For decades, initial therapy for chronic lymphocytic leukemia (CLL) consisted of alkylators such as chlorambucil (Leukeran). The introduction of nucleoside analogs such as fludarabine and monoclonal antibodies such as rituximab (Rituxan) markedly changed the initial therapy of CLL, particularly in the United States. Fludarabine and combination regimens such as fludarabine/cyclophosphamide (FC) have achieved higher complete response (CR) rates and progression-free survival (PFS) than chlorambucil in previously untreated CLL, but long-term overall survival has not improved, due to concurrent improvement in salvage therapy of relapsed CLL patients. Upfront chemoimmunotherapy regimens such as fludarabine/rituximab (FR) and fludarabine/cyclophosphamide/rituximab (FCR) have similarly improved CR rates and PFS in previously untreated CLL patients, but it is unclear whether overall survival is improved. Advances in cytogenetic analysis and other biologic prognostic factors have greatly enhanced clinicians' ability to risk-stratify newly diagnosed CLL patients, and knowledge of such prognostic factors is necessary to properly interpret results of clinical treatment studies. The choice of initial therapy for an individual patient should depend upon the patient's age and medical condition, cytogenetic and other prognostic factors, and whether the goal of therapy is maximization of CR and PFS or palliation of symptoms with minimal toxicity.
The past decade has seen significant advances in our understanding of the effects of cytogenetic abnormalities and other biologic factors on the natural history of chronic lymphocytic leukemia (CLL). Deletion of 17p13 and 11q22—corresponding to loss of the p53 and ataxia telengiectasia mutated (ATM) tumor-suppressor genes, respectively—is associated with the need for earlier therapy and a poor long-term prognosis.[1,2] The mutational status of the immunoglobulin heavy chain variable region (IgVH) also predicts time to treatment and long-term survival.[3-6] Patients whose CLL exhibits unmutated (germline) IgVH have a markedly inferior prognosis to that of patients with mutated IgVH. Expression of CD38 and zeta-associated protein (ZAP)-70 correlates with unmutated IgVH, the need for earlier therapy, and inferior long-term survival.[3,5-9]
|What is the ideal initial treatment for patients with chronic lymphocytic leukemia?|
These invaluable prognostic tools help clinicians predict the biologic behavior of a patient's CLL over time. Risk-stratification provides critical information on the percentage of high-risk patients in a clinical trial and is essential for proper interpretation of the results of clinical treatment studies in CLL. However, the use of these prognostic factors in selecting the optimal initial therapy for the individual CLL patient is less clear. While the impact of adverse cytogenetic abnormalities on response to therapy has been documented,[1,10] the effect of IgVH mutational status, CD38, and ZAP-70 on response to treatment is less clear. This review will pay particular attention to the efficacy of the various upfront treatment options in patients with poor-risk features such as del(17p13) and del(11q22).
When to Initiate Treatment
The National Cancer Institute (NCI) Working Group on CLL established guidelines for initiating treatment in 1996. These indications included autoimmue and nonautoimmune cytopenias, bulky or symptomatic lymphadenopathy or organomegaly, disease-related B-symptoms or fatigue, and rapid lymphocyte doubling time. However, CLL is often diagnosed by routine complete blood count examination, and most patients are asymptomatic with a normal hemoglobin and platelet count at diagnosis. Such asymptomatic patients should be followed expectantly and should receive treatment only upon disease progression.
Several studies in asymptomatic patients failed to show a benefit in overall survival (OS) with early chlorambucil (Leukeran) therapy. However, chemoimmunotherapy regimens combining monoclonal antibody therapy with purine analogs achieve much higher complete response (CR) rates than chlorambucil.[13-15] Thus, early treatment needs to be reconsidered, particularly in patients with high-risk biologic or genetic markers predicting a poor long-term prognosis.
Ongoing efforts by the German CLL Study Group (GCLLSG) and several US cooperative groups will address whether early intervention with chemoimmunotherapy can improve long-term survival in high-risk CLL. High-risk, previously untreated CLL patients in the United States who do not meet NCI 1996 treatment criteria but wish to be considered for early therapy should be referred to the Intergroup study randomizing such patients to observation or early chemoimmunotherapy.
Alkylating agents served as initial therapy for CLL for decades, and chlorambucil is still given as first-line therapy, particularly for older patients and patients who cannot tolerate purine analogs. Chlorambucil is typically given as a single pulse dose of 40 mg/m2 orally every 28 days. The use of concurrent steroids did not improve long-term survival; thus, chlorambucil is typically administered as a single agent.
