Role of Age and Fitness in Selecting Treatment for Chronic Lymphocytic Leukemia
The risks of administering chemoimmunotherapy (CIT) such as fludarabine, cyclophosphamide, and rituximab (FCR) in advanced age have been clearly demonstrated in clinical trials, resulting in a suggested age cutoff of approximately 65 years. In clinical studies, older patients were more susceptible to myelosuppression and infection from CIT with FCR than were younger groups. Age and fitness are key drivers in the decision about CIT use in elderly patients, for whom reduced-intensity regimens have been developed and continue to be used (eg, bendamustine-rituximab, chlorambucil plus CD20 antibody). In contrast, in the novel treatment era, age appears to generally have less of an influence on the choice of novel agents compared with the choice of CIT, although age-related comorbidities remain important considerations. Our featured experts discuss the impact of patient age and fitness on treatment selection for CLL, noting that age, alone, is not necessarily a sufficient measure of fitness.
Q: How do advanced age and/or reduced fitness impact the treatment of patients with CLL?
Jennifer R. Brown, MD, PhD
Director, Center for Chronic Lymphocytic Leukemia
“In the era of novel agents, the immediate impact of increasing age is, perhaps, less evident.”
The risks of advanced age have been clear in the CIT era—particularly those related to reduced renal function, which, in many cases, renders fludarabine-based therapy difficult to tolerate. Risks related to reduced bone marrow reserve also make fludarabine-based therapy difficult to tolerate. FCR has strong benefits in young, fit patients, particularly those with mutated immunoglobulin heavy chain variable region (IGHV ) gene. However, patients who are over the age of approximately 60 to 65 years do not do as well with FCR, and studies from the German CLL Study Group suggested that a cutoff of 65 years was grounded in the observation that more infectious complications occurred in the older age group. In the era of novel agents, the immediate impact of increasing age is, perhaps, less evident. This is, in part, due to the lesser effects of the novel agents on bone marrow and also to the lesser intolerance with respect to renal function, although, with venetoclax, having intact renal function is helpful when we need to escalate the dose and still avoid tumor lysis syndrome. However, there are age-associated comorbidities that are important to consider with the novel agents, such as cardiac comorbidities and bleeding risk with ibrutinib, for instance.
Jan A. Burger, MD, PhD
Professor, Tenured, Department of Leukemia
“My view is that age-related comorbidities generally have less influence on the choice of novel agents when compared with CIT, but there are still age-related conditions that should be taken into consideration.”
With CIT, younger age and the lack of comorbidities have been strong factors to favor a more intensive chemotherapy-based regimen (eg, FCR as the prototype regimen for patients under the age of 65). For elderly patients, reduced-intensity CIT regimens have been developed: bendamustine-rituximab continues to be used, and chlorambucil plus CD20 antibody regimens have been developed for older patients with comorbidities. So, comorbidity and age have been strong influential factors for the selection of CIT, where either an intensive backbone (eg, fludarabine-cyclophosphamide) or less intensive backbone (eg, bendamustine, chlorambucil) is used. However, with the emergence of the novel agents, these treatments are currently used less often. So now, the question becomes, do age and fitness influence the choice of a Bruton’s tyrosine kinase inhibitor vs a phosphatidylinositol 3-kinase inhibitor or a BCL-2 antagonist? My view is that age-related comorbidities generally have less influence on the choice of novel agents when compared with CIT, but there are still age-related conditions that should be taken into consideration.
Anthony R. Mato, MD, MSCE
Director, Chronic Lymphocytic Leukemia Program
“Fitness assessment is more important than chronologic age. Age alone is not necessarily a sufficient measure of fitness. There is huge variability in comorbidities, vital organ function, and muscle mass among patients at a given age.”
I agree with what has been said with regard to age and age-related comorbidity as factors that influence treatment. I would add that fitness assessment is more important than chronologic age. Age alone is not necessarily a sufficient measure of fitness. There is huge variability in comorbidities, vital organ function, and muscle mass among patients at a given age. We are fortunate to have had the introduction of several new CLL therapies, and current options for treatment include oral targeted agents, engineered antibodies, and chemotherapy. Deciding on an appropriate treatment involves consideration of the patient’s treatment history, risk level, and overall health.
Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advance chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 study). Blood. 2014;124(21):19.
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(25):2745-2760.
Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. Lancet. 2018;391(10129):1524-1537. Mato AR, Samp JC, Gauthier G, et al. Drivers of treatment patterns in patients with chronic lymphocytic leukemia stopping ibrutinib or idelalisib therapies. Cancer Biol Ther. 2018;19(7):636-643.