Fludarabine increases complete response but not survival compared with conventional alkylator-based regimens for previously untreated chronic lymphocytic leukaemia: Abstracted from: Zhu Q, Tan DCL, Samuel M, Chan ESY, Linn YC. Fludarabine in comparison to alkylator-based regimen as induction therapy for chronic lymphocytic leukaemia: A systematic review and meta-analysis. Leukaemia Lymphoma 2004; 45:2239–45.

doi:10.1016/j.ctrv.2005.04.002

Cancer Treatment Reviews

Volume 31, Issue 4, June 2005, Pages 332-335

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Background

Disease progression and life expectancy varies widely among people with chronic lymphocytic leukaemia, but consensus suggests that people with more advanced stages should undergo chemotherapy. The relative efficacy of fludarabine chemotherapy compared with conventional alkylator-based regimens has not been firmly established.

Objective

To determine whether fludarabine increases survival and response rate compared with conventional alkylator-based chemotherapy regimens in people with chronic lymphocytic leukaemia.

Method

Systematic review and meta-analysis.

Search strategy

MEDLINE, OVID including Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club and Database of Abstracts of Reviews of Effect searched from 1966 to June 2003; meeting proceedings published before June 2003 hand searched.

Inclusion criteria

English and foreign language publications of randomised controlled trials (RCTs) comparing fludarabine with alkylator-based regimens in people with previously untreated chronic lymphocytic leukaemia were included. Only studies whose groups were comparable at baseline were included.

Main outcomes

Overall survival; complete response; overall response (complete and partial response); adverse events. The National Cancer Institute chronic lymphocytic leukaemia working group definitions of complete and partial response were used.

Evidence Profile: Benefits

Empty Cell	RCTs	Fludarabine	Alkylator-based regimens	Significance	P value
Mortality	2	NR	NR	Hazard ratio 0.95 (95% CI 0.70–1.30)^a	0.75
Complete response	3	203/579 (35.1%)	135/606 (22.3%)	Relative risk 1.87 (95% CI 1.10–3.19)^a	0.02
Overall response	3	397/579 (68.6%)

Main results

Five RCTs (1329 people) met inclusion criteria. One RCT used CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) as a comparator treatment, while the other studies used chlorambucil. Benefits. There was no significant difference in overall survival between fludarabine and alkylator-based regimens (meta-analysis of 1093 people in two RCTs; hazard ratio for death: 0.95, 95% CI 0.70–1.30; P = 0.75; significant heterogeneity). Fludarabine significantly increased complete response at 6

Authors’ conclusions

In people with previously untreated chronic lymphocytic leukaemia, fludarabine increases complete response compared with alkylator-based regimens, with an acceptable level of adverse events. However, there is no significant difference between fludarabine and alkylator-based regimens in overall survival at 5–6 years follow up.

Method notes

Search method	Adequate
Selection criteria	Adequate: Inclusion and exclusion criteria clearly specified. Selection was by three independent reviewers

Assessment of

Commentary

Chronic lymphocytic leukaemia is a common type of leukaemia, with over 8000 new cases diagnosed in the United States in 2004. For many years the alkylating agent chlorambucil has been the mainstay of therapy for chronic lymphocytic leukaemia. Cyclophosphamide, another alkylating agent, is used where serious side effects prevent the further use of chlorambucil.

The introduction of purine analogues provided a new treatment option for chronic lymphocytic leukaemia. Fludarabine has been the most

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References (4)

M. Leporrier et al.
Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients
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T. Robak et al.
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Cited by (2)

Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: A systematic review and meta-analysis
2006, Cancer Treatment Reviews
Recent trials suggest improved response rates for purine analogues compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. Thus, a systematic Cochrane review may be able to further define the role of purine analogues in the first-line treatment of B-CLL.
Randomized controlled trials comparing single-agent purine analogues with alkylator-based regimens were included. Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and trial registers were searched. We included full-text and abstract publications as well as unpublished data. Relative risks (RR) and hazard ratios (HR) were calculated under a fixed-effects model, clinical and statistical heterogeneity was examined with sensitivity analyses and meta-regression. If applicable, numbers needed to treat or harm (NNT, NNH) were also determined.
Five trials with 1838 randomized patients were included. Importantly, four trials had a cross-over design. There was a trend for improved overall survival for patients receiving purine analogues as initial therapy but statistical significance was just not reached (HR 0.89 [95% CI 0.78–1.01]). The RR for achieving an overall (RR 1.22 [95% CI 1.13–1.31]; NNT 8 [95% CI 6–13]) and complete response (RR 1.94 [95% CI 1.65–2.28]; NNT 6 [5–8]) was significantly improved, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61–0.82]). Incidence of grade III/IV infections (RR 1.83 [95% CI 1.30–2.58]; NNH 20 [95% CI 12.5–50]) and haemolytic anaemia (RR 3.36 [95% CI 1.27–8.91]; NNH 21 [95% CI 6–185]) was significantly higher in patients receiving purine analogues.
Despite significantly increased response rates and longer progression-free survival with purine analogues as first-line therapy, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine analogues augments the risk for grade III/IV infections and haemolytic anaemia.
Chronic lymphocytic leukemia in the elderly
2007, Blood Disorders in the Elderly

^☆: Sources of funding: Not stated.

^☆☆: For c.orrespondence: Linn YC, Department of Hematology, Singapore General Hospital, Blk 6, Level 3, Outram Road, Singapore 169608, Singapore. E-mail: [email protected]

^☆☆☆: Abstract provided by Bazian Ltd., London.

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