Although TKIs have significantly improved life expectancy for patients with chronic myeloid leukemia, investigators are actively examining ways to safely discontinue treatment without sacrificing benefit.
Martha Wadleigh, MD
Although TKIs have significantly improved life expectancy for patients with chronic myeloid leukemia (CML), investigators are actively examining ways to safely discontinue treatment without sacrificing benefit. To effectively do this, patient selection is key, said Martha Wadleigh, MD.
First- and second-generation TKIs have altered the natural course of CML, explained Wadleigh in a presentation during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies.
“When imatinib (Gleevec) was first developed, the initial benchmarks of success included cytogenetic response and major molecular response,” said Wadleigh, clinical director, Adult Leukemia, institute physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School.
Now, the use of second-generation nilotinib (Tasigna), dasatinib (Sprycel), and bosutinib (Bosulif) is leading to deep molecular response and greater potential for TKI discontinuation.
Definitions regarding evaluating deep molecular response now pertain to MR4 and MR4.5, also synonymous with BCR-ABL transcripts by International Scale <.01% and <.0032%, respectively.
The first study to explore TKI discontinuation was the STIM1 trial, said Wadleigh. For the trial, if patients treated with imatinib had an undetectable transcript level ≥2 years, they were taken off therapy. Among patients who had been treated with imatinib for a median of 58 months, 38% experienced a successful treatment-free remission (TFR) after 60 months of follow-up.1 Although the majority of patients (n = 57/61) were restarted on treatment after losing MR3 (BCR-ABL <.1%), 55 were quick to attain undetectable minimal residual disease (UMRD) and showed no evidence of disease progression. A high Sokal score at the time of diagnosis and treatment duration of <54 months indicated a greater likelihood of molecular relapse, explained Wadleigh.
Several other trials have examined the parameters by which to choose appropriate candidates for treatment discontinuation, added Wadleigh.
In the A-STIM trial, patients treated with imatinib with undetectable transcript levels ≥2 years were taken off imatinib and were restarted on treatment only if they lost MMR. At 36 months of follow-up, 61% remained in TFR. For this trial, UMRD was not essential for TFR. Notably, the majority of relapses occurred within 6 months of discontinuation.2
The criteria for discontinuation in the EURO-SKI trial3 were more stringent, said Wadleigh, although its findings were similar to those seen in A-STIM. In the trial, 50% of patients who discontinued treatment after achieving MR4 ≥1 year after receiving 3 years of frontline imatinib, or second-line nilotinib or dasatinib remained in TFR at 24 months.
“In this study, it was the duration of deep molecular response and how long patients were in MR4 or greater that predicted the success of TFR at 6 months,” explained Wadleigh.
The smaller STOP 2G-TKI study2 looked at patients who had been treated with frontline dasatinib or nilotinib, although prior imatinib exposure was allowed. After 3 years of therapy on either dasatinib or nilotinib with undetectable transcript levels ≥2 years, 53.57% of patients remained in TFR at 48 months of follow-up. In this study, prior suboptimal response or resistance to first-line imatinib were the only identifiable factors linked with loss of MMR, said Wadleigh.
Similarly designed, the ENESTop trial4 patients who had received TKI therapy for at least 3 years (>4 weeks with imatinib and switched then ≥2 years with nilotinib) and achieved MR4.5 were then entered into a consolidation phase. Seventy-seven patients (n = 126) who sustained MR4.5 for the additional year of consolidation with nilotinib were eligible to enter TFR, and as such, discontinued therapy.
Distinguishing features among patients who entered the TFR phase versus those who did not included a shorter time from diagnosis to study entry (77.9 months vs 93.1 months), a shorter duration of TKI therapy (75.2 months vs 86.3 months), a shorter duration of imatinib therapy prior to study entry (23.5 months vs 45.4 months), and a longer time from MR4.5 with nilotinib to study entry (19.8 months vs 11.9 months).5
At the 2018 ASCO Annual Meeting, the 144-week follow-up data of ENESTop were presented and showed that approximately half of patients (n = 61) who entered the TFR phase of the trial remained in remission with a median time off therapy of 139.3 weeks (6.0-196.0 weeks). Among the 65 patients who came out of remission, 58 restarted therapy. At the time of data cutoff, 42 patients remained on therapy, the remainder of which were taken off the study due to adverse events (AEs), lack of efficacy, noncompliance, death, or patient decision.
In counseling patients on treatment discontinuation, conversations surrounding the likelihood of treatment reinitiation should be emphasized, stressed Wadleigh. For example, in ENESTop, 58 patients restarted nilotinib due to loss of MR4 (n = 24) or loss of MMR (n = 34). Fifty-four patients regained MR4 and MR4.5 with median times of 11.9 weeks and 13.1 weeks, respectively, a smaller proportion of patients (n = 42) were able to maintain MR4.5 for an additional 48 weeks.
Potential safety concerns should also be a point of discussion with patients, explained
Wadleigh, as some of the discontinuation studies with imatinib illustrated the commonality of withdrawal symptoms. Several AEs of special interest were experienced by patients in ENESTop who remained in TFR >96 weeks, said Wadleigh. Most notable were occurrences of grade 1/2 musculoskeletal pain in the first 48 weeks off treatment, she added.
If, after consulting the NCCN criteria, patients are candidates for discontinuation, access to high quality standardized PCR tests with high sensitivity to detect <4.5 log reduction per the IS scale is critical, said Wadleigh.
In the first year off therapy, patients should be monitored every month, after which they can be monitored every 2 months and 3 months in years 2 and 3, respectively. However, a rising BCR-ABL transcript should prompt resumption of monthly monitoring, if not treatment reinitiation, advised Wadleigh.
Although clinicians cannot confidently say why some patients stay in TFR and some fall out of it, the trials that have been conducted to date suggest that a longer duration of TKI treatment and time in DMR, prior resistance to imatinib, and high-risk features, all correlate with greater success. These features will have to be taken in context of the 2019 National Comprehensive Cancer Network Criteria for TKI Discontinuation if pursued, concluded Wadleigh.