Highlights from the American Society of Hematology (ASH) annual meeting, San Diego CA, December 3-6, 2016
Part 1 of this article summarized the results of recent Stop trials, which found that about 50% of people who try stopping their CML medication can remain in TFR (treatment-free remission) for at least a year without suffering a relapse. But before entering a TFR study, it’s essential that the person achieve a deep molecular response to a medication. This is generally defined as a 4.5-log molecular response (called MR4.5) sustained for two or more years. MR4.5 can be reached with any of the current CML medications, but is more likely to occur sooner with one of the more potent second-generation agents (i.e. Tasigna, Sprycel or Bosulif).
The finding that many people stopping treatment can remain in remission for at least a year is an encouraging result. It means that many people are able to avoid the trouble, expense and side effects associated with treatment for an extended period.
However, these results also mean that about 50% will have a relapse if they stop their medication. A relapse, in this context, means that the numbers (the BCR-ABL transcripts) are slowly getting worse – an early indicator that you are starting to lose control over the disease process. In some studies, this means a a deep molecular response (MR4.5) slips to MR4, while in other studies it has meant a loss of a major molecular response (MMR, equivalent to MR3), or loss of a complete cytogenetic response (CCyR, or roughly MR2).
The important question is: if I lose my response, can I get it back? Because after all the effort spent trying to get your CML under control – and maintaining those low numbers for years on end – who would want to squander those hard-fought gains for a short period of being medication-free?
This issue of whether starting treatment again can regain control was addressed in several studies presented at this year’s ASH meeting. The following summarizes the results.
The Canadian TRAD study (for TFR by dasatinib) looked at people initially treated with Gleevec who had tried unsuccessfully to stop. All participants had achieved MR4.5 for at least two years. The question the study asked was: if I lose my response, can I re-gain it if I start taking Sprycel (Kim and colleagues. ASH 2016; abstract 1922)? During the TFR phase of the study, about 1 in 3 people lost their response within 6 months of stopping treatment. Twelve of the 21 people (57%) who lost their response were able to re-attain MR4.5 within 2 months of starting Sprycel. After 3 months, everyone had achieved at least a major molecular response (MMR, i.e. MR3). So their level of disease control was not quite as good as before, but all of them did manage to achieve very good control of their CML with a second-generation medication.
One CML clinic reviewed its records for 95 people who went off their medication (Chamoun and colleagues. ASH 2016; abstract 1923). This was not a TFR trial; rather, it involved people who decided to stop therapy on their own. The most common reason for stopping was medication-related side effects; other reasons included pregnancy, other health problems, or financial difficulty. People had been on treatment for about 8-9 years before they stopped. Overall, 92 people were at MR4.5, while the remaining three were at MMR, when they stopped. Over the next two years off treatment, 37% of people with MR4.5 lost their response, typically within 4 months of stopping treatment; and all 5 people with MMR lost their response, usually within 8 months. The study found that how long a person was in MR4.5 was important: if longer than 5 years, the relapse rate was 15%, whereas it was 77% if MR4.5 had been sustained for less than 5 years. Of the 24 people who re-started treatment, 21 were able to re-attain the level of disease control that they’d had before. Three people had a lesser response (e.g. partial cytogenetic response). The researchers concluded that stopping treatment on your own (outside of a formal trial) isn’t advisable. It’s best to be patient: work at achieving a deep molecular response, remain at that level for at least five years, then ask your doctor if you’re a candidate for a TFR study.
If stopping treatment doesn’t work and you respond well to a renewed course of treatment, can you ever try stopping again?
Two studies have now tackled this question.
The first was a study in France, which looked at 67 people who had relapsed after a first TFR period (Pagliardini and colleagues. ASH 2016; abstract 788). After going back on treatment, re-achieving a complete molecular response and maintaining that level for 2-3 years, this group tried again. For this second attempt, 44% of people were able to maintain TFR for at least 22 months, indicating that many people may still be able to go off treatment if a first attempt fails.
The second study in Japan came to a different conclusion (Matsuki and colleagues. ASH 2016; abstract 1887). People who relapsed following a first attempt stopping therapy were re-started, most commonly on Sprycel. After achieving and maintaining a deep molecular response for another two years, 10 people tried discontinuing again. However, only one person was able to remain treatment-free on this second attempt. So more research will be needed to resolve this question of whether people who relapse after a first attempt at going off treatment can try being drug-free again.