Effective and tolerable treatments are needed for older patients [with CLL], most of whom will die of the disease or its complications.— Vicki A. Morrison, MD
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Significant progress has been made in the past 2 decades in the care of patients with chronic lymphocytic leukemia (CLL). Recently, the therapeutic armamentarium has expanded for such patients with the introduction of new targeted agents.
CLL is predominantly a disease of the elderly, with a median age at diagnosis of 72 years, 30% of patients aged 70 to 79 years, and 23% > 80 years of age. Older patients have been underrepresented in prior treatment trials, as have patients of poor performance status (PS > 2), those with significant comorbidities or frailty, and those who are unfit.
Important Assessments
Only select elderly individuals will tolerate standard therapies used in younger patients such as fludarabine, cyclophosphamide, and rituximab (Rituxan). Effective and tolerable treatments are needed for older patients, most of whom will die of CLL or its complications. Assessment of fitness through measures such as comprehensive geriatric assessment is essential
in treatment decisions for the elderly CLL patient.
Not all older patients are alike with regard to comorbidity burden, fitness/frailty, and physiologic function. Chronologic age is not a surrogate for these measures. Comorbidities can be assessed by measures including the Cumulative Index Rating Scale and the Charlson Comorbidity Index. The vast majority of newly diagnosed CLL patients will have at least one comorbid condition, with almost half having multiple comorbidities.
The Comprehensive Geriatric Assessment includes evaluation of functionality, coexisting medical issues, social support, cognitive ability, nutritional status, and geriatric syndromes. These assessments are important in predicting treatment tolerance in the elderly.
Initial Therapy
First-line therapy in select healthy, fit older patients with a Cumulative Index Rating Scale score < 6 and normal renal function may include regimens used in younger patients such as fludarabine/cyclophosphamide/rituximab. In the phase III trial comparison to fludarabine and cyclophosphamide as initial therapy in fit patients, fludarabine/cyclophosphamide/ rituximab resulted in improved overall response rate and progression-free survival, regardless of age.
The “fludarabine/cyclophosphamide/rituximab–lite” regimen, with low-dose fludarabine and cyclophosphamide and high-dose rituximab (and including rituximab maintenance therapy) has been examined in phase II studies and is an alternative regimen associated with less myelosuppression than with traditional fludarabine/cyclophosphamide/rituximab. In addition, cladribine has been combined with rituximab or cyclophosphamide for alternative purine-based therapy in trials including some elderly patients.1
Bendamustine-based regimens are reasonably tolerated in the elderly. A recent phase III trial compared initial bendamustine-and-rituximab therapy to fludarabine/cyclophosphamide/rituximab in patients with a median age of 61 years and total Cumulative Index Rating Scale score of 2. In patients > 65 years of age, the risk-benefit profile was favorable.2
Another phase III trial compared initial therapy with bendamustine and rituximab vs chlorambucil (Leukeran) and rituximab in older patients, finding improved progression-free survival but more toxicity with bendamustine and rituximab.3 Bendamustine has also been combined with other anti-CD20 agents with demonstrated efficacy and tolerability; some of these studies have included older patients.
Treatment Alternatives
Alternative regimens should be considered for first-line therapy in frail, unfit patients (Cumulative Index Rating Scale scores > 6, compromised renal function). Pentostatin can be substituted for fludarabine, in combination with rituximab or rituximab and cyclophosphamide, with less myelosuppression and comparable response rates and progression-free survival.
Chlorambucil also remains a tolerable and efficacious option for such patients. In a phase III trial in which older patients were randomized to therapy with fludarabine or chlorambucil, fludarabine resulted in superior response rates and prolonged time to treatment failure, compared with chlorambucil.4 However, as there were no differences in progression-free survival and overall survival, the researchers concluded that initial fludarabine therapy in older patients does not result in major clinical benefit as compared with chlorambucil. Chlorambucil plus rituximab is considered a preferred initial regimen for unfit patients.5
Several anti-CD20 antibodies have been studied in combination regimens as initial therapy for older, frail, unfit patients, including rituximab plus high-dose methylprednisolone, as well as ofatumumab (Arzerra) plus chlorambucil. More recently, a phase III trial in treatment-naive CLL patients (median age, 73 years) with Cumulative Index Rating Scale score > 6 and/or creatinine clearance of 30–69 mL/min compared chlorambucil, rituximab plus chlorambucil, or obinutuzumab (Gazyva) plus chlorambucil.6 Efficacy, as assessed by median progression-free survival and response rates, was best with the obinutuzumab/chlorambucil therapy. Although single-agent lenalidomide (Revlimid) has been studied as initial therapy for elderly CLL patients, it is currently not available for CLL therapy outside of clinical trials.
Other Novel Agents
Several new small-molecule agents have been approved for CLL therapy in recent years. Ibrutinib (Imbruvica), a Bruton’s tyrosine kinase inhibitor, is now approved in both treatment-naive and previously treated patients, with diarrhea and fatigue the most common toxicities. Less common, unique toxicities with this agent include a low incidence of atrial arrhythmias and bleeding complications.
Ibrutinib also has demonstrated efficacy in and clinical approval for patients with TP53 deletions. These patients have a poor prognosis, with lower response rates and decreased progression-free and overall survival on fludarabine-based regimens.7
The PI3 kinase inhibitor idelalisib (Zydelig), in combination with rituximab, has been studied as initial therapy for elderly CLL patients.8 Similar to ibrutinib, it has demonstrated activity in patients with 17p deletion. Although this is an efficacious treatment, unique adverse events include autoimmune colitis, pneumonitis, and hepatitis. More recently, a small number of opportunistic infections have been reported (Pneumocystis jirovecii, cytomegalovirus), for which prophylaxis/serial monitoring is now recommended.
Venetoclax (Venclexta) is a Bcl-2 inhibitor that was recently approved for treatment of CLL with 17p deletion after at least one prior therapy. Adverse events include the potential for tumor lysis syndrome.9
Closing Thoughts
Many questions remain unanswered in the care of CLL patients, especially with the advent of newer agents. It is not fully clear how best to incorporate these agents for first-line therapy, as appropriate comparative trials are lacking. There is no standard therapy for relapsed/refractory CLL, with treatment decisions based on prior therapy, remission duration, age, fitness, and adverse prognostic factors. Data on sequencing of these agents is also needed.
What is clear is that in this disease of predominantly an elderly population, assessment of fitness, function, comorbidities, and quality of life is essential in treatment decisions, to choose not only efficacious, but also tolerable, therapy. Ongoing prospective treatment trials including older patients, some of which have formal comprehensive geriatric assessment as a study component, will provide the framework for future treatment approaches in the elderly CLL patient. ■
Disclosure: Dr. Morrison serves on speakers bureaus for Celgene, Genentech, Pharmacyclics, and Gilead and is a consultant for Merck, GlaxoSmithKline, and Celgene.
References
1. Foon KA, et al: Blood 119:3184-3185, 2012.
2. Eichhorst BA, et al: 2014 ASH Annual Meeting. Abstract 19. Presented Dec 6, 2014.
3. Michallet AS: XVI Int’l Workshop on CLL. Abstract 88. Presented Sept 9, 2015.
4. Eichhorst BF, et al: Blood 114:3382-3391, 2009.
5. Hillmen P, et al: J Clin Oncol 32:1236-1241, 2014.
6. Goede V, et al: N Engl J Med 370:1101-1110, 2014.
7. Burger JA, et al: N Engl J Med 373:2425-2437, 2015.
