alvocidib cytarabine and mitoxantrone treatment regimen in an exploratory subgroup of newly diagnosed high-risk AML patients who had MCL-1 dependence by the same BH3 profiling technique. We defined newly diagnosed high-risk AML patients in this study as those between the ages of 18 to 65 years, who either had treatment-related AML or therapy-related AML, AML for preexisting MDS or MPN, a secondary AML subtype, or those with adverse risk disease by European Leukemia Net classification. And so we enrolled 14 patients on this exploratory, newly diagnosed high-risk cohort with alvocidib, cytarabine, and mitoxantrone.

And I should mention that alvocidib is a CDK9 inhibitor, which leads to suppression of RNA polymerase 2-mediated genes, such as MCL-1, c-Myc and others. And so alvocidib leads to the suppression of apoptosis regulatory factors in AML, most notably the inhibition of MCL-1. 14 patients enrolled on this exploratory cohort with alvocidib, cytarabine, and mitoxantrone, and we saw very similar safety profile with alvocidib, cytarabine, mitoxantrone in this MCL-1 dependent cohort, as we’ve seen in our previously published studies with alvocidib, cytarabine and mitoxantrone in both the relapsed/refractory and newly diagnosed setting. The most common severe side effects were diarrhea, which grade three diarrhea was actually seen in about 29% of patients on this study. And the diarrhea is self-limiting, it’s a secretory diarrhea that occurs very rapidly after the first dose of alvocidib and is controlled with antidiarrheals and again, very temporary and reversible.

And we also saw tumor lysis syndrome in 21% of patients who enrolled in this study, which is again consistent with our previously published studies of alvocidib in this setting. Overall, the complete remission rate of the evaluable patients, there were 13 evaluable patients who were enrolled on this cohort, the overall complete remission rate, which included CRI was 62%. And then if you include partial remissions, the overall response rate was 69%. And this was a very poor risk subgroup of patients. As I mentioned, these were all high-risk AML patients by our definition that we used for this study, 64% of patients who enrolled on the study had adverse risk disease by European Leukemia Net standards and had unfavorable risk cytogenetics by SWOG cytogenetic classification. The overall survival on this study that the median followup who was eight months and the median overall survival to date was eight and a half months.

So poor risks of group of patients, modest survival, and need more follow-up in order to assess small numbers of patients, but overall, the response rates were encouraging to us. So I think in conclusion, this is the first study Zella 201, assessing a novel agent in patients who have MCL-1-dependent AML. This was a biomarker driven study, and again, patients were only eligible for this cohort if they had MCL-1 dependence. We saw very similar side effect profile compared with alvocidib, cytarabine, and mitoxantrone in those without MCL-1 dependence. And we saw encouraging response rates and overall CR/CRI rate of 62%, however, duration of remission and survival was relatively modest and a further investigation, certainly warranted, incorporating alvocidib with diverse induction chemotherapy backbones in newly diagnosed AML patients. And hopefully, these data will form the framework for other CDK9 inhibitors and perhaps even MCL-1 inhibitors in this setting.