Blood cancers

Cure in CLL requires disease control plus immune restoration


Disease eradication combined with immune restoration represent the “holy grail” of treatment for CLL, according to Australian haematologists.

Writing in Leukemia & Lymphoma, Dr Sasanka Handunnetti and Professor Con Tam from the Peter MacCallum Cancer Centre, said the immune impacts of Bruton tyrosine kinase (BTK) inhibitors and possibly selective BCL-2 inhibitors might help achieve that goal.

Dr Handunnetti and Professor Tam were responding to a report on two trials of BTKi monotherapy – ibrutinib and the more selective acalabrutinib – and indicators of subsequent immunological change in CLL patients.

The study reported that in both trials, serum IgA levels increased as early as six months after initiation of the BTKis and were sustained at two years with acalabrutinib and out to five years with ibrutinib.

Absolute IgA levels were below the lower limit of normal before the start of therapy and reached normal reference range values at 24 and 42 months of follow-up with acalabrutinib and ibrutinib respectively.

The changes in IgA levels also correlated with infection risk as patients with a ≥50% increase in IgA had a significantly lower number of infections compared to those with <50% increase in IgA.

The study also found that elevated CD4+ and CD8+ T lymphocyte counts returned to normal ranges and were sustained in both treatment groups.

“While this study did not interrogate previously described ITK-mediated immunologic effects such as TH1 and TH2 development and effector NK cell function to more specifically distinguish between the immune impacts of ibrutinib and acalabrutinib, it did demonstrate partial restoration of humoral immunity and an association with reduced infection rate,” the Commentary article said.

Its authors added that the fact that serum IgA levels seemed to be clinically relevant in BTKi treated CLL patients was “fascinating” given that IgA deficiency in the non-CLL population is largely of no clinical consequence.

Dr Handunnetti and Professor Tam said there was little evidence yet on the immunological impacts of newer generation BTKis such as zanubrutinib and other novel therapies such as venetoclax.

“Multiple combination therapies for CLL, using novel therapy, anti-CD20 antibodies and chemotherapy are currently being evaluated in clinical trials and emerging data around immune recovery, alongside deep and durable CLL responses, is highly promising,” they said.

“In CLL, early data suggest that venetoclax-ibrutinib-treated patients have some restoration of innate immunity, with the restoration of neutrophil and monocyte immunophenotype, and improved monocyte function.”

“Therefore, further work is needed to evaluate the impacts of novel therapies and their combinations on the residual immune system and the niche microenvironments of CLL and non-CLL models and patients.”

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