The Pill That Could · What Cure Means

What Cure Means, part 3

* * *

The question of stopping the drug is the question that, more than any other, has defined what ’cure' has come to mean in CML.

By the mid-2000s, with patients accumulating years of imatinib at deep molecular response, the natural question began to be asked. If the disease is undetectable at the most sensitive level of testing, do you still need to be taking the drug? The drug is not without cost — it is taken every day, indefinitely, with side effects that, while generally mild, are not zero. There is muscle and joint pain; there is fluid retention; there is fatigue; there are skin and gastrointestinal effects. There is the psychological weight of being a chronic-disease patient who takes a medication every morning forever. There is the financial cost, which we will come to in chapter eleven. If a patient could safely stop, even sometimes, that would be a substantial change in what living with CML actually means.

The first formal trials of stopping imatinib, in patients in deep molecular remission, ran in France in the late 2000s. The largest of them was called STIM — Stop Imatinib — led by a French hematologist named François-Xavier Mahon. STIM enrolled patients who had been on imatinib for at least three years and who had achieved complete molecular response (undetectable BCR-ABL on the available PCR assays) for at least two consecutive years. They stopped the drug. They were monitored monthly, by sensitive PCR, for any reappearance of the BCR-ABL transcript.

What STIM showed, when it reported in 2010, was that about 40 percent of patients who stopped imatinib in deep molecular response remained in remission at a year, with no reappearance of detectable disease. The other 60 percent relapsed — their molecular signal returned, usually within the first six months — and were restarted on the drug. Crucially, essentially all of the relapsed patients responded to imatinib again when they restarted; the relapse, when it happened, did not represent the emergence of resistance. Their disease had simply re-emerged from the reservoir, the way chapter nine described, and the same drug was still able to suppress it.

STIM established something new in the CML field. It established that, in a substantial minority of patients in deep molecular remission, stopping the drug was a feasible thing to do. The patients who stayed in remission off the drug were not, on any reasonable interpretation of the data, suppressing the disease through residual drug effects — imatinib washes out of the body in days. They were keeping the disease at zero, or near enough to zero, through some combination of having so few residual cells to begin with and the body's own mechanisms keeping those few cells from re-expanding. They were, for as long as the remission held, functionally cured. Whether this could be called cure in the traditional sense was a definitional question. They were certainly off the drug, off therapy, with no detectable disease, going about their lives.

STIM also established that this was a minority phenomenon. Most patients who stopped the drug relapsed. The disease, in those patients, was still there, suppressed below detection but not to zero, and as soon as the drug was removed, it resumed. The reservoir, in chapter nine's language, was still active.

Subsequent trials — EURO-SKI in Europe, A-STIM and others elsewhere — expanded the picture. They confirmed the basic finding, refined the criteria for who could safely attempt a treatment-free remission attempt, and produced clinical guidelines that have, by 2026, become part of standard CML practice. The current rough consensus is that a patient who has been on a TKI (tyrosine kinase inhibitor — imatinib, dasatinib, nilotinib, or one of the others) for at least five years, who has been in deep molecular response (MR4.5 or deeper) for at least two years, who is willing to be monitored frequently, and whose physician judges them to be a candidate, can attempt a treatment-free remission. About 40 to 50 percent of such patients will succeed in remaining off therapy long-term, with the precise number depending on the criteria used and the duration of follow-up. The rest will relapse and need to restart.

This is, by any reasonable historical comparison, an extraordinary state of affairs. CML in 1993 was uniformly fatal. CML in 2026, for patients who reach deep molecular response and choose to attempt treatment-free remission, is a disease from which roughly half of those patients can walk away. The other half remain on a daily pill, with normal life expectancy. Some patients in the second group, with continued treatment and continued deep response, will become candidates for treatment-free remission attempts later. Some won't. Either way, the disease has become something most patients live with, rather than something they die of.

* * *

There is, however, a complication, and it is one of the things that makes ’cure' a more interesting word in CML than it might first appear.

Even patients who achieve treatment-free remission — patients who have been off all therapy for years, with no detectable disease — sometimes have, on the most sensitive testing available, a small number of BCR-ABL-positive cells still present somewhere in their bone marrow. Specialized research assays that look at single cells have, in several published studies, detected rare leukemic stem cells in patients who by all clinical measures are in long-term treatment-free remission. The cells are there. They are not, in these patients, expanding. They appear to be held in check by mechanisms that the field is still working out — some combination of the cells' own dormancy, the bone marrow microenvironment they sit in, the ongoing surveillance of the immune system, and, possibly, factors specific to each patient that no one has fully characterized.

All 13 chapters of The Pill That Could · Library · All courses