Clinical efficacy and safety of high-dose imatinib for chronic myeloid leukemia patients: An updated meta-analysis

Yonghua Liu; Bingmu Fang; Jinhong Jiang; Peng Wang

doi:10.4103/0973-1482.191623

ORIGINAL ARTICLE

Year : 2016 | Volume : 12 | Issue : 5 | Page : 23-26

Clinical efficacy and safety of high-dose imatinib for chronic myeloid leukemia patients: An updated meta-analysis

Yonghua Liu¹, Bingmu Fang¹, Jinhong Jiang¹, Peng Wang²
¹ Department of Hematology, The 6^th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang Province, P.R. China
² Department of Clinical Laboratory, The 6^th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang Province, P.R. China

Date of Web Publication

7-Oct-2016

Correspondence Address:
Peng Wang
Department of Clinical laboratory, The 6th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang Province
P.R. China

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/0973-1482.191623

> Abstract

Objective: The aim of this study was to evaluate the clinical efficacy and safety of high-dose imatinib (IM) for chronic myeloid leukemia (CML) patients by pooled published studies.
Methods: Through searching the databases of PubMed, EMBASE, ASCO, ESMO, CNKI, and Wanfang, we collected open published clinical controlled trials-related high-dose IM treatment of CML. The pooled complete cytogenetic response (CCyR) and hematologic toxicities were calculated by the statistical software.
Results: Seven studies were included in this study with 1137 cases received high-dose IM treatment and 958 cases received regular-dose IM treatment. The pooled results showed that patients received high-dose IM had higher CCyR compared with regular-dose with the odds ratio (OR) of 1.75 (95% confidence interval [95% CI]: 1.44–2.1, P < 0.05) and 1.58 (95% CI: 1.38–1.81, P < 0.05) in 6 and 12 months. However, the hematologic toxicities risk of neutropenia (OR = 1.76, 95% CI: 1.22–2.54) and thrombopenia (OR = 1.88, 95% CI: 1.42–2.50) were much higher in the high-dose group.
Conclusion: High-dose IM for CML treatment was superior to standard-dose IM in the aspects of CCyR, but the risk of developing neutropenia and thrombopenia was much higher.

Keywords: Chronic myeloid leukemia, complete cytogenetic response, imatinib, meta-analysis

How to cite this article:
Liu Y, Fang B, Jiang J, Wang P. Clinical efficacy and safety of high-dose imatinib for chronic myeloid leukemia patients: An updated meta-analysis. J Can Res Ther 2016;12, Suppl S1:23-6

How to cite this URL:
Liu Y, Fang B, Jiang J, Wang P. Clinical efficacy and safety of high-dose imatinib for chronic myeloid leukemia patients: An updated meta-analysis. J Can Res Ther [serial online] 2016 [cited 2021 Apr 14];12:23-6. Available from: https://www.cancerjournal.net/text.asp?2016/12/5/23/191623

> Introduction

Chronic myeloid leukemia (CML), also known as chronic granulocytic leukemia, is a malignant tumor of the white blood cells.^[1],[2] CML was the first cancer to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome.^[3] In this translocation, parts of two chromosomes (the 9^th and 22^nd) switch places.^[4] As a result, part of the “breakpoint cluster region” gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal “fusion” gene generates a protein of p210 or sometimes p185 weight with abnormal function.^[5]

Imatinib (IM) has been approved by the US Food and Drug Administration (FDA) as a first-line treatment for CML. The standard treatment dosage is 400 mg/day.^[2],[6] However, several studies reported the high-dose IM can improve the complete cytogenetic response (CCyR) compared with standard dosage. However, for small cases included in each study, the statistical power is limited.

> Methods

Publication search strategy and inclusion criteria

Through searching the databases of PubMed, EMBASE, ASCO, ESMO, CNKI, and Wanfang, we collected open published clinical controlled trials-related high-dose IM treatment of CML. The searching terms were “CML” and “IM/Glivec” and no language restriction. The inclusion criteria were: (1) CML should be confirmed by cytology; (2) patients received high-dose or standard-dose IM; (3) without other types of malignant tumor history; (4) the CCyR can be extracted from the original studies.

