Effectiveness and Safety of FCR Regimen for Chronic Lymphocytic Leukemia: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

ZHAO Long ,  XI Yaming , GUO Min , CHAO Rong , JIN Ruirui

Institute of Hematology and Department of Hematology, the First Clinical Hospital of Lanzhou University, Lanzhou 730000, China;

Corresponding author：

XI Yaming, Email: xiyaming02@163.com

Keywords：

Chronic lymphocytic leukemia; Rituximab; Fludarabine; Cyclophosphamide; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.20110221

Video：

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Objective 　To assess the clinical effectiveness and safety of fludarabine and cyclophosphamide (FC) combined with rituximab chemotherapy regimen (FCR regimen) for patients with chronic lymphoblastic leukemia (CLL).
Methods 　The databases such as PubMed, The Cochrane Library, SpringerLink, CNKI, and CBM were searched from 2000 to 2011. The randomized controlled trials (RCTs) on FC regimen versus FCR regimen for CLL were retrieved. The methodological quality of the included studies was assessed according to the Cochrane Reviewer’s Handbook, and meta-analyses were performed using RevMan 5.0 software.
Results 　Three RCTs involving 1 623 patients with CLL were included. The results of meta-analyses showed that significant differences were found in the progression-free survival (PSF)(P lt;0.001), overall response (OR=1.94, 95%CI 1.49 to 2.53, P lt;0.000 01), complete remission (OR=2.54, 95%CI 2.00 to 3.22, P lt;0.000 01), and grade III or IV neutropenia (OR=1.60, 95%CI 1.33 to 1.92, P lt;0.000 01); but no significant differences were found in the partial response (OR=0.74, 95%CI 0.35 to 1.55, P=0.43), grade III or IV thrombocytopenia (OR=0.97, 95%CI 0.74 to 1.27, P=0.83) and autoimmune hemolytic anemia (OR=0.86, 95%CI 0.59 to 1.27, P=0.45) between FCR and FC regimen.
Conclusion 　The FCR regimen can improve the progression-free survival, overall response and complete remission. Meanwhile, it sometimes increases the incidence of Grade III or IV events, such as neutropenia, thrombocytopenia, autoimmune hemolytic anemia and nausea and vomiting.

Citation： ZHAO Long,XI Yaming,GUO Min,CHAO Rong,JIN Ruirui. Effectiveness and Safety of FCR Regimen for Chronic Lymphocytic Leukemia: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2011, 11(11): 1321-1326. doi: 10.7507/1672-2531.20110221 Copy

1.	2 Ricci F, Tedeschi A, Morra E, et al . Fludarabine in the treatment of chronic lymphocytic leukemia: a review. Ther Clin Risk Manag , 2009, 5(1): 187-207.
2.	3 Wierda W, O'Brien S, Faderl S, et al . A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer , 2006, 106(2): 337-345.
3.	4 Hallek M, Fischer K, Fingerle-Rowson G, et al . Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet , 2010, 376(9747): 1164-1174.
4.	5 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 , 2006, 107(3): 885-891.
5.	6 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. Journal of Clinical Oncology , 2007, 25(7): 799-804.
6.	8 Robak T, Dmoszynska A, Solal-Celigny P, et al . Rituximab Plus Fludarabine and Cyclophosphamide Prolongs Progression-Free Survival Compared With Fludarabine and Cyclophosphamide Alone in Previously Treated Chronic Lymphocytic Leukemia. Journal of Clinical Oncology , 2010, 28(10): 1756-1765.
7.	9 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. Journal of Clinical Oncology , 2007, 25(7): 793-798.
8.	10 Dretzke J, Barton P, Kaambwa B, et al . Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia. Health Technol Assess , 2010, 14(Suppl. 2): 19-26.
9.	11 O'Brien S, Osterborg A. Ofatumumab: a new CD20 monoclonal antibody therapy for B-cell chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk , 2010, 10(5): 361-368.
10.	12 Byrd JC, Kipps TJ, Flinn IW, et al . Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood , 2010, 115(3): 489-495.
11.	13 Wierda W, O'Brien S, Wen S, et al . Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol , 2005, 23(18): 4070-4078.
12.	14 Casak SJ, Lemery SJ, Shen YL, et al . U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia. Oncologist , 2011, 16(1): 97-104.
13.	16 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 , 1995, 85 (6): 1580-1589.
14.	17 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 , 2007, 25 (7): 799-804.
15.	18 Dohner H, Stilgenbauer S, James MR, et al . 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood , 1997, 89(7): 2516-2522.
16.	19 Tsimberidou AM, Tam C, Abruzzo LV, et al . Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer , 2009, 115(2): 373-380.
17.	20 Schlette EJ, Admirand J, Wierda W, et al . p53 expression by immunohistochemistry is an important determinant of survival in patients with chronic lymphocytic leukemia receiving frontline chemo-immunotherapy. Leuk Lymphoma , 2009, 50 (10): 1597-1605.
18.	21 Moreno C, Villamor N, Colomer D, et al . Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol , 2005, 23 (15): 3433-3438.
19.	顾卫军, 徐卫, 钱思轩, 等. 利妥昔单克隆抗体联合氟达拉滨及环磷酰胺治疗慢性淋巴细胞白血病. 中国实验血液学杂志, 2008, (04):938-942.
20.	王欣, 刘林, 陈建斌, 等. 氟达拉滨联合环磷酰胺治疗慢性淋巴细胞白血病的临床研究. 重庆医学, 2009, 38(10): 1210-1212.
21.	方成, 徐卫, 徐敏, 等. 氟达拉滨和环磷酰胺联合利妥昔单抗治疗慢性淋巴细胞白血病疗效分析. 中华血液学杂志, 2011, 32(1): 3-7.

