Clonal Hematopoiesis Is Quietly Reshaping CLL Treatment

As patients age on therapy for their chronic lymphocytic leukemia (CLL), which is the most common leukemia in Western adults,¹ thanks to modern targeted therapies, their extended survival is becoming increasingly known for a largely silent process quietly unfolding in their bone marrow, accounted for by few treatment algorithms.

The results of an investigation into clonal hematopoiesis (CH) in patients with CLL and its impact on their health appeared in a recent issue of Clinical and Translational Medicine.² The team synthesized current evidence and argues that it is time to take CH seriously in the management of CLL.

“CLL should be viewed not solely as a B-cell malignancy, but as part of an age- and therapy-modified, chronically inflamed haematopoietic ecosystem in which CH and the leukaemic clone co-evolve,” the authors wrote.

CH is the age-related accumulation of genetic mutations in blood-forming stem cells that expand without causing overt malignancy, the study authors explained. Once considered a footnote in hematology, it has begun to emerge as a determinant force in the course of CLL with the ability to amplify treatment toxicities, raise cardiovascular risk, and predispose patients to a subsequent, more aggressive cancer.

Why This Question Needed Answering

CH is not rare, and large studies have published their findings on the most common genetic mutations driving it—DNMT3A, TET2, and ASXL1—found in 10% to 20% of people over age 70. CLL itself is predominantly a disease of older adults. The study authors explain that studying CH in this setting has been difficult because the leukemic B cells that dominate the blood can obscure CH mutations hiding in other cell lineages. However, the arrival of error-corrected sequencing technologies and large prospective trials has created a new opportunity. Also, although the advent of newer targeted agents, such as Bruton tyrosine kinase and BCL2 inhibitors, has transformed the field, their interactions with CH have not been systematically examined.

Rather than conduct a new clinical trial, the authors performed a comprehensive synthesis of existing data from prospective clinical trials, real-world patient cohorts, and translational laboratory studies. Special emphasis was placed on data from 2 landmark phase 3 German CLL Study Group trials: CLL12, which compared ibrutinib to placebo in early-stage disease, and CLL14, which compared venetoclax-obinutuzumab to chlorambucil-obinutuzumab. In both trials, CH was assessed using error-corrected sequencing in non–B-cell fractions, allowing researchers to separate true CH from CLL-restricted mutations for the first time at scale.

Key Findings

CH was detected in approximately 58% of patients with CLL across both trials, with 35% meeting formal criteria for CH of indeterminate potential. This is far higher than earlier estimates and confirms that CH is not an incidental finding in CLL. The clinical impact of CH was also highly context-dependent. In patients receiving older chemotherapy regimens (particularly chlorambucil-based therapy), large CH clones were associated with shorter progression-free survival (PFS) and worse overall survival (OS). TP53 and PPM1D mutations were particularly hazardous: cytotoxic drugs appear to selectively expand these preexisting clones, dramatically increasing the risk of therapy-related myelodysplastic syndrome or acute myeloid leukemia.

Targeted therapies told a different story. In patients treated with ibrutinib or fixed-duration venetoclax-obinutuzumab, large CH clones had little to no impact on PFS or OS. CH clones carrying BAX and U2AF1 mutations, transiently selected by venetoclax, contracted after therapy ended, and their presence did not worsen outcomes.

CH also influenced treatment tolerability across the board, as patients exhibiting CH experienced higher rates of cytopenias during therapy, particularly neutropenia. In addition, CH carrying DNMT3A or TET2 mutations was associated with elevated cardiovascular risk, a finding relevant to BTK inhibitor therapy, which itself carries a cardiovascular safety profile that requires monitoring.

The review also situates CH and CLL within a broader biological framework: the chronic, low-grade inflammatory state that accumulates with age. In this model, aging does not merely create fertile ground for cancer; it actively fuels CH expansion and CLL development through shared inflammatory pathways, immune dysfunction, and oxidative stress. This means that treating the leukemia without addressing the inflammatory background may leave patients vulnerable to CH-driven complications that emerge years later.

Practical Implications for Clinicians

The authors explain that their findings do not serve as a call for routine CH testing in all patients with CLL, as there is not yet enough evidence to support the move, and the tools needed for precise CH assessment remain largely research-grade. They do, however, outline several scenarios where assessment is clinically meaningful.

Patients with TP53- or PPM1D-mutated CH who might otherwise be candidates for cytotoxic therapy should be steered toward chemo-free regimens when possible. The data from the CLL14 study alone make clear that genotoxic drugs can turn a manageable CH clone into a life-threatening secondary malignancy. Clinicians managing CH-positive patients on therapy should anticipate a higher burden of cytopenias and build monitoring strategies accordingly. The cardiovascular implications of CH should factor into long-term management and risk reduction planning.

Looking ahead, the authors argue that CH assessment may one day sit alongside IGHV mutation status, TP53 disruption, and minimal residual disease as a routine pillar of CLL risk stratification. Prospective CH-stratified clinical trials, longitudinal multiomic studies, and focused investigations are needed to confirm whether CH-guided therapy selection improves outcomes. In the meantime, the message for practicing oncologists is clear: in an aging patient with CLL, the leukemia may not be the only thing worth watching.

“As evidence accumulates, CH is poised to become a central component of risk-adapted CLL management,” they conclude.

References

1. Emadi A, Byrd RC, Law JY. Chronic lymphocytic leukemia. Merck Manual Professional Version. Revised February 2026. Accessed March 18, 2026. https://www.merckmanuals.com/professional/oncology/leukemias/chronic-lymphocytic-leukemia-cll
2. Martino EA, Caserta S, Skafi M, et al. Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy. Clin Transl Med. 2026;16(3):e70633. doi:10.1002/ctm2.70633