CLL Immune Dysfunction Drives Infections, Cytopenias, and Cancer Risk

Persistent innate and adaptive immune dysfunction in chronic lymphocytic leukemia (CLL) is an early, intrinsic feature of the disease, and it has been implicated as a major driver of increased risks of infections, autoimmune cytopenias, and secondary malignancies that make this cancer one of the most clinically complex hematologic malignancies to manage, according to a new review published in Cancers (Basel).¹

Despite targeted therapeutics showing great promise for disease control and immune balance, this immune dysfunction is an ongoing issue for these patients, and it begins long before treatment starts. The analysis synthesizes evidence to map how CLL-associated immunosuppression shapes clinical outcomes and where targeted therapies are falling short of full immune restoration.

How CLL Dismantles Immunity

Clonal expansion of dysfunctional B cells interferes with normal antibody production, resulting in hypogammaglobulinemia in up to 85% of patients, the present study authors wrote. Even patients with adequate immunoglobulin levels have demonstrated immune defects that blunt responses to encapsulated organisms and vaccines. For example, T cells display features of chronic exhaustion despite being preserved or elevated, including overexpression of inhibitory receptors such as PD-1 and cytotoxic T-lymphocyte antigen 4; reduced cytotoxic capacity; and impaired cytokine production.

In addition, regulatory T cells expanding to a number that is larger than it should can contribute to an impaired immune microenvironment that experiences a “loss of peripheral tolerance” of leukemic cells, the authors explained. Neutrophils also show defective migration and phagocytosis, and natural killer cells can exhibit reduced cytotoxicity.

Infections remain among the leading causes of death in CLL, according to data published within the last decade,^2,3 and they occur across all disease stages, including in untreated patients. Serious infections also impose a substantial financial burden on the health system, with population-based data highlighting direct hospital costs attributable to infectious complications in CLL.⁴

The targeted therapy era has shifted, but not resolved, the infection landscape. Bruton tyrosine kinase (BTK) inhibitors have reduced classical opportunistic infections but introduced new risks, and venetoclax is frequently associated with severe neutropenia.¹ The review authors advocate a personalized prevention approach: antiviral and Pneumocystis jirovecii pneumonia prophylaxis where indicated, and early vaccination before treatment initiation despite suboptimal immunogenicity.

Autoimmune Cytopenias: Biology Over Burden

Autoimmune cytopenias (AICs) affect 4% to more than 10% of patients with CLL patients and may arise before diagnosis, at presentation, or at any point during the disease course, making them “a manifestation of underlying immune imbalance intrinsic to CLL biology,” the authors wrote. CLL cells rarely produce pathogenic autoantibodies themselves. Patients with trisomy 12 face a particularly elevated risk, with up to 24% developing AICs.¹ The picture with BTK inhibitors is largely favorable. Ibrutinib and its successors appear to reduce most AICs through IL-2–inducible T-cell kinase inhibition and Th1 polarization, whereas venetoclax carries a higher rate of treatment-emergent AICs.

Second Malignancies: A Surveillance Gap With Cost Implications

CLL is associated with a markedly elevated risk of second primary malignancies. Standardized incidence ratios for any secondary neoplasm range from 1.14 to 2.17 across national registry analyses, the study authors explained. Clonal hematopoiesis of indeterminate potential (CHIP) also is emerging as a key biological link between CLL, aging, and therapy-related myeloid neoplasms,⁵ and CHIP-associated mutations in the epigenetic regulators DNMT3A, TET2, and ASXL1 can expand under treatment-induced selective pressure into myelodysplastic syndromes or acute myeloid leukemia.¹ Richter syndrome, which is the transformation of CLL into aggressive lymphoma, occurs in approximately 2% to 10% of patients and typically carries a poor prognosis.¹

The present review endorses National Comprehensive Cancer Network CLL/SLL Guidelines recommendations for annual full-body dermatologic skin exams, with every-6-month frequency in high-risk patients, alongside standard age-appropriate screening for breast, cervical, colorectal, and prostate cancers.¹ Systematic skin surveillance represents a relatively low-cost intervention with meaningful potential to detect aggressive squamous cell carcinomas, which occur disproportionately in CLL, at earlier, more treatable stages.

The Unfinished Business of Immune Restoration

Controlling leukemic burden is not the same as restoring immune competence, the authors conclude. Many immune defects in CLL persist despite effective disease control with targeted therapies, and this gap continues to drive morbidity. They call for strategies that address immune restoration alongside tumor eradication, with direct implications for how payers and health systems design long-term supportive care pathways.

References

1. Juárez-Salcedo LM, Loscertales J. Clinical implications of immune dysfunction in chronic lymphocytic leukemia. Cancers (Basel). 2026;18(9):1323. doi:10.3390/cancers18091323
2. Crassini KR, Best OG, Mulligan SP. Immune failure, infection and survival in chronic lymphocytic leukemia. Haematologica. 2018;103(7):e329. doi:10.3324/haematol.2018.196543
3. van der Straten L, Levin MD, Dinnessen MAW, et al. Causes of death among patients diagnosed with chronic lymphocytic leukemia: a population‐based study in the Netherlands, 1996–2020. Hemasphere. 2024;8(11):e70015. doi:10.1002/hem3.70015
4. Shaw ML. Serious infections drive major hospital costs in CLL. AJMC^®. March 26, 2026. Accessed June 5, 2026. https://www.ajmc.com/view/serious-infections-drive-major-hospital-costs-in-cll
5. Shaw ML. Clonal hematopoiesis is quietly reshaping CLL treatment. AJMC. March 18, 2026. Accessed June 5, 2026. https://www.ajmc.com/view/clonal-hematopoiesis-is-quietly-reshaping-cll-treatment