While continuous daily dosing attained superior results, higher doses resulted in increased myelosuppression and frequent dose reductions, particularly in older or frailer patients. Thus, less-intensive pulse dosing should generally be used. Its primary advantages are a well established toxicity profile and low cost, whereas its disadvantages are a low CR rate, even in previously untreated patients, and the risk of myelodysplasia with extended use.
The introduction of purine analogs in the 1980s dramatically altered the treatment of CLL.[17-21] Fludarabine was approved for alkylator-refractory CLL, but several large, prospective, randomized studies demonstrating improved response rates and progression-free survival (PFS) established fludarabine as standard initial therapy for CLL in the United States.[22-24] These studies are summarized in Table 1.
A multicenter European study randomized 196 evaluable patients to fludarabine or the alkylator-based regimen CAP (cyclophosphamide, doxorubicin [Adriamycin], prednisone). The overall response (OR) rate favored fludarabine (60% vs 44%) in both relapsed (n = 96, 48% vs 27%) and previously untreated (n = 100, 71% vs 60%) patients, although the difference in the untreated group was not statistically significant. Fludarabine achieved a longer median duration of response and a tendency toward improved OS in previously untreated patients.
A randomized, multicenter study confirmed these findings in 509 previously untreated CLL patients. Patients were randomized to receive fludarabine at 25 mg/m2 IV daily for 5 days every 28 days, chlorambucil at 40 mg/m2 orally every 28 days, or fludarabine at 20 mg/m2 IV daily for 5 days and chlorambucil at 20 mg/m2 orally every 28 days, for up to 12 cycles. Patients who failed to respond or relapsed were allowed to cross over to the other arm. The combination arm was closed due to excessive toxicity. Fludarabine achieved superior CR, OR, median duration of remission, and median PFS (20%, 63%, 25 months, 20 months) than chlorambucil (4%, 37%, 14 months, 14 months). However, due to the crossover design, no statistically significant OS difference (66 vs 56 months) was observed.
A multicenter French study randomized 938 patients with previously untreated Binet stage B or C CLL to fludarabine, CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone), or CAP. While fludarabine achieved better response rates than CAP, OS was identical (67–70 months) in all three groups.
Most recently, the GCLLSG randomized 180 patients over age 65 to standard IV fludarabine for up to 6 cycles or chlorambucil at 0.4 to 0.8 mg/kg orally on days 1 and 15 every 28 days for up to 12 cycles. Patients in the fludarabine arm experienced more hematologic toxicity (63% vs 39%) but had a similar infection rate (5%) and better quality of life than patients treated with chlorambucil. Fludarabine induced higher CR rates (13% vs 0%) and OR rates (85% vs 68%), but there was no difference in PFS or OS. Thus, while single-agent fludarabine achieves superior response rates and PFS than alkylator-based regimens, OS is unchanged, due to the ability to salvage alkylator failures (Table 1).
Combining Fludarabine and Alkylator Therapy
Studies of the combination of fludarabine and cyclophosphamide (FC) in relapsed CLL have demonstrated promising clinical activity and acceptable toxicity.[20,21] Based on these results, the GCLLSG randomized 375 previously untreated CLL patients (age ≤ 65 years) to standard fludarabine or FC (fludarabine at 30 mg/m2 IV and cyclophosphamide at 250 mg/m2 IV daily for 3 days) every 28 days for 6 cycles. The OR rate (94% vs 83%), CR rate (24% vs 7%), median PFS (48 vs 20 months), and treatment-free survival (37 vs 25 months) favored FC, but no difference in OS was observed. FC was superior to fludarabine in IgVH unmutated patients (median PFS = 52 vs 20 months) and del(11q22) patients (median PFS = 36 vs 16 months). However, patients with del(17p13) did poorly regardless of treatment arm, with a median PFS and OS of 11 and 16 months, respectively. Thus, FC mitigated the poor prognosis associated with unmutated IgVH status and del(11q22), but not of del(17p13).
The US Eastern Cooperative Oncology Group (EGOG) randomized 278 patients to single-agent fludarabine or FC. FC consisted of fludarabine at 20 mg/m2 IV on days 1 through 5 and cyclophosphamide at 600 mg/m2 IV on day 1 every 28 days for up to 6 cycles. FC achieved a superior OR (74% vs 59%), CR (23% vs 5%), and median PFS (32 vs 19 months), but no OS advantage was seen. Information on genetic and molecular prognostic factors was available on 235 patients. CR and OR were not affected by cytogenetics, IgVH mutational status, CD38, ZAP-70, or p53 mutational status. There was no statistically significant difference in median PFS between IgVH-mutated (29.6 months) and -unmutated patients (20.8 months), and FC was superior to fludarabine in both groups. However, the presence of del(17p13) or del(11q22) negatively affected PFS, with hazard ratios (HRs) of 3.43 and 1.90, respectively. This study suggested that cytogenetics, but not IgVH mutational or ZAP-70 status, predicts the clinical outcome of fludarabine-based therapy.
