Gleevec still the winner

[Guest guest]

Gleevec is still the winner in treating CML. Dr. Cortes wonders what would be

needed to dethrone imatinib as the standard of care for patients with newly

diagnosed CML. He points out that although we would ultimately like to improve

survival, it is unrealistic to expect an improvement in the short term, given

the excellent survival at 5 years for patients treated with imatinib. " Improving

survival free from transformation is similarly difficult, " he writes. However,

an improvement in event-free survival would be valuable and is a more reachable

goal, particularly if a broader definition of " event free " is used, such as the

one suggested by the authors of the current study, which includes toxicity and

failure to achieve (or loss of) major cytogenetic remission (MCyR) or CCyR.

Most of the available data on imatinib efficacy in newly diagnosed CML patients

is drawn from the International Randomized Study of Interferon (IRIS), which was

conducted under the supervision of the manufacturer. Most patients achieved a

durable CCyR, with an estimated overall survival of 89% at 5 years, but 20% of

patients were censored for various reasons, and event-free survival and

progression to accelerated or blastic phase were only evaluated for patients who

continued to use imatinib.

Comparison with IRIS

Hugues de Lavallade, MD, and colleagues from Hammersmith Hospital and Imperial

College, in London, United Kingdom, performed a single-center trial that

evaluated the efficacy of imatinib in 204 consecutive adult patients with newly

diagnosed BCR-ABL-positive CML in the chronic phase who were treated from June

2000 until August 2006. The primary goal of their study was to see whether

overall results differed from those obtained from an analysis performed on an

intention-to-treat basis where all events were recorded. All patients received

imatinib as first-line therapy; it was started within 6 months of their

diagnosis. The researchers evaluated hematologic, cytogenetic, and molecular

response, and progression-free and overall survival.

Even though the median follow-up of 38 months in their study was shorter than

that in the IRIS study, the results were similar. In the IRIS trial, the

cumulative incidence of CCyR at 60 months was 87%, event-free survival was 83%,

and overall survival was 89%. In the current study, the rates were 82.7%, 81.3%,

and 83.2%, respectively. After a median of 15.5 months, 54 patients (26%) had

permanently discontinued imatinib, for reasons that included adverse events,

loss of complete hematologic response, progression to accelerated or blastic

phase, and loss of MCyR. The dose of imatinib was increased in 75 patients (37%)

during the study period.

Kinase domain (KD) mutations have been associated with an acquired resistance to

tyrosine kinase inhibitors and, during follow-up, 12 different KD mutations were

detected in 11 patients. The development of KD mutations was significant for

predicting loss of CCyR, but not for predicting loss of a complete hematologic

response, progression-free survival, or overall survival. The researchers also

noted that the major predictor for both overall and progression-free survival

was a cytogenetic response at 1 year, which has been reported previously. " It is

difficult to define imatinib failure, in part because some patients achieve

hematologic response rapidly but take substantial time to achieve a CCyR, " write

the authors. " However, it may be inappropriate to wait indefinitely for a CCyR. "

They point out that in the IRIS study, patients who did not achieve a MCyR but

who discontinued imatinib before loss of a complete hematologic response were

not considered to have failed imatinib therapy. In addition, patients who

stopped treatment because of adverse effects were censored. " Consequently,

event-free survival, as defined in the IRIS study, is likely to be an

overestimate, " they write. " When these failures are considered appropriately, as

in an intention-to-treat analysis, the real response rate to imatinib at 5 years

is 62.7%. "

The study was supported by the Health Research Biomedical Research Centre

Funding Scheme and a grant from the " Fondation de France " The authors have

disclosed no relevant financial relationships.

Entire article can be read at this website:

http://www.medscape.com/viewarticle/577662

Blessings,

Lottie