Opportunities Remain for Expanding Precision Medicine in CLL

Although precision medicine (PM)-based strategies have been adopted in chronic lymphocytic leukemia (CLL), several challenges remain in unlocking the full potential of PM write researchers in a new review article published in HemaSphere.¹

As the CLL treatment landscape has moved into an era where targeted treatments, such as Bruton’s tyrosine kinase inhibitors and the BCL2 inhibitor venetoclax (Venclexta; AbbVie/Genentech), are mainstays of treatment, new opportunities to tailor therapy have emerged.

“Some of the promise of PM for CLL has already been realized. Indeed, PM concepts are routinely applied to establish a correct diagnosis (precision diagnostics), decide about the treatment among different therapeutic options (precision therapy), and assess response (precision monitoring). At the same time, basic and translational research is gradually identifying new potential biomarkers and druggable targets to further improve and differentiate PM approaches,” wrote the researchers. “Against this progress, however, major challenges remain to be addressed.”

These challenges, they continued, span across current biomarkers used in CLL treatment, as well as the continuous pursuit of novel biomarkers that can be leveraged before, during, and after treatment.

There has been major progress in precision medicine for CLL, state the study authors; however, major challenges remain | Image Credit: leowolfert-stock.adobe.com

Well-established predictive biomarkers for guiding CLL treatment, including TP53 mutations and IGHV status, have been some of the most consequential outcomes of PM in CLL. These biomarkers are used to guide both treatment choice and treatment duration (ie, fixed duration vs continuous treatment). Use of genetic sequencing assays to inform treatment sequencing have also been explored.

Biomarkers to help determine which patients will need treatment vs those who can forgo treatment continue to be explored.

“In CLL, the need exists for biomarkers that can help discriminate between patients who will experience a stable disease with no treatment requirement during their lifetime from those who will eventually progress and need to be treated,” described the group. “This would allow tailoring the management of patients at the time of diagnosis, sparing unnecessary visits and tests let alone the psychological burden for them and their careers. However, the possibility of applying biomarker‐based information to the individual patient is hampered by the fact that the association, for example, between IGHV gene [somatic hypermutation] status and clinical outcome, only reaches 80% concordance.”

Treatment decisions during and post treatment often account for measurable residual disease (MRD). Use of MRD as a prognostic indicator in CLL is not new,² although prospective randomized data are lacking, with just 1 study assessing the value of MRD-guided treatment. The phase 3 FLAIR study compared MRD-guided treatment with ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech) plus venetoclax vs chemoimmunotherapy, showing improved progression-free survival with the ibrutinib and venetoclax combination.³

For MRD to become a standard practice in CLL, several barriers must be overcome, including developing a standardized approach for measuring MRD, explained the present researchers. Although flow cytometry had been widely adopted due to efforts from the European Research Initiative on CLL, regulatory authorities often require standardization of each assay component, which has not yet been done.

Consensus on undetectable MRD cutoff is also needed. A threshold of 10^-4 is often used, due to being feasible and having shown prognostic value, although some patients can achieve the threshold while still having detectable disease in the bone marrow. A cutoff of 10^-5 has been suggested to overcome this challenge. Certain next-generation sequencing-based assays can be used for a 10^-6 threshold, although prognostic values of these have not been determined.

References

1. Stamatopoulos K, Sarka Pavlova, Al-Sawaf O, et al. Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities. HemaSphere. 2024;8(7):e113. doi:10.1002/hem3.113

2. Kwok M, Rawstron AC, Varghese A, et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood. 2016;128(24):2770-2773. doi:10.1182/blood-2016-05-714162

3. Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063