Veneoclax has revolutionized the treatment of chronic lymphocytic leukemia. It blocks the cancerous chronic lymphocytic leukemia cell’s overexpression of BCL-2. The high level of BCL-2 stops CLL cells from dying when they should. When BCL-2 is blocked there can be very rapid cell death or apoptosis. If the apoptosis is too fast, that can be dangerous as the kidneys may not be able to handle the chemical consequences of too many cells dying in too short a time. That’s called tumor lysis syndrome or TLS and it can be very dangerous.
To avoid TLS, the only FDA approved BCL-2 inhibitor, venetoclax, is usually ramped up slowly over five weeks when used to CLL. This works great and TLS is rarely seen, but it is inconvenient and the rare patient with fast-moving CLL may not have the five weeks to wait to get to the recommended dose.
In this ASCO 2021 abstract by Ailawadhi from Mayo and others, we learn of the first in-human trial of a novel BCL-2 inhibitor (BCL-2i), lisaftoclax, or APG-2575.
Lisafloclax uses a much quicker more patient-friendly daily ramp-up to avoid TLS, starting at 20mg/day and going up daily to 1,200 mg/day.
Fifteen relapsed/refractory CLL patients were included in the study. Prior use of venetoclax would exclude you from the trial. The patients averaged two prior therapies before trying the lisaftoclax. The average age was 70.
Side effects were low neutrophils (22.9%) and anemia (17.1%) and fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%).
After a median of seven cycles of 28 days each, 12 of 14 evaluable R/R CLL / SLL patients had achieved a partial remission or PR, for an overall response rate or ORR of 85.7%.
No TLS was observed, even with the daily ramp-up schedule.
This is early but encouraging data on the 14 CLL patients in a first in-human trial of lisafloclax. MRD data has not yet been reported, but it is very early. Another effective BCL-2 inhibitor, especially one with a lower TLS risk with a quicker ramp-up, would be a great addition to the CLL treatment armamentarium. Much larger trials will be needed, but this is a promising start.
Here is the link to the ASCO abstract to get more of the details: First-in-human study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), in patients (pts) with relapsed/refractory (R/R) CLL and other hematologic malignancies (HMs).
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Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.