Data extraction and quality assessment

Two reviewers (Yonghua Liu and Jinhong Jiang) extracted the data from the original included publications independently. The disagreement for data extraction was discussed and consulted to the third reviewer (Bingmu Fang) for consensus. The general information such as first and correspondence author name, the paper publication year, publication language, median age of included cases, and risk of prognosis distribution were extracted. Moreover, the number of CCyR was carefully extracted from each of the included study and cross-checked by the reviewers. The methodological qualities of the publications were evaluated according to the Cochrane Reviews Handbook 5.0 for the aspects of adequate sequence generation, blinding, incomplete outcome data address, free of selective reporting, and free of other biases.

Statistical analysis

Stata 11.0 (http://www.stata.com; Stata Corporation, College Station, TX, USA) and Review Manager (RevMan 5.0 provided by The Cochrane Collaboration, http://ims.cochrane.org/revman/download) were used to do the statistical analysis. Dichotomous data were calculated as the odds ratio (OR) with the 95% confidence interval (95% CI). Statistical heterogeneity across the included studies was assessed by Chi-square test,^[7] and the inconsistency was calculated by I².^[8] If heterogeneity was existed (P < 0.05 or I² > 50%), the random-effect method was used to pool the data otherwise, without significant heterogeneity, fixed-effect method was used.

> Results

General characteristics of included publications

According to the inclusion and exclusion criteria, several clinical trials were included in our meta-analysis. For the included seven studies, 1137 cases received high-dose IM treatment and 958 cases received regular-dose IM treatment. Six studies published in English and one study published in Chinese. Six trials provide the prognosis risk distribution. The general information is demonstrated in [Table 1].

Table 1: General characteristics of included publications

Click here to view

Quality of included studies

The general methodological quality was assessed by a five-question instrument described in the Cochrane Reviews Handbook 5.0. In general, the methodological quality for the included studies was considered to be of moderate risk of bias. Three papers reported the adequate sequence generation, none of the seven studies reported the blinding, six papers reported the incomplete outcome address, six studies addressed free of selective reporting, and four papers addressed free of other biases. The general outcome of methodological quality for each study is shown in [Figure 1].

Figure 1: The quality of included publication

Click here to view

Complete cytogenetic response

Six and five studies reported the CCyR in the time of 6 and 12 months. No significant heterogeneity was found across the included studies; the pooled results indicated that patients received high-dose IM had higher CCyR compared with standard-dose with the OR of 1.75 (95% CI: 1.44–2.1, P < 0.05) and 1.58 (95% CI: 1.38–1.81, P < 0.05) in 6 and 12 months, respectively, by fixed-effects model [Figure 2]. Funnel plot was eudipleural for the evaluation of publications, which indicated no significant publication bias [Figure 3].

Figure 2: The forest plot of complete cytogenetic response between high-dose imatinib and regular-dose imatinib

Click here to view

Figure 3: The funnel plot of evaluation of publication bias for complete cytogenetic response

Click here to view

Hematologic toxicities

Five and four studies reported the neutropenia and thrombopenia toxicity, respectively. The data were pooled by fixed-effect model for lack of heterogeneity among the studies. The pooled data indicated that the hematologic toxicities risk of neutropenia (OR = 1.76, 95% CI: 1.22–2.54) and thrombopenia (OR = 1.88, 95% CI: 1.42–2.50) was much higher in the high-dose group compared to standard-dose group [Figure 4]. Moreover, the funnel plot indicated no statistical publication bias [Figure 5].

