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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia

A Gafter-Gvili, A Leader, R Gurion, L Vidal, R Ram, A Shacham-Abulafia, I Ben-Bassat, M Lishner, O Shpilberg, and P Raanani.

Review published: 2011.

Link to full article: [Journal publisher]

CRD summary

The review concluded that there was insufficient evidence available to support the routine use of higher doses of imatinib as frontline treatment for chronic phase chronic myeloid leukaemia. The review was generally well conducted, and the authors' conclusion is likely to be reliable.

Authors' objectives

To assess the efficacy and safety of higher doses of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukaemia patients when compared with the standard 400mg dose.

Searching

PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and conference proceedings from four relevant organisations were searched, without language restrictions, to March 2011; search terms were reported. Reference lists of identified articles were searched for additional studies. ClinicalTrials.gov was also searched to identify ongoing and unpublished studies.

Study selection

Randomised controlled trials (RCTs) that compared single agent imatinib 400mg daily with higher doses of imatinib (600mg or greater daily) as frontline treatment for newly diagnosed (during the prior six months), previously untreated chronic phase chronic myeloid leukaemia patients were included.

Included trials assessed patients with Ph positive or negative BCR-ABL1 positive disease with established diagnosis by cytogenetic analysis and/or fluorescence in situ hybridisation (FISH) and/or polymerase chain reaction (PCR). Populations could include any Sokal or Hasford (Euro) prognostic risk groups and patients had to be aged 18 years or older. Studies were excluded if they assessed patients who had received prior treatment with any antileukaemic drugs, other than hydroxyurea, anagrelide or imatinib administered for less than six weeks. Complete cytogenetic response and major molecular response (both at one year) were the primary outcomes.

All but one of the studies included patients of all prognostic risk groups. Treatment group median ages ranged from 45 to 54 years. The high doses of daily imatinib used were 800mg in all studies except one (which used 600mg). Most studies allowed prior hydroxyurea treatment and some permitted previous treatment with anagrelide.

Two reviewers independently selected studies for inclusion.

Assessment of study quality

Two reviewers independently evaluated study quality by assessing randomisation, allocation concealment, blinding and use of intention-to-treat (ITT) or per protocol analysis.

Data extraction

Intention-to-treat data were extracted to calculate risk ratios (RR) with 95% confidence intervals (CI). Time points ranged from 18 months to four years. Authors were contacted for additional information.

Two reviewers independently extracted data; when disagreements occurred a third reviewer extracted the data.

Methods of synthesis

Meta-analyses were performed using a fixed-effect model, or a random-effects model when significant heterogeneity was detected (50% or greater Ι²), to calculate pooled risk ratios and 95% confidence intervals. Sensitivity analyses were also performed.

Results of the review

Four RCTs (1,673 patients) were included. No trials were blinded, and the methods of randomisation and allocation concealment were unclear in all trials. Median follow up periods ranged from 17 to 47 months.

After one year following high-dose imatinib, both the complete cytogenetic response (RR 1.17, 95% CI 1.08 to 1.26; four RCTs; Ι²= 33%) and the major molecular response (RR 1.26, 95% CI 1.12 to 1.42; four RCTs; Ι²= 0%) were statistically significantly improved. A sensitivity analysis for major molecular response, which excluded a study with fewer high-risk patients, yielded similar results. Statistically significant benefit from high dose treatment was also evident at the three, six, 18 and 24 month time points for major molecular response, and at six months for complete cytogenetic response.

There were no statistically significant differences between groups in all-cause mortality or disease progression (both three RCTs).

Adverse events resulting in discontinuation of treatment were significantly more frequent with high-dose imatinib (RR 1.98, 95% CI 1.20 to 3.26; three RCTs; Ι²=0%), as were Grade III/IV neutropenia and thrombocytopenia. There were no significant differences between groups for incidence of anaemia and Grade III/IV non-haematologic adverse events (except for diarrhoea).

Authors' conclusions

There was insufficient evidence available to support the routine use of higher doses of imatinib as frontline treatment for chronic phase chronic myeloid leukaemia.

CRD commentary

The review addressed a clear question and was supported by appropriate inclusion criteria. Attempts to identify studies in any language were undertaken by searching two electronic databases and checking references; attempts were also made to identify unpublished studies. Suitable methods were employed to reduce the risks of reviewer error and bias throughout the review. Study quality was assessed, but poor reporting seen in all trials precluded sensitivity analyses based on quality. Sufficient study details were provided and appropriate methods were used to pool data and to assess and investigate heterogeneity. The evidence that suggested treatment benefit with a higher dose was based on surrogate outcomes. The authors' conclusions were therefore suitably cautious, they reflected the limited evidence available, and they appear likely to be reliable.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that future studies should ascertain what the optimal ‘‘higher’’ imatinib dose was, and a RCT that compared 600mg imatinib with second generation tyrosine kinase inhibitors was warranted. Future trials that compared high-dose imatinib with standard dose imatinib or second generation tyrosine kinase inhibitors should also focus on different risk groups separately.

Funding

Not stated.

Bibliographic details

Gafter-Gvili A, Leader A, Gurion R, Vidal L, Ram R, Shacham-Abulafia A, Ben-Bassat I, Lishner M, Shpilberg O, Raanani P. High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia. American Journal of Hematology 2011; 86(8): 657-662. [PubMed: 21761431]

Indexing Status

Subject indexing assigned by NLM

MeSH

Antineoplastic Agents /administration & dosage /adverse effects /therapeutic use; Benzamides; Disease Progression; Dose-Response Relationship, Drug; Humans; Leukemia, Myeloid, Chronic-Phase /drug therapy /mortality; Piperazines /administration & dosage /adverse effects /therapeutic use; Protein Kinase Inhibitors /administration & dosage /adverse effects /therapeutic use; Pyrimidines /administration & dosage /adverse effects /therapeutic use; Randomized Controlled Trials as Topic

AccessionNumber

12011005251

Database entry date

12/09/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21761431