IMATINIB MAY CURE SOME CML PATIENTS-STOP AND GO TACTIC AFTER CMR?

October 27, 2010 — Some patients with chronic myeloid leukemia (CML) might be cured by treatment with imatinib (Gleevec, Novartis), according to French researchers.

This suggestion of a possible drug cure for CML comes from the Stop Imatinib (STIM) study, in which imatinib treatment was halted in 100 patients who had been on the drug for at least 2 years and who had achieved complete molecular remission during treatment.

After stopping imatinib treatment, 41% of patients maintained complete molecular remission for 1 year, and 38% continued in complete molecular remission for up to 2 years, according to the investigators. The team, led by François-Xavier Mahon, MD, from the Centre Hospitalier Universitaire de Bordeaux in France, report their findings in a study published online October 19 in the Lancet Oncology.

"There is now hope for drug-induced cure in CML," writes Peter Valent, MD, in an editorial that accompanies the study. He is from the Medical University of Vienna in Austria.

The idea of a drug cure is contrary to theories about CML, said Dr. Valent. "Previous studies [have indicated] that CML stem cells show intrinsic resistance against imatinib in all patients," he writes, but "this theory is now in question."

As the study authors point out, current practice is for patients to continue treatment indefinitely because the ability of imatinib to eradicate CML is not clear.

This study might ultimately redefine treatment duration for some patients. "Our results suggest that some patients with CML could be cured with tyrosine kinase inhibitor treatment alone," write the authors.

However, only a minority of patients can hope for such a positive outcome.

"Sustained deep molecular remission, [which] 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 write.

Dr. Valent holds out hope that second-generation tyrosine kinase inhibitors, such as nilotinib and dasatinib, might produce "even faster and deeper responses," with more frequent occurrence of complete molecular remission than imatinib.

Despite his hopes, Dr. Valent suggests that the idea of a cure might not be accurate. "Imatinib might only be capable of eliminating rapidly cycling stem cells, but not all small subclones and their slowly cycling stem cells," he writes.

"If this postulation were true, most or all patients in [complete molecular remission] would relapse after a variable latency period, sometimes after years," he continues.

Who Will Most Likely Benefit?

The STIM study provided hints about which patients might most benefit from drug stoppage.

In exploratory analyses, being male, having a low prognostic Sokal score, and receiving longer treatment with imatinib were predictive of a better prognosis. These are factors that could help select patients for treatment withdrawal, according to the study authors.

However, until more is known about discontinuing treatment, clinicians should stick to standard practice. "Tyrosine kinase inhibitor therapy should be discontinued only in the context of an ongoing clinical trial," say the study authors.

The STIM trial is not the only research on discontinuation. Australian investigators reported much the same results some time ago (Blood.2008;112[Suppl 1]:402-403).

In the STIM trial, sustained complete molecular remission was defined as remission lasting more than 2 consecutive years. The 2-year timeframe is somewhat arbitrary, note the investigators.

"Conscious of patient safety, we believe that achievement of [complete molecular remission] for at least 2 years is a reasonable starting point for investigations into possible discontinuation of imatinib," they write.

The Safety of Stopping

In their interim analysis of the STIM data, the investigators assessed 69 patients with at least 12 months of follow-up. The rate of relapse (BCR–ABL levels) was measured every month for the first year using reverse-transcription polymerase chain reaction, and every 2 months thereafter.

The investigators found that 42 (61%) of the 69 patients relapsed, 35 within 3 months.

"We confirmed that most molecular relapses were rapid," explained the authors.

Importantly, all 42 patients who relapsed responded to the reintroduction of imatinib: 16 showed decreases in their BCR–ABL levels and 26 achieved complete molecular remission that was sustained after imatinib rechallenge.

These results provide good news about safety — that patients who relapsed after discontinuation retained sensitivity to the drug, suggesting that "discontinuation does not lead to acquired resistance," say the study authors.

The researchers have disclosed no relevant financial relationships.

Lancet Oncol. Published online October 19, 2010. Abstract, Abstract