Finally, the UK CLL4 study randomized 777 patients to oral chlorambucil, fludarabine, or FC. Patients randomized to FC enjoyed a superior OR, CR, and 5-year PFS (94%, 38%, 36%, respectively), compared to patients who received chlorambucil (72%, 7%, 10%) or fludarabine (80%, 15%, 10%). FC was superior in all age groups, including patients over 70 years old. However, patients with del(17p13) had markedly inferior CR/nodular partial response (nPR) and OR rates compared to patients without loss of 17p13, whether therapy was fludarabine (22% and 44% vs 38% and 79%) or FC (25% and 38% vs 65% and 97%).
Thus, FC achieves superior response rates and PFS compared to single-agent fludarabine (Table 1). However, no OS advantage for upfront FC has been observed to date. Furthermore, patients with del(17p13), which occurs in 5% of CLL patients at diagnosis, do poorly even with FC. Therefore, clinical research to identify effective initial therapy regimens in this cytogenetic group remains a priority.
1. Dohner H, Fischer K, Bentz M, et al: p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 85:1580-1589, 1995.
2. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916, 2000.
3. Damle RN, Wassil T, Fais F, et al: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840-1847, 1999.
4. Hamblin TJ, Davis Z, Gardiner A, et al: Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848-1854, 1999.
5. Hamblin TJ, Orchard JA, Gardiner A, et al: Immunoglobulin V genes and CD38 expression in CLL. Blood 95:2455-2457, 2000.
6. Hamblin TJ, Orchard JA, Ibbotson RE, et al: CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 99:1023-1029, 2002.
7. Wiestner A, Rosenwald A, Barry TS, et al: ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101:4944-4951, 2003.
8. Crespo M, Bosch F, Villamor N, et al: ZAP-70 expression as a surrogate for immunoglobulin variable region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764-1775, 2003.
9. Rassenti LZ, Huynh L, Toy TL, et al: ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351:893-901, 2004.
10. Byrd JC, Smith L, Hackbarth ML, et al: Interphase cytogenetic abnormalities in chronic lymphocytic leukemia may predict response to rituximab. Cancer Res 63:36-38, 2003.
11. Cheson BD, Bennett JM, Grever MR, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996.
12. CLL Trialists' Collaborative Group: Chemotherapeutic options in chronic lymphocytic leukemia: A meta-analysis of the randomized trials. J Natl Cancer Inst 91:861-868, 1999.
13. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6-14, 2003.
14. Keating MJ, O'Brien S, Albitar M, et al: Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23:4079-4088, 2005.
15. Kay NE, Geyer SM, Call TG, et al: Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chroinc lymphocytic leukemia. Blood 109:405-411, 2007.
16. Kay NE, Hamblin TJ, Jelinek DF, et al: Chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program, pp 193-213, 2002.
17. Grever MR, Leiby J, Kraut E, et al: A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol 17(5 suppl 8):39-48, 1990.
18. Keating MJ, Kantarjian H, Talpaz M, et al: Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74:19-25, 1989.
19. Keating MJ, Kantarjian H, O'Brien S, et al: Fludarabine: A new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol 9:44-49, 1991.
20. Flinn IW, Byrd JC, Morrison C, et al: Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 96:71-75, 2000.
21. O'Brien SM, Kantarjian HM, Cortes J, et al: Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 19:1414-1420, 2001.
22. Johnson S, Smith AG, Loffler H, et al: Multicentre prospective randomised trial of fludarabine versus cyclophoshamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 347:1432-1438, 1996.
23. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000.
24. Leporrier M, Chevret S, Cazin B, et al: Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319-2325, 2001.
25. Eichhorst BF, Busch R, Hopfinger G, et al: Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885-891, 2006.
26. Stilgenbauer S, Kröber A, Busch R, et al: 17p deletion predicts for inferior overall survival after fludarabine-based first line therapy in chronic lymphocytic leukemia: First analysis of genetics in the CLL4 trial of the GCLLSG (abstract 715). Blood 106, 2005.
27. Flinn IW, Neuberg DS, Grever MR, et al: Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25:793-798, 2007.
28. Grever MR, Lucas DM, Dewald GW, et al: Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: Results from the US Intergroup phase III trial E2997. J Clin Oncol 25:799-804, 2207.
