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Your FAQs... Answered!

TOP - September 2011 Vol 4, No 6 published on October 1, 2012

Q: What are some treatment options for elderly patients with chronic lymphocytic leukemia?

A: Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by the accumulation of monoclonal lymphocytes in blood, bone marrow, and lymphoid tissue.1 It is the most common form of leukemia in adults worldwide, with prevalence increasing with age. The median age at diagnosis of CLL is 70 years.2 CLL is diagnosed by the presence of at least 5000/µL monoclonal B lymphocytes (positive for CD5, CD19, CD20, and CD23) by peripheral flow cytometry of the blood. Patients typically are followed with a watch-and-wait approach until indications for treatment are met. Decisions regarding treatment selection are based on severity of CLL in addition to patient characteristics, including comorbidities.3

Results of German CLL Study Group-8 and the international Study of Relapsed Chronic Lymphocytic Leukemia (REACH) showed that combination therapy with fludarabine/cyclophosphamide/rituximab (FCR) improves the overall response rate (ORR) and complete remission (CR) rate, as well as prolongs progression-free survival (PFS) and overall survival (OS) when used in the first line.4,5 FCR, therefore, currently is accepted as the gold standard in physically fit patients. Further analysis of the data, however, showed that the FCR regimen provided no benefit in the 10% of patients who were 70 years of age or older.6 There is no clearly superior first-line therapy for elderly patients with CLL, and despite the fact that two-thirds of the patients diagnosed with CLL are aged older than 65 years, few studies have explored the efficacy and toxicities of therapies in this population. Clinicians often have concern about offering elderly patients chemo­therapy because of their increased comorbidity and higher rates of treatment-related toxicities.

First-Line Treatment Options for Elderly/Comorbid Patients
Current recommendations by the National Comprehensive Cancer Network (NCCN) for frail patients or those with significant comorbidity (unable to tolerate purine analogs, ie, fludarabine) include chlorambucil with/without prednisone, single-agent rituximab, and pulse steroids.3 Chlorambucil was first used for the treatment of CLL in the 1950s and remains the standard treatment for frail elderly patients. Of the several possible dosing schedules for chlorambucil, the most optimal regimen has not yet been identified.

For patients aged 70 years or older, NCCN Guidelines currently recommend 8 different regimens: chlorambucil, with/without prednisone; bendamustine/rituximab; cyclophosphamide/prednisone, with/without rituximab; alemtuzumab/rituximab/fludarabine, with/without rituximab; and cladribine. None are specified as preferred.3 German CLL Study Group-5, which focused on the elderly, randomized 193 patients aged 65 years or older to receive therapy with fludarabine or chlorambucil. Results demonstrated higher response rates with fludarabine, but these did not translate to prolonged PFS or OS. Hillmen and colleagues compared alemtuzumab and chlor­ambucil as initial therapy for CLL. Results showed a higher response rate with alemtuzumab (83% vs 55%).7 However, in a subgroup analysis of 105 patients aged 65 years or older, median PFS did not increase, remaining at 12.5 months.8

Myelotoxicity and infection are potential complications of treatment with fludarabine-based regimens. Dose-reduced regimens, therefore, were developed to ameliorate treatment toxicity while maintaining efficacy. Several small studies have reported decent response rates and modest toxicity of either low-dose fludarabine monotherapy or low-dose fludarabine/cyclophosphamide combination. Foon and colleagues evaluated a regimen with decreased doses of fludarabine/cyclophosphamide, dubbed FCR-Lite, in untreated CLL patients. Results showed a 79% CR, with a 95% ORR and a reduction in grade 3/4 neutropenia (13%) compared with 52% in the full-dose FCR regimen. The median age, however, was 58 years, which does not represent the median age for patients with CLL. Of 7 patients >70 years, 4 achieved a CR and completed 6 cycles of FCR-Lite (full course of treatment); 3 achieved partial remission, but none completed 6 cycles of therapy. In addition, 1 patient aged 69 years also did not complete 6 cycles, suggesting that FCR-Lite is better tolerated in a younger patient population.9

Pentostatin/cyclophosphamide/rituximab (PCR) also has been studied in older patients with CLL. Shanafelt and colleagues found that older patients (18 of 64 patients >70 years) tolerated PCR as well as younger patients and were just as likely to complete 6 cycles of therapy and to achieve complete or partial remission without excess grade 3/4 toxicity.10 More data are needed, however, to answer the question of whether pentostatin is less toxic than fludarabine in elderly/comorbid patients.

