New Biological Insights and Recent Therapeutic Advances in the Management of Acute and Chronic Leukemias and Myelodysplastic SyndromesClinical experience with the Bcl-2 inhibitor venetoclax (ABT-199) as treatment for relapsed/refractory CLL
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TRANSCRIPTION:
DR BROWN: So that’s an inhibitor specific for BCL-2, which has been very exciting in Phase I studies, in part because, I think, in contrast to the B-cell receptor pathway inhibitors, it actually does drop the white count and clear bone marrow and result in a higher rate of complete remissions. So in the single-agent study, the complete remission rate was about 25% to 30%, with an 80% overall response rate. And so the potential for combining the BCL-2 inhibitor with a BCR pathway inhibitor could be very exciting in terms of clearing residual disease. The toxicity of it has been not insignificant, however. The prior generation BCL-2 inhibitor inhibited not just BCL-2 but also BCL-X long, which is in platelets. And this led to thrombocytopenias and dose-limiting toxicity. Have not seen that with ABT-199. However, we are seeing tumor lysis syndrome, which actually resulted in a couple of deaths in the early phases of both the single-agent study and the 199/rituximab study. And so there have been several modifications to the study protocol so that now the drug is given by very slow dose escalation, weekly over about 5 weeks, to get to the final cohort dose. And patients with high tumor burden are still escalated in the hospital for each dose with very careful tumor lysis monitoring. Patients with lower tumor burden are potentially managed as outpatients in the most recent trials. DR LOVE: And what’s your own clinical experience with the drug? DR BROWN: My own clinical experience with the drug is that it is very potent and we have seen bone marrow clearance. And we have complete remissions. And even some of the partial remissions are MRD-negative. And the criteria for many of these trials for calling someone a complete remission requires that even the long axis of a single lymph node be less than 10 millimeters. So we have occasional patients with, say, a 15-mm by 6-mm lymph node who are called a partial response. And many of them are MRD-negative, as it turns out. And so the MRD-negative rate on even these relapsed patients has been on the order of 35% to 40%, it looks like. |