Myeloid venetoclax resistance observed in CLL patients

An Australian haematologist is backing time-limited therapy after his research showed long-term venetoclax (Venclexta) use could drive drug resistance in myeloid cells.

A study of 89 chronic lymphocytic leukaemia (CLL) patients on median 75 months’ venetoclax showed prolonged BCL2 inhibitor use could give rise to anti-apoptotic myeloid BAX mutations — a potentially significant adaptation for a drug that relies on apoptosis to treat CLL and myeloid malignancies.

BAX mutations were observed in 13 patients and some were likely selected for in the context of other clonal haematopoiesis mutations.

Persistent cytopenias, which can be managed with dose reductions or granulocyte colony stimulating factor, occurred in 52% of patients, consistent with the known cytopenia incidence in venetoclax-treated CLL patients, lead author and Peter MacCallum Cancer Centre haematology consultant Dr Piers Blombery told the limbic.

While 20 patients had clonal haematopoiesis, only 10 had therapy-related myeloid neoplasms. These were associated with prior fludarabine-alkylator exposure, not venetoclax use or the presence of BAX mutations, the paper read.

These findings bolster the case for time-limited therapy, which, in CLL, is one to two years on venetoclax, according to Dr Blombery.

“It should be noted that the patients in this study were some of the earliest patients treated with venetoclax in the world and, back then, we were using continuous therapy until progression, and so there aren’t many people nowadays who are going to be treated like this with CLL from here,” he said.

“But it does give more weight to this concept of using time-limited therapy, because clearly, venetoclax has effects throughout the haematopoietic system, not just in the tumour compartment and so, whilst we don’t think currently that that’s caused an increased risk of therapy-related myeloid neoplasms, it’s pertinent that once you see a mutation developing, we should aim to limit exposure in the absence of evidence of efficacy of prolonged treatment.”

While his results warrant further study of BAX-related venetoclax resistance in myeloid malignancies, Dr Blombery does not currently recommend routine screening for the mutation in CLL.

“I don’t think there’s the evidence to routinely screen for it at the moment. BAX mutations rarely occur in the CLL compartment, weren’t associated with therapy-related myeloid neoplasms and weren’t obviously associated with cytopenias in our data,” he said.

At this point, it’s “an intriguing finding … which may have implications in the future once we have done further experimental work and research in different cohorts”, he concluded.

The study is published in Blood

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