Figure 4: The forest plot of hematologic toxicities between high-dose imatinib and regular-dose imatinib

Click here to view

Figure 5: The funnel plot of evaluation of publication bias for hematologic toxicities

Click here to view

> Discussion

IM (marketed as Gleevec or Glivec), the first drug that was approved by the US FDA in 2001 for the treatment of CML. IM was found to inhibit the progression of CML in the majority of the CML patients sufficiently to achieve regrowth of their normal bone-marrow stem-cell population with stable proportions of maturing white blood cells. Because some leukemic cells persist in nearly all patients, the treatment has to be continued indefinitely. The standard dosage of IM for the treatment of CML was 400 mg/day. The prospective, randomized controlled trial (RCT) International Research InstituteS (IRIS) showed a promising results with 8-year follow-up for patients with CML in chronic phase (CP-CML) treated with 400 mg IM orally once daily (IM 400) with an 83% cumulative CCyR rate.^[16] With the promising results, IM 400 mg/day is considered an option for first-line treatment of CML by the National Comprehensive Cancer Network (http://www.nccn.org) and the European LeukemiaNet. Subsequently, several prospective RCTs reported the results of IM 400 mg/day for the treatment of CML. Deininger et al. reported a RCT of IM 800 mg daily induces deeper molecular responses than IM 400 mg daily: Results of SWOG S0325, an intergroup randomized Phase II trial in newly diagnosed CP-CML. They found that IM 800 could induce deeper molecular responses than IM 400, with a trend for improved progression-free and overall survival, but more severe toxicity also was found. However, Petzer et al.^[13] believed that standard-dose IM remains the standard of care for pretreated patients with CP-CML.

In our present meta-analysis, we included seven prospective clinical trials reported the clinical efficacy and safety of high-dose versus standard-dose IM for CML. The pooled results indicated that high-dose IM for CML treatment was superior to standard-dose IM in the aspects of CCyR, but the risk of developing neutropenia and thrombopenia was much higher. The pooled results were in accordance with most of the previously published studies.

However, an obvious limitation of this meta-analysis was existed. The methodology quality of included studies was not high with none of the seven publications reported the blinding. This limitation may affect the results stability of this meta-analysis.

Financial support and sponsorship

Project of science and Technology Department of Zhejiang Province(No.2012C33110);Project of Zhejiang Provincial Administration of traditional Chinese Medicine(No.2016ZQ036) ;Lishui Municipal Science and Technology Bureau(2014ZDXK04).

Conflicts of interest

There are no conflicts of interest.

> References

1.	Wieczorek A, Uharek L. Management of chronic myeloid leukemia patients resistant to tyrosine kinase inhibitors treatment. Biomark Insights 2016;10 Suppl 3:49-54.
2.	Saußele S, Silver RT. Management of chronic myeloid leukemia in blast crisis. Ann Hematol 2015;94 Suppl 2:S159-65.
3.	Thompson PA, Kantarjian HM, Cortes JE. Diagnosis and treatment of chronic myeloid leukemia in 2015. Mayo Clin Proc 2015;90:1440-54. [PUBMED]
4.	Zhang Y, Rowley JD. Chronic myeloid leukemia: Current perspectives. Clin Lab Med 2011;31:687-98, x. [PUBMED]
5.	Nowell PC. Discovery of the Philadelphia chromosome: A personal perspective. J Clin Invest 2007;117:2033-5. [PUBMED]
6.	Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011;103:553-61. [PUBMED]
7.	DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. [PUBMED]
8.	Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
9.	Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: A European LeukemiaNet Study. Blood 2009;113:4497-504. [PUBMED]
10.	Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim DW, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: Tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 2010;28:424-30. [PUBMED]
11.	Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010;363:2511-21. [PUBMED]
12.	Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-a in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011;29:1634-42.
13.	Petzer AL, Fong D, Lion T, Dyagil I, Masliak Z, Bogdanovic A, et al. High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients – final analysis of a randomized, multicenter, phase III trial. Haematologica 2012;97:1562-9. [PUBMED]
14.	Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E, et al. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: Results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 2014;164:223-32. [PUBMED]
15.	Guanghong L. High-dose imatinib compared standard-dose in the treatment of chronic myeloid leukemia patients. World Latest Med Inf 2015;15:91-2.
16.	Hughes TP, Hochhaus A, Branford S, Müller MC, Kaeda JS, Foroni L, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: An analysis from the international randomized study of interferon and STI571 (IRIS). Blood 2010;116:3758-65.