Treating CLL now and in the future: where the science is leading us
Treatment of chronic lymphocytic leukaemia (CLL) has greatly improved over the last decade with a wave of innovation that’s seen the standard of care shift from chemoimmunotherapy (CIT) to highly effective targeted, oral agents and combination therapies.1,2 Overall survival (OS) for patients with CLL at five years ranges from about 20% among very high-risk patients to more than 90% in those with low-risk disease.3 Yet, CLL remains incurable.4 The current goals of therapy are to relieve symptoms and improve the quality of life, stop the cancer from advancing, or achieve remission.
The most prominent therapeutic advances have included the introduction of Bruton’s tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors. The latter is an attractive therapeutic target in CLL due to its ability to induce apoptosis of CLL cells, and BcL-2 inhibitors have had a positive impact in improving outcomes in CLL.5 Similarly, BTK inhibitors have become a recommended treatment option across all settings and characteristics, due to their well-established efficacy and safety as compared to CIT.6
As the arsenal of new and effective agents continues to grow, and we work towards a future where cure may not be far out of sight,7 identifying treatment regimens and navigating the most suitable treatment sequence for each individual patient becomes increasingly important.
Navigating the Current CLL Treatment Landscape
Risk-factor testing as a guide to treatment decision-making
The prognosis of CLL patients is mainly determined by the presence or absence of genetic markers, such as del(17p), TP53 and IGHV mutations. As genetic aberrations may change during the course of the disease, they should be tested before starting treatment, so the most appropriate therapy is selected.8 For example, standard CIT is not recommended for people with del(17p) or TP53 mutations, which are associated with aggressive, CIT-resistant disease. Patients with these markers have better outcomes when treated with novel agents.8
The good news is the value of patient risk factor testing is being widely recognised, with many national and international guidelines recommending routine testing to inform treatment choice.4,9,10,11 Unfortunately, this has not yet become standard clinical practice with an observational registry study (informCLL) finding testing results to be poor - approximately one-third of high-risk patients (those with del(17p) or TP53 mutations) in the study received CIT, which is not aligned to current treatment guidelines.12 A wider appreciation of the importance of patient risk stratification and risk-factor testing to guide clinical decision making will enable the prescription of the most suitable treatment for each individual patient, at the right time and will, ultimately, improve outcomes.13
Looking Towards the Future
Achieving MRD negativity and treatment-free periods with combinations of novel therapies
The best outcome for a patient with CLL needing therapy is to obtain a complete response (CR) with undetectable (or negative) minimal residual disease (MRD). With combinations of novel agents, such as anti-CD20 monoclonal antibodies, or even newer combinations of BTK inhibitor-based regimens, we may be able to achieve a higher proportion of MRD negative complete responses. This is very important as it permits us to shorten the duration of therapy, limiting side effects and, importantly treatment costs. MRD-guided studies are ongoing looking at optimal combinations according to the risk of different patients and considering when to stop treatment as well as when to resume again - if the MRD appears or if the patient progresses. To date, the use of MRD as treatment guide in routine practice is not recommended.
CAR-T cell therapy
Chimeric antigen receptor T Cell (CAR-T) cell therapy, whereby the patient’s own immune cells are collected and re-targeted against their cancers, is one of the biggest developments on the horizon for CLL treatment. CAR-T therapies have the potential to become a standard therapy both alone and in combination with immune-modifying agents, including for patients with refractory disease or in earlier lines of therapy.14
Conclusion: Treating the individual patient
Novel agents are replacing CIT as the standard of care and scientific advances will continue, with additional small molecules, immunotherapies, and novel combinations of existing targets on the immediate horizon. This is positive news for patients and for the medical community. Yet, achieving the best possible outcomes for patients requires prescribing physicians to confidently navigate the treatment landscape to determine how best to treat their patients. Staying up to date on the latest clinical and real-world evidence is the best approach to making considered decisions, which must be based on a careful weighting of patient and disease characteristics, available agents, and the patient’s expectations and preference. Patient preference should also inform decision-making – some patients may prefer and be suitable for a fixed-duration therapy, while continued single-agent use may be preferable, and necessary to others. Looking at the future, a scenario in which CLL is controllable for long periods of time, equivalent to a functional cure of the disease, is becoming a plausible reality.
- Yosifov DY, Wolf C, Stilgenbauer S, Mertens D. From biology to therapy: the CLL success story. Hemasphere. 2019;3:e175.
- Smolewski P, Robak T. Current treatment of refractory/relapsed chronic lymphocytic leukemia: a focus on novel drugs. Acta Hematol. 2020 Nov 25 [epub ahead of print].
- International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17:779-790.
- Mukkamalla SKR, Taneja A, Malipeddi D, et al. Chronic lymphocytic leukemia. Updated 2021 Mar 7. In: StatPearls. Treasure Island: StatPearls Publishing; 2021 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470433/ Last accessed: June 2021.
- Lampson BL, Davids MS. The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep. 2017;12(1):11-19. doi:10.1007/s11899-017-0359-0
- Scheffold A, Stilgenbauer S. Revolution of chronic lymphocytic leukemia therapy: the chemo-free treatment paradigm. Curr Oncol Rep. 2020;22:16.
- Milne K, Sturrock B, Chevassut T. Chronic Lymphocytic Leukaemia in 2020: the Future Has Arrived. Curr Oncol Rep. 2020;22(4):36. Published 2020 Mar 14. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072049/. Last accessed: June 2021.
- Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32:23-33.
- Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124:49-62.
- Wierda WG, O’Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 2011;29:4088-4095.
- Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745-2760.
- Mato AR, Barrientos JC, Ghosh N, et al. Prognostic testing and treatment patterns in chronic lymphocytic leukemia in the era of novel targeted therapies: results from the inform CLL Registry. Clin Lymphoma Myeloma Leuk. 2020;20:e174-e183.3
- Moreno C. Standard treatment approaches for relapsed/refractory chronic lymphocytic leukemia after frontline chemoimmunotherapy. Hematology Am Soc Hematol Educ Program. 2020;2020:33-40.
- Steinberg A. CAR T-Cell therapy poised to become routine care in CLL. Targeted Therapies in Oncology 2019. Available at: https://www.targetedonc.com/view/car-tcell-therapy-poised-to-become-routine-care-in-cll Last accessed: June 2021.