29. Catovsky D, Richards S, Hillmen P: Early results from LRF CLL4: A UK multicenter randomized trial (abstract 716). Blood 106:212a, 2005.
30. Hainsworth JD, Litchy S, Barton JH, et al: Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 21:1746-1751, 2003.
31. Thomas DA, O'Brien S, Giles FJ, et al: Single agent Rituxan in early stage chronic lymphocytic leukemia (CLL) (abstract 1533). Blood 98:364a, 2001.
32. Lozanski G, Heerema NA, Flinn IW, et al: Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 103:3278-3281, 2004.
33. Byrd JC, Gribben JG, Peterson BL, et al: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: Justification for risk-adapted therapy. J Clin Oncol 24:437-443, 2006.
34. Byrd JC, Rai K, Peterson BL, et al: Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previoulsy untreated chronic lymphocytic leukemia: An updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105:49-53, 2005.
35. Schulz H, Klein SK, Rehwald U, et al: Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood 100:3115-3120, 2002.
36. Wierda WG, O'Brien S, Faderl S, et al: Combined cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR), an active regimen for heavily treated patients with CLL (abstract 32). Blood 108:14a, 2006.
37. Bosch F, Ferrer A, Villamor N, et al: Combination chemotherapy with fludarabine, cyclophosphamide and mitoxantrone (FCM) induces a high response rate in previoulsy untreated CLL (abstract 718). Blood 106:213a, 2005.
38. Polliack A, Cohen Y, Daas N, et al: Fludarabine (FLU)-containing regimen and rituximab (RI) as primary therapy with curative intent for younger patients with progressive and advanced B-CLL: High rate of initial response including molecular remissions (abstract 1532). Blood 98:364a, 2001.
39. Shanafelt TD, Lin TS, Geyer SM, et al: Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 109:2291-2298, 2007.
40. Flynn JM, Byrd JC: Campath-1H monoclonal antibody therapy. Curr Opin Oncol 12:574-581, 2000.
41. Hale G, Bright S, Chumbley G, et al: Removal of T cells from bone marrow for transplantation: A monoclonal antilymphocyte antibody that fixes human complement. Blood 62:873-882, 1983.
42. Hale G, Swirsky D, Waldmann H, et al: Reactivity of rat monoclonal antibody CAMPATH-1 with human leukaemia cells and its possible application for autologous bone marrow transplantation. Br J Haematol 60:41-48, 1985.
43. Salisbury JR, Rapson NT, Codd JD, et al: Immunohistochemical analysis of CDw52 antigen expression in non-Hodgkin's lymphomas. J Clin Pathol 47:313-317, 1994.
44. Keating MJ, Byrd JC, Rai K, et al: Multicenter study of Campath-1H in patients with chronic lymphocytic leukemia (B-CLL) refractory to fludarabine (abstract 1544). Blood 96:722a, 2000.
45. Keating MJ, Flinn I, Jain V, et al: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 99:3554-3561, 2002.
46. Osterborg A, Dyer MJ, Bunjes D, et al: Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia: European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol 15:1567-1574, 1997.
47. Rai KR, Freter CE, Mercier RJ, et al: Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 20:3891-3897, 2002.
48. Moreton P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23:2971-2979, 2005.
49. Stilgenbauer S, Winkler D, Kröber A, et al: Subcutaneous Campath-1H (alemtuzumab) in fludarabine-refractory CLL: Interim analysis of the CLL2H study of the German CLL Study Group (GCLLSG) (abstract 478). Blood 104:140a, 2004.
50. Lundin J, Kimby E, Bjorkholm M, et al: Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100:768-773, 2002.
51. Hillmen P, Skotnicki A, Robak T, et al: Alemtuzumab (Campath, Mabcampath) has superior progression free survival (PFS) vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia (BCLL) (abstract 301). Blood 108:93a, 2006.
52. O'Brien SM, Kantarjian HM, Thomas DA, et al: Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer 98:2657-2663, 2003.
53. Wendtner CM, Ritgen M, Schweighofer CD, et al: Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission: Experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia 18:1093-1101, 2004.
54. Schweighofer C, Ritgen M, Eichhorst BF, et al: Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukemia (CLL) in first remission: Long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Blood 108:14a, 2006.
55. Rai KR, Byrd JC, Peterson BL, et al: Subcutaneous alemtuzumab following fludarabine for previously untreated patients with chronic lymphocytic leukemia (CLL): CALGB study (abstract 2506). Blood vol 102, 2003.