Report on ASH 2014 – Part 2
American Society of Hematology annual meeting, San Francisco, USA, December 6-9, 2014
A good proportion of people with CML treated with a TKI (tyrosine kinase inhibitor) can achieve undetectable levels of disease. This means that the burden of leukemic cells is below the level that can be identified with PCR testing. These tests are highly sensitive, and can often detect up to a 5-log reduction (i.e. to 1/100,000th) in BCR-ABL transcripts. So if the disease is this undetectable, it raises the important question: has CML been completely eliminated (i.e. cured)? And even if very low levels of CML are still present, is the disease suppressed enough that people don’t necessarily need to keep taking their TKI?
These questions have prompted a series of “stop trials”, in which people with very good disease control (usually a 4-log reduction or better) for a sustained period (usually a year or more) are taken off their TKI. The first of these studies was STIM (for Stop Imatinib), which found that 41% of people maintained a complete molecular response (CMR; also called molecularly undetectable leukemia) after one year off treatment (Mahon and colleagues. Lancet Oncol 2010;11:1029-1035).
Stopping treatment is perhaps the hottest topic in CML research, and a number of new studies presented at ASH 2014 looked at this issue. In the EURO-SKI (for European LeukemiaNet Stop TKI) study, TKI therapy was stopped in 498 people who had maintained a 4-log reduction for at least one year (Mahon and colleagues. ASH 2014; abstract 151). The interim analysis looked at 200 people. Most were male (58%) who had been diagnosed at a median age of 53 years. The median time from CML diagnosis to stopping treatment was eight years. Most started treatment with Gleevec, but some had switched to Sprycel or Tasigna. The median duration of a deep molecular response (4-log reduction or better) was five years.
Overall, 61.5% maintained good disease control for six months after stopping treatment. However, the amount of time previously spent on treatment appeared to make a difference. Among those on a TKI for eight years or more, only 26% lost their major molecular response (MMR) within six months of stopping treatment, compared to 47% of those on a TKI for fewer than eight years. The duration of a deep molecular response was also important. Loss of MMR was 32% in those with a sustained 4-log reduction for more than five years, compared to 46% for those with a 4-log reduction for a shorter time. Some people said that they developed muscle pain when they stopped treatment, which some have called a “TKI withdrawal syndrome” (Richter and colleagues. J Clin Oncol 2014;32:2821-2823).
The ISAV (for Imatinib Suspension And Validation) study was conducted in five countries (including Canada) and used a new digital PCR test which is reportedly 100-fold more sensitive than conventional PCR testing (Mori and colleagues. ASH 2014; abstract 813). The 112 people enrolled in the study were required to be in CMR for at least 18 months. The median time on imatinib (Gleevec) was 8-9 years, and the median duration of CMR was 26 months. In the first 16 months off treatment, 43.5% of people relapsed, typically within the first nine months. All of those who relapsed were able to regain MMR or CMR with two months of re-starting treatment. In this study, the amount of time on Gleevec didn’t have an impact on the risk of relapse. However, a person’s age was inversely related to the risk of relapse. Relapses occurred in 90% of people aged 45 years or younger, compared to 37.5% in those aged 45-64, and 27.5% in those aged 65 years or older.
This age effect wasn’t seen in the KIDS (for Korean Imatinib Discontinuation) study (Oh and colleagues. ASH 2014; abstract 3155). Data were analysed for 115 people. The median age was much younger (44 years) than in the other Stop trials. The median time on a TKI was seven years; and the median duration of deep molecular response was 3-4 years. The estimated probability of maintaining MMR for one year off treatment was 67%.
Most of the people enrolled in Stop trials were taking Gleevec. But one study (called French STOP 2G-TKI) has now looked at whether people taking a second-generation TKI (Tasigna or Sprycel) can discontinue treatment (Rea and colleagues. ASH 2014; abstract 811). All had been on treatment for at least three years, and had a 4.5-log reduction sustained for at least two years. In contrast to the previously mentioned studies, most people in this study were female (61.5%) and older (median age 60 years).
At one year off treatment, 61.4% had maintained MMR; at two years, 57% were still remission-free. The risk of relapse was not affected by age, sex, type of TKI, time since diagnosis or duration of MMR. However, people with a prior history of resistance to Gleevec appeared to have a greater risk of relapse.
These studies show that many people – perhaps 60% or so – who achieve a deep molecular response can go off treatment without having a relapse of their CML. However, stopping therapy is best reserved for clinical trials rather than daily practice. More information is needed about who would be the best candidates for going medication-free.