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Wave of Targeted CLL Therapies Raises Questions About Autoimmune Complications

Jared Kaltwasser
New targeted therapies like ibrutinib, idelalisib, and venetoclax appear to be highly successful in the treatment of chronic lymphocytic leukemia (CLL), but investigators say it’s unclear how those therapies impact autoimmune complications of the cancer.
As new therapies change the way physicians treat chronic lymphocytic leukemia (CLL), a new study is highlighting the need to consider how these therapies might affect autoimmune complications associated with the cancer.

About 20,000 cases of CLL are diagnosed in the United States each year, and up to one-quarter of those patients also suffer from autoimmune complications. Writing in the journal Cancers, investigators from the University of Torino, Italy, evaluated the impact of a new wave of targeted cancer therapies on the autoimmune phenomena associated with CLL.

Specifically, the review article looks at the impacts of Bruton tyrosine kinase (BTK) inhibitor ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib, and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. The new therapies appear to be a strong option to treat CLL, particularly as an alternative to standard chemotherapy in patients with CLL-associated autoimmune cytopenias (AICs). AICs are the most common autoimmune complications in patients with CLL, an association that has been known for some 6 decades, and which affects between 4% and 7% of patients will CLL.

However, corresponding author Marta Coscia, MD, PhD, and colleagues note that it can be particularly difficult to quantify AIC cases in patients with CLL, in part because of inconsistency in how studies define AICs.

“Non-hematological autoimmune manifestations are less frequent and encompass a wide range of different clinical disorders, rendering even more arduous a precise characterization of their incidence, correlation with CLL, and prognostic impact,” they write.

While AICs tend to correlate with late-stage disease, Coscia and colleagues say there’s no good measure yet of the extent to which AICs impact survival of patients.

They say that the advent of therapies like ibrutinib, idelalisib, and venetoclax to treat CLL creates a need to better understand how these molecules affect autoimmune complications. The need is even more pronounced since patients with AICs were usually excluded from clinical trials for the new targeted therapies, limiting the amount of solid data available. However, that dearth of data seems to be changing as the drugs become more common.

Coscia and colleagues say the 3 drugs each appear to have different impacts. Ibrutinib, for instance, has been linked with flare-ups of AIC in the earliest phases of treatment, but over the longer term it seems to lessen rates of treatment-emergent AIC.

Less data is available on idelalisib’s impact on AIC management, but it appears to be most active in causing non-hematological autoimmune complications, the authors said.

With regard to venetoclax, Coscia and colleagues found that while there are indications of treatment-emergent AIC in patients given the new therapy, it’s unclear what impact the therapy has on the treatment of autoimmune complications.

In summarizing their findings, the authors write that there are still plenty of questions that need to be answered. They also noted that newly emerging therapies will need to be evaluated in the context of autoimmune impacts.

For instance, studies of chimeric antigen receptor modified T cells (CAR T cells) ought to also weigh the impact on autoimmune complications, the authors argue.

“Many uncertainties still remain regarding the impact of targeted agents on autoimmune phenomena in CLL, but we can anticipate that a wide range of information coming from translational studies, as well as the increasing availability of long-term follow-up data from clinical trials and the extended use of these drugs in the clinical practice will provide more conclusive data in the near future,” Coscia and colleagues state.

Reference

Vitale C, Montalbano MC, Salvetti C, Boccellato E, Griggio V, Boccadoro M, et al. Autoimmune complications in chronic lymphocytic leukemia in the era of targeted drugs. Cancers. 2020; 12(2):282. doi:10.3390/cancers12020282.

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