ENESTgoal Treatment-Free Remission Study: Updated Preliminary Results and Digital Polymerase Chain Reaction Analysis in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Switched from Imatinib to Nilotinib

Background: Treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] therapy without loss of response) has been demonstrated in multiple trials in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with stable deep molecular response (DMR) after long-term TKI therapy. Enabling TFR requires frequent molecular response (MR) assessments near the limit of detection (LOD) for real-time quantitative polymerase chain reaction (RQ-PCR) before and after stopping treatment. Digital PCR (dPCR) may have the potential for more sensitive detection of BCR-ABL1. ENESTgoal is an open-label phase 2 study in pts receiving imatinib (IM) who achieved major MR (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) but not MR^4.5 (BCR-ABL1^IS ≤ 0.0032%) and were switched to nilotinib (NIL) upon enrollment.

Methods:Pts (aged ≥ 18 years) with Philadelphia chromosome-positive CML-CP who had MMR but not MR^4.5 after ≥ 1 year of IM were switched to NIL 300 mg twice daily in a monitoring phase of up to 2 years. Pts who achieved confirmed MR^4.5 during the monitoring phase entered a 2-year NIL consolidation phase (changed via protocol amendment from randomization to 1 or 2 years of consolidation). Pts with no confirmed loss of MR⁴ (BCR-ABL1^IS ≤ 0.01%) during consolidation were eligible to stop NIL and enter the TFR phase; pts who were randomized to a 1-year consolidation and had already entered TFR prior to the protocol amendment continued in the TFR phase. Pts with molecular relapse, defined as confirmed loss of MMR (2 samples within ≈ 4 weeks) during TFR, reinitiated NIL. RQ-PCR was performed every 3 months before TFR, monthly for the first 6 months of TFR, and every 2 months thereafter during TFR. When sufficient sample was available, dPCR was also performed for samples from the consolidation and TFR phases that were expected to be below the RQ-PCR LOD (BCR-ABL1^IS < 0.0032%).

Results:As of the data cutoff (May 9, 2016), 59 pts were enrolled (median follow-up in monitoring phase, 297 days): median age, 54 years; male, 66%; median prior IM duration, 64 months. Of these,42 pts (71%) remained on study (monitoring phase, n = 9; consolidation phase, n = 29; TFR phase, n = 1; reinitiation phase, n = 3). Median NIL exposure on study was 21 months (range, < 1-31 months).

A total of 39 pts (66%) achieved confirmed MR^4.5 (median follow-up in consolidation phase, 336 days); median time to MR^4.5 was 220 days (range, 56-757 days). As of the data cutoff, 25 pts did not have confirmed loss of MR⁴ during consolidation, and 4 pts had entered the TFR phase; of these 4, 3 had only 1 year of NIL consolidation. Three pts restarted NIL after 70, 99, and 153 days in the TFR phase (final BCR-ABL1^IS during TFR: 0.5722%, 0.0216%, and 0.2258%, respectively); all regained MR^4.5 with NIL retreatment. As of the data cutoff, 1 pt remained in TFR (duration, 138 days; BCR-ABL1 undetectable at last measurement). However, longer follow-up is needed to determine the rate and duration of TFR.

Adverse events (AEs) reported in ≥ 10 pts during NIL treatment included fatigue (n = 22; 37%), constipation (n = 15; 25%), rash (n = 14; 24%), headache (n = 12; 20%), abdominal pain and pruritus (n = 11; 19% each), and diarrhea, lipase increased, and weight decreased (n = 10; 17% each). The majority of events were grade 1/2. Serious NIL-related AEs were unstable angina, arterial stenosis, pericardial effusion, peripheral arterial occlusive disease, and transient ischemic attack (n = 1 each). Seven pts discontinued from the study due to AE/abnormal laboratory value; the remaining study discontinuations were due to withdrawal of consent (n = 6) and unsatisfactory therapeutic effect (n = 4). No deaths occurred on study.

In 97 samples from pts in the consolidation and TFR phases that had undetectable BCR-ABL1 by RQ-PCR, dPCR analysis was performed. BCR-ABL1 was detected by dPCR in 11 of these samples (11%); none of these pts have relapsed.

Conclusion: The majority (66%) of pts with MMR but not MR^4.5 on IM achieved confirmed MR^4.5 after switching to NIL on study. The safety profile of NIL was generally consistent with that seen in previous NIL studies. dPCR detected BCR-ABL1 transcripts in samples from some pts with undetectable BCR-ABL1 by RQ-PCR. Achievement of sustained DMR and maintenance of TFR in ENESTgoal continue to be evaluated with ongoing follow-up; future dPCR analysis will compare BCR-ABL1 transcript levels at the time of stopping NIL in pts who did or did not have molecular relapse.