Study gives new hope of a drug cure for some patients with chronic myeloid leukaemia

October 19, 2010

Some patients with chronic myeloid leukaemia (CML) in complete molecular remission (CMR) * are able to survive without relapse for up to 2 years after stopping imatinib treatment. These results, published Online First in The Lancet Oncology, suggest that some CML patients might be cured by tyrosine-kinase inhibitors, contrary to the belief that all leukaemia-initiating stem cells are resistant to imatinib and enable the disease to return if treatment is stopped.

Imatinib is the standard treatment for CML and significantly improves survival by blocking the activity of an abnormal protein called BCR/ABL which is responsible for the disease. In a small group of patients, imatinib can generate CMR, where there is an undetectable level of the BCR/ABL protein. Whether indefinite treatment is necessary to maintain this response, or if imatinib can be safely discontinued in the long term, and might cure the disease in some cases, is not clear.

The Stop Imatinib (STIM) study was established to examine whether imatinib treatment can be stopped without triggering molecular relapse** in 100 CML patients after at least 2 years of treatment with imatinib who were in sustained CMR. In this interim analysis, 69 patients with at least 12 months follow-up were assessed. The rate of relapse (BCR-ABL levels) was measured every month for the first year using RT-PCR, and every 2 months thereafter.

One year after stopping imatinib treatment, 41% of patients maintained CMR, while 38% remained in CMR for up to 2 years following discontinuation.

Of the 42 (61%) patients who lost their CMR, 40 relapsed before 6 months, one at month 7, and one at month 19. Importantly, all patients responded to the reintroduction of imatinib, suggesting that interrupting treatment does not lead to resistance or other safety issues.

In exploratory analyses, being male, a low prognostic Sokal score, and long treatment with imatinib were predictive of a better prognosis--factors that could help to select the patients most likely to benefit from treatment withdrawal.

The authors point out: "Sustained deep molecular remission, as we have used as an entry criteria for this trial, is not a frequent outcome of imatinib treatment. Therefore, patients treated with imatinib who are candidates for treatment interruption are rare...[and] might represent 10% of patients."

They conclude: "Our results confirm that imatinib can be safely stopped, provided that stable CMR has been obtained...Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured by tyrosine-kinase inhibitors."

In a Comment, Peter Valent from the Medical University of Vienna in Austria says that these results question the theory that all CML stem cells "show intrinsic resistance" against imatinib in all patients.

He adds: "There is now hope for drug-induced cure in CML. The questions that remain are whether most patients will be cured with new tyrosine-kinase inhibitors, and what drugs or drug combinations will be needed."
Professor François-Xavier Mahon, Université Victor Segalen Bordeaux 2, Bordeaux, France. T) +33 646 487 562 E)

Dr Peter Valent, Medical University of Vienna, Vienna, Austria. T) +43 1 40400 6085/6086/5488 E)

For full Article and Comment, see:

Notes to Editors: * Complete molecular remission (CMR) is defined as undetectable residual disease on RT-PCR (the disappearance of BCR/ABL transcripts which produce the abnormal protein responsible for too many white blood cells being made in the bone marrow that results in chronic myeloid leukaemia).

**Molecular relapse is defined as the detection of BCR/ABL transcripts on two successive occasions using RT-PCR.


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