Bendamustine is a chemotherapy agent that combines the properties of an alkylating agent and a purine analog. In a study of treatment-naïve patients with CLL, bendamustine was shown to be more efficacious than chlorambucil, with a CR rate of 31% and PFS of 21.6 months.11 However, the median age of these patients was 64 years and the number of elderly patients enrolled was small, making it difficult to determine if it is appropriate for this population.

Danese and colleagues recently published an observational study of patients aged 66 years or older with CLL who were registered in the Surveillance, Epidemiology and End Results program. Of 6433 patients, 2040 received infused therapy: 16% received rituximab monotherapy, 14% rituximab plus chemotherapy, and 70% chemotherapy alone. Rituximab plus chemotherapy was associated with a 25% lower risk of overall mortality compared with chemotherapy alone.6 These results suggest that initial treatment with rituximab was associated with improved survival in a heterogeneous group of older CLL patients.

Future Directions
Results of a recent phase 2 study to evaluate the therapeutic potential of len­alidomide in elderly patients for initial treatment were recently published.8 Len­alidomide, an immunomodulatory agent that activates the T and natural killer cells, downregulates several critical prosurvival cytokines, and affects antibody-dependent cell-mediated cytotoxicity. ORR was 65%, with a 2-year OS rate of 88%, which compares favorably with studies involving chlorambucil, fludarabine, or alemtuzumab mono­therapy. Neutropenia was the most common side effect, occurring in 34% of cycles. Grade 1 and 2 tumor flare reactions were common; no severe reactions were noted. Study investigators noted that tumor flare was associated with a higher likelihood of response, as suggested by other published findings in patients with CLL. Additional phase 2 clinical trials are on­going to evaluate combination immuno­modulating agents and rituximab in untreated patients with CLL.

Conclusion
Optimal treatment of elderly patients with CLL has not been clearly defined. Patients aged 70 years or older have been underrepresented in past clinical trials, making the selection of treatment regimens complex compared with selection for younger patients. Multiple chemotherapy regimens exist for elderly patients with good performance stat­us and without comorbidities. Chlor­a­mbucil is the current standard treat­­ment for elderly frail patients. Supportive therapy is always an option for severely comorbid patients. Pro­mising new agents, such as lenalidomide with or without monoclonal antibody therapy, are being studied. On­going clinical trials enrolling pa­tients older than 70 years hopefully will improve survival and quality of life in this population in the future.

References

  1. Amrein PC. Chronic lymphocytic leukemia. In: Chabner BA, Lynch TJ Jr, Longo DL, eds. Harrison’s Manual of Oncology. New York, NY: McGraw-Hill; 2008:263-274.
  2. Rai KR, Keating MJ. Initial treatment of chronic lymphocytic leukemia. June 13, 2011. www.uptodate.com/contents/initial-treatment-of-chronic-lymphocytic-leukemia. Accessed August 26, 2011.
  3. 3. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymph­omas. Version 4.2011. www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed August 26, 2011.
  4. 4. Hallek M, Fingerle-Rowson G, Fink AM, et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group. Blood (ASH Annual Meeting Abstracts). 2009; 114:Abstract 535.
  5. 5. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010;28:1756-1765.
  6. 6. Danese MD, Griffiths RI, Gleeson M, et al. An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia. Blood. 2011;117:3505-3513.
  7. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-5623.
  8. Badoux XC, Keating MJ, Wen S, et al. Lenalidomide as initial therapy of elderly patients with chronic lympho­cytic leukemia. Blood. July 1, 2011. Epub ahead of print.
  9. Foon KA, Boyladzis M, Land SR, et al. Chemo­immunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:498-503.
  10. 10. Shanafelt TD, Lin T, Geyer SM, et al. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007;109:2291-2298.
  11. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlor­ambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4378-4384.

 

Last modified: July 22, 2021