Glivec improves long-term survival prospects for chronic myeloid leukaemia patients

Most patients who develop chronic myeloid leukaemia (CML) can now expect to live more than 20 years from diagnosis if they are treated with the tyrosine kinase inhibitor (TKI) Glivec (imatinib) according to haematologists involved in the IRIS (International Randomized Interferon versus STI571) study.  Before availability of current treatments, median survival from diagnosis was 3.5 years.

Around 95 per cent of patients diagnosed with CML have the Philadelphia chromosome positive (Ph+) form that responds well to Glivec, said Professor Goldman.  The chromosome is the result of translocation between the long arms of chromosomes 9 and 22.  Part of the breakpoint cluster region (Bcr) gene from chromosome 22 fuses with part of the abelson leukaemia virus (Abl) gene on chromosome 9 producing the abnormal tyrosine kinase protein Bcr-Abl.  It is this protein that causes the proliferation of white blood cells resulting in CML.

 Four-year data from IRIS were presented at this year’s American Society of Hematology (ASH) meeting by Professor John Goldman, professor of haematology at Imperial College, London.  More than 90 per cent of patients with Ph+ CML in the chronic phase, randomised initially to Glivec 400mg daily in the year 2000, were still alive and free of progression to advanced disease at 54 months, he said. 

The study confirmed that patients who achieved a major molecular response within one year, ie, a more than 1000-fold reduction in residual leukaemia, fared best.  Patients achieving a three-log reduction in Bcr-Abl transcript levels within oneyear were all free of progression to advanced disease at year four.

“This patient population is likely to live decades rather than years,” Professor Goldman commented.  “In contrast to older therapies where progression rates to advanced disease were around 15 per cent per annum, with continuing Glivec it was less than 1 per cent by the fourth year of treatment.  We have the prospect now of turning CML into a disease analogous to diabetes where you receive regular treatment and monitoring but you don’t expect the disease to shorten life substantially.”

Survival rates with IFN inferior to Glivec

Survival data for the control arm in IRIS could not be calculated because the majority had crossed over to Glivec within nine months.   Control arm patients began treatment with daily interferon plus cytarabine added for 10 days each month (IFN + Ara-C) but the trial design allowed for patients to cross over if they experienced loss of treatment response or could not tolerate therapy. 

Restrospective data, also presented at ASH, compared 3-year survival of patients treated with Glivec in IRIS with 3-year survival of patients receiving IFN + Ara-C in a similarly-designed trial conducted before Glivec became available.  Results showed overall survival rates of 92 per cent for Glivec and 84 per cent for IFN + Ara-C.  “This difference was highly significant,” commented Professor Francois Guilhot, professor of oncology at University of Poitiers, France.

 “Seventy to 80 per cent of patients show a good response to Glivec and these patients have the prospect of being well for the next 20 years or more”. Said Professor Goldman.  Those who do not respond or who develop partial resistance may benefit from an escalated dose to 600mg or 800mg.  Data presented at ASH from several international studies show Glivec at doses up to 800mg daily produce higher rates of molecular response than the 400mg dose.

More potent agents on way

However, drugs targeting the proteins responsible for CML are now in development which are much more potent than Glivec in suppressing activity of Bcr-Abl.  They are also able to control disease in patients who have developed mutations resistant to Glivec.  AMN107, is one such agent in development by Novartis primarily for CML. 

Described as a novel aminopyridine inhibitor of Bcr-Abl, AMN 107’s activity is similar to Glivec’s but is up to 50 times more powerful.  It is active against 32 of the 33 Bcr-Abl mutations associated with varying degrees of resistance to Glivec.

Speaking during ASH, Professor Hagop Kantarjian, chairman of the Department of Leukaemia at the MD Anderson Cancer Centre,Texas, said AMN 107 attaches more strongly than Glivec to the Bcr-Abl protein and at a different site.  Phase 1 studies in Glivec-resistant patients with advanced disease showed around 60 per cent treated with AMN 107 achieved a haematological response, he said.

AMN 107 is now being compared against Glivec 400mg and 800mg in a Phase III trial, TOPS (Tyrosine kinase inhibitor Optimisation and Selectivity).  “If studies confirm safety and efficacy seen to date AMN 107 could either replace Glivec as the standard in future or be used in combination with it,” predicted Prof Kantarjian.  The drug is expected to be submitted to regulators for approval in the near future and could be available in 2006.

Olwen Glynn Owen
glynnowen@macline.co.uk

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