1. 2 Ricci F, Tedeschi A, Morra E, et al . Fludarabine in the treatment of chronic lymphocytic leukemia: a review. Ther Clin Risk Manag , 2009, 5(1): 187-207.
2. 3 Wierda W, O'Brien S, Faderl S, et al . A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer , 2006, 106(2): 337-345.
3. 4 Hallek M, Fischer K, Fingerle-Rowson G, et al . Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet , 2010, 376(9747): 1164-1174.
4. 5 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 , 2006, 107(3): 885-891.
5. 6 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. Journal of Clinical Oncology , 2007, 25(7): 799-804.
6. 8 Robak T, Dmoszynska A, Solal-Celigny P, et al . Rituximab Plus Fludarabine and Cyclophosphamide Prolongs Progression-Free Survival Compared With Fludarabine and Cyclophosphamide Alone in Previously Treated Chronic Lymphocytic Leukemia. Journal of Clinical Oncology , 2010, 28(10): 1756-1765.
7. 9 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. Journal of Clinical Oncology , 2007, 25(7): 793-798.
8. 10 Dretzke J, Barton P, Kaambwa B, et al . Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia. Health Technol Assess , 2010, 14(Suppl. 2): 19-26.
9. 11 O'Brien S, Osterborg A. Ofatumumab: a new CD20 monoclonal antibody therapy for B-cell chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk , 2010, 10(5): 361-368.
10. 12 Byrd JC, Kipps TJ, Flinn IW, et al . Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Blood , 2010, 115(3): 489-495.
11. 13 Wierda W, O'Brien S, Wen S, et al . Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol , 2005, 23(18): 4070-4078.
12. 14 Casak SJ, Lemery SJ, Shen YL, et al . U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia. Oncologist , 2011, 16(1): 97-104.
13. 16 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 , 1995, 85 (6): 1580-1589.
14. 17 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 , 2007, 25 (7): 799-804.
15. 18 Dohner H, Stilgenbauer S, James MR, et al . 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood , 1997, 89(7): 2516-2522.
16. 19 Tsimberidou AM, Tam C, Abruzzo LV, et al . Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer , 2009, 115(2): 373-380.
17. 20 Schlette EJ, Admirand J, Wierda W, et al . p53 expression by immunohistochemistry is an important determinant of survival in patients with chronic lymphocytic leukemia receiving frontline chemo-immunotherapy. Leuk Lymphoma , 2009, 50 (10): 1597-1605.
18. 21 Moreno C, Villamor N, Colomer D, et al . Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol , 2005, 23 (15): 3433-3438.
19. 顾卫军, 徐卫, 钱思轩, 等. 利妥昔单克隆抗体联合氟达拉滨及环磷酰胺治疗慢性淋巴细胞白血病. 中国实验血液学杂志, 2008, (04):938-942.
20. 王欣, 刘林, 陈建斌, 等. 氟达拉滨联合环磷酰胺治疗慢性淋巴细胞白血病的临床研究. 重庆医学, 2009, 38(10): 1210-1212.
21. 方成, 徐卫, 徐敏, 等. 氟达拉滨和环磷酰胺联合利妥昔单抗治疗慢性淋巴细胞白血病疗效分析. 中华血液学杂志, 2011, 32(1): 3-7.

Chinese Journal of Evidence-Based Medicine

Effectiveness and Safety of FCR Regimen for Chronic Lymphocytic Leukemia: A Systematic Review

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