Blood cancers

Early excitement seen with imatinib remains a decade on

The tyrosine kinase inhibitor imatinib (Glivec) appears to prevent chronic myeloid leukaemia from progressing a decade into treatment – with no signs of additional long-term toxicity a follow-up study finds.

Of more than 500 chronic myeloid leukaemia (CML) patients given imatinib as their initial therapy, just over 83% had survived the disease 10 years later, the open label multicenter cross-over design study published in the New England Journal of Medicine found.

Professor Tim Hughes, Head of Translational Leukaemia Research at the South Australian Health & Medical Research Institute and one of the investigators on the worldwide study told the limbic the results confirmed the early excitement that many clinicians had for the drug when it was first approved in 2001.

“It’s an incredible achievement compared to what we could achieve prior to the era of TKIs with interferon where 10 year survival was only 20-30%,” Professor Hughes said.

According to Professor Hughes, after more than a decade of follow up, imatinib had shown itself to be a remarkably safe drug – a finding that surprised the investigator.

“Imatinib does not just inhibit the ABL kinase – the target – it also inhibits quite a large number of other kinases. When we first started these trials we thought we were going to see toxicity emerge down the track – but it’s really hard to point to any particular toxicity that has been a major burden for the patients receiving the drug.”

In fact, Professor Hughes said there was some indication that the drug could be protective against some vascular events.

“There’s certainly a hint towards imatinib reducing the risk of vascular events and more than a hint towards it improving the profile of diabetes,” he said.

But while the long-term toxicity of imatinib was low Professor Hughes said patients still have to battle the day-to-day side effects of the drug.

“Yes, the long term toxicity is low – we don’t see major toxicities that are going to shorten your life span but we what we do see with imatinib is the day-to-day toxicities.

“About a third of patients say they have very significant daily side effects that impact on their quality of life substantially and do make it a struggle for patients to stay on the drug.”

Typically, patients will develop fatigue, muscle cramps, pigment loss or gain and swelling in the face and around the eyes.

Acknowledging the challenge that many clinicians faced in trying to keep patients motivated to stay on their therapy Professor Hughes said disease was often monitored with a PCR test so that clinicians could see if a patient was taking the drug inconsistently.

“[this] becomes a very useful way to remind the patient that their treatment is an ongoing active struggle against the leukaemia and that they have to maintain their part of the equation to take the drug to maintain their excellent response,” he said.

Another important motivator for good compliance, Professor Hughes said, was the fact that patients now recognised that if they achieved a deep molecular response there was a reasonable chance that they might be able to come off the drug altogether.

“That’s a huge motivator for patients,” he said.

While CML therapy with imatinib was generally considered a lifelong treatment, in recent years a small number of patients had been able to achieve treatment free remission, he said.

“We now have some patients who have been off their therapy for more than five years and a few patients as much as 10 years but [those kinds of results] are still only achievable in about 15-20% of patients because you first have to achieve a deep molecular response and maintain it”.

While Professor Hughes acknowledged that patients on the newer drugs seemed to have a better chance of a deep molecular response, which might allow them to try coming off the drug after a few years, he said there was still ‘no great argument’ that every patient should be given a second generation drug.

According to Professor Hughes, the current study demonstrated that for those patients who are at low risk of adverse outcomes from their CML and who can tolerate the drug, imatinib continued to be a ‘fantastic’ long-term treatment.

“We know about a third of patients will have a low Sokal prognostic score – a very low risk of any adverse outcomes from CML. If you can identify these low-risk patients with confidence then it’s quite appropriate to treat them with imatinib.

If the Sokal score was high then a substantial number of those patients would experience disease progression on imatinib Professor Hughes noted.

“We would normally prefer to use a second generation drug upfront to reduce the risk of those patients’ CML transforming and in those cases we would accept the slightly higher risk of adverse vascular events such as heart attack and stroke once we’ve weighed those risks up against the risk of the CML to decide what the best drug is for that patient.”

The study randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. The current analysis focused on patients who had been randomly assigned to receive imatinib. Long-term analyses included overall survival, response to treatment, and serious adverse events.

The study was supported and funded by Novartis Pharmaceuticals who manufacture imatinib (Glivec). 

Dr. Hughes reported receiving lecture fees and fees for serving on advisory boards from Novartis Pharmaceuticals, Bristol-Myers Squibb, and Ariad Pharmaceuticals.

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