Study: CLL Therapies Cannot Overcome Increased Infection, Malignancy Risk

A new comparison of chemoimmunotherapy and ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech) in patients with chronic lymphocytic leukemia (CLL) shows that although both treatments reduce clonal B cells, neither led to a significant recovery of normal B cells.

The report, published in Frontiers in Oncology, suggests that patients with CLL remain at a heightened risk of infection and secondary malignancy, regardless of which treatment they receive.

The study authors noted that increased rates of infection and secondary malignancies are a major problem among people with CLL.

Chronic lymphocytic leukemia | Image credit: momius - stock.adobe.com

“Many CLL patients present with recurrent bacterial infections, which are a leading cause of morbidity and mortality among untreated and treated patients, indicating that the CLL disease process reduces immune function,” they wrote.

Historically, chemoimmunotherapy with anti-CD20 monoclonal antibodies was used to treat the disease, the authors said. The treatment drove down CLL B-cell numbers, but was only suitable for patients who were young and fit. Fludarabine-based chemoimmunotherapy was not an option for older, frail patients, they added.

More recently, pentostatin-based chemoimmunotherapy has been used, the authors said, which unlike fludarabine did not increase the risk of bone marrow toxicity and other complications. However, most patients with CLL now receive novel targeted agents such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), although the study investigators said the therapy is also known to have effects on immune competency “ranging from beneficial to unfavorable.”

They wanted to better understand how the 2 treatment options—pentostatin-based chemoimmunotherapy and ibrutinib—affected the immune repertoire of patients with CLL. To do so, they accessed cryopreserved blood samples from 10 patients with CLL who underwent frontline chemoimmunotherapy, 5 patients who were given ibrutinib in a frontline setting, and 18 patients with relapsed or refractory CLL who were treated with ibrutinib. They also used samples from 8 age-matched healthy controls.

In addition to baseline analysis, samples were tested at standard response–evaluation intervals for each therapy. In the case of chemoimmunotherapy, that meant 6 months; in the case of ibrutinib, evaluation took place at 12- and 24-month timepoints.

The authors found that both CD4+ conventional T cells and CD8+ cytotoxic T cells had similar responses regardless of treatment, although they said there were notable differences in exhaustion status between the two therapies.

“Both treatments dramatically increased the prevalence and functional status of monocyte, dendritic cell, and natural killer cell subsets,” they wrote. “As expected, both regimens reduced clonal B-cell levels; however, we observed no substantial recovery of normal B cells.”

They concluded that although most immune subsets showed improvement on both therapies, patients in both therapeutic cohorts continued to be at a heightened risk of infection or secondary malignancy. They said further research is needed to figure out how better to overcome this conundrum.

“Restoration of immune function, particularly of innate immune effector subsets, as they provide frontline protection against infectious agents, is critical to limit clinical complications and improve vaccine responses,” they wrote.

The authors said assessment of CLL B-cell population kinetics with immune subset levels and function “is highly informative in patients undergoing any treatment regimen.

“Our approach to perform a deep dive into innate and adaptive immune subset status in conjunction with assessment of clinical complications and outcomes can be a platform for future designs of treatment evaluation in CLL or other hematologic malignancies.”

As the development of novel strategies to treat B-cell malignancies continues, the authors it will be important to prioritize the potential effects of the therapy on patient immune status.

Reference

Welch BM, Manso BA, Gwin KA, et al. Comparison of the blood immune repertoire with clinical features in chronic lymphocytic leukemia patients treated with chemoimmunotherapy or ibrutinib. Front Oncol. 2023;13:1302038. doi:10.3389/fonc.2023.1302038