High-dose imatinib for newly diagnosed chronic phase

chronic myeloidleukemia patients—Systematic review and

meta-analysis

Anat Gafter-Gvili,1,2 Avi Leader,3 Ronit Gurion,1,2 Liat Vidal,1,2 Ron Ram,1,2 Adi
Shacham-Abulafia,1,2 Isaac Ben-Bassat,2 Michael Lishner,2,3 Ofer Shpilberg,1,2 and
Pia Raanani1,2*
 Introduction
Chronic myeloid leukemia (CML) is characterized by a unique cytogenetic
abnormality, the Philadelphia (Ph(1)) chromosome, resulting from reciprocal
translocation between chromosomes 9 and 22.

Imatinib mesylate (Gleevec,Novartis) is a relatively specific inhibitor of the BCR-

ABL1 tyrosine kinase with proven efficacy in CML

This trial succeeded in showing higher rates of complete cytogenetic response

(CCyR) and major molecular response (MMolR), as well as decreased progression
to accelerated phase (AP)/blastic crisis (BC) with imatinib treatment compared
with the control arm with interferon and cytarabine
 Material and Methods
Data sources. A comprehensive search with the purpose of identifying
all eligible trials regardless of language, year of publication, or status of
publication was conducted.

s of language, year of publication, or status of publication was conducted.

The search included PubMed (January 1966 to March 2011), the Cochrane
Central Register of Controlled Trials (CENTRAL) published in The Cochrane
Library (issue 1, 2011)
• pict
All RCTs that compared single agent imatinib 400 mg daily with higher doses of
imatinib (600 mg daily) as frontline treatment fornewly diagnosed (during the prior 6
months), previously untreated CP-CML patients were included.

Trials assessing patients aged 18 years or older, with Ph(1) positive or negative, BCR-ABL1
positive, CML in CP, with established diagnosis by cytogenetic analysis and/or FISH and/or
PCR, and with any Sokal or Hasford (Euro) prognostic risk
groups, were included

Data extraction and assessment of quality and risk of bias. Data from included trials were
independently extracted by two reviewers (A.G. and A.L.), regarding case definitions, patient
characteristics, and safety and efficacy outcomes. In case of disagreement, a third reviewer
(R.G.) extracted the data
Allocation concealment and generation of allocation sequence were classified as
adequate, unclear, or inadequate [24] according to the criteria specified in the
Cochrane Handbook [23]. We also ascertained whether the primary outcome was
analyzed according to the intention-to-treat principle or per protocol.

Definition of outcome measures. For primary outcome, we chose both CCyR at

12 months and MMolR at 12 months. This is due to the fact that there is still
controversy regarding which is the best surrogate outcome between these two
outcomes. CCyR remains the most studied and validated treatment goal [25,26],
whereas MMolR has also been considered as a surrogate marker for improved
long term outcomes according to some studies, remaining a primary outcome in
many trials and commonly used in clinical practice for monitoring treatment
with imatinib [27].
Secondary outcomes were divided into efficacy outcomes and safety outcomes.
Efficacy outcomes included: all-cause mortality at the end of follow up; CCyR at 3 and
6 months; MMolR at 3, 6, 18, and 24 months; the number of patients with AP/BC at the
end of follow up. Safety outcomes included: Grade III/IV hematologic adverse events;
Grade III/IV nonhematologic adverse events (diarrhea, edema, hypophosphatemia,
liver toxicity, muscle cramps or myalgia, and rash); discontinuation of imatinib due to
adverse drug reactions; discontinuation of imatinib for any reason.

Data synthesis and statistical analysis. We analyzed dichotomous data by

extracting the number of patients with an event and the number of patients
evaluated and compared study groups by assessing risk ratios (RR) and their
corresponding 95% confidence intervals (CI) (Review Manager [RevMan], version
5 for Windows, The Cochrane Collaboration,Oxford, United Kingdom).
Result
• tabel
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Our results of improved cytogenetic and molecular outcomes are in concert
with several prior observations which suggested that higher doses of
imatinib may be more efficacious than standard doses [7,12–14,30–34

Interestingly, a subanalysis of imatinib pharmacokinetics from the IRIS study

showed that imatinib trough levels correlate significantly with CCyR,
MMolR, and event-free survival [35,36]]
Our meta-analysis showed no difference in survival or progression to AP/BC between
the high and standard dose groups, albeit after restricted follow up, ranging from a
median of 17 to 47 months

These findings must be considered in the context of prior studies which, after shortterm
follow up, have shown improvement in CCyR, MMolR, and progression to AP/BC, but not in
overall survival [5,37]

Our meta-analysis showed improved cytogenetic and molecular outcomes with higher
imatinib doses. Subsequently, it is imperative in future studies to ascertain what the optimal
‘‘higher’’ imatinib dose is. It seems from observations of the actual dose taken, that doses
around 600 mg maybe more suitable than higher doses.
 Conclusion
Higher doses of imatinib compared with standard dose imatinib
significantly improved CCyR and MMolR at 12 months, though associated
with greater toxicity. There was no difference in all-cause mortality or
progression to AP/BC, although this should be taken with reservation due
to the short period of follow up
there is currently insufficient evidence to support the routine use of higher
imatinib doses as frontline treatment for CP-CML. Extended follow up
periods are needed to evaluate whether the superior CCyR and MMolR
with higher doses of imatinib will translate to long-term clinical benefit.