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 MR4.5 (BCR-ABL1IS ≤ 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 MR4.5 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 MR4.5 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-ABL1IS ≤ 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-ABL1IS < 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 MR4.5 (median follow-up in consolidation phase, 336 days); median time to MR4.5 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-ABL1IS during TFR: 0.5722%, 0.0216%, and 0.2258%, respectively); all regained MR4.5 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 MR4.5 on IM achieved confirmed MR4.5 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.
Ritchie: Incyte: Speakers Bureau; Celgene: Speakers Bureau; Arian: Speakers Bureau; Novartis: Honoraria; Pfizer: Honoraria. Pinilla-Ibarz:Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Speakers Bureau. Deininger:Gilead: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Erba:Incyte: Consultancy, DSMB, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Pfizer: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Jannsen: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Ariad: Consultancy; Sunesis: Consultancy. Radich:BMS: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy. Savona:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Research Funding; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dautaj:Novartis: Employment. Wolff:Novartis: Employment. Mauro:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy.