ENESTop 5-Year Update: Durability of Treatment-Free Remission Following Second-Line Nilotinib and Exploratory Analysis of Molecular Response Regain after Nilotinib Re-Initiation in Patients with Chronic Myeloid Leukemia
Authors: Mahon Francois-Xavier , Clementino Nelma D , Fominykh Mikhail , Lipton Jeffrey H. , Turkina Anna G. , Moiraghi Beatriz , Nicolini Franck E , Takahashi Naoto , Sacha Tomasz , Kim Dong-Wook , Fellague-Chebra Rafik , Tiwari Ranjan , Bouard Catherine , Hughes Timothy P. 
Published: February 2021

Background: The ENESTop study (NCT01698905) evaluates treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with sustained deep molecular response following second-line (2L) treatment with nilotinib (NIL). In the primary analysis, 57.9% of pts remained in TFR 48 weeks after stopping NIL and previous analysis at ≥3.7 years showed durability of TFR. The present analysis first assessed long-term TFR outcomes at ≥5 years and then a post-hoc analysis evaluated rates of regain of molecular response following NIL re-initiation in pts with loss of major molecular response (MMR) or confirmed loss of MR4.0 at a follow-up of 5 years.
Methods: Eligible pts had received ≥3 years of treatment (including &gt;4 weeks of imatinib followed by ≥2 years of NIL) and had achieved MR4.5 (BCR-ABL1IS ≤0.0032%) on NIL. Pts without confirmed loss of MR4.5 after 1 year of consolidation treatment (CONS) could attempt TFR. NIL was re-initiated upon loss of MMR (BCR-ABL1IS &gt;0.1%) or confirmed loss of MR4.0 (BCR-ABL1IS &gt;0.01% in 2 consecutive assessments). By data cut-off (29 Jan 2020) pts had completed ≥5 years of TFR, resumed NIL, or discontinued the study.
Results: At the data cut-off, of the 126 pts who entered TFR, 52 remained in TFR, 59 had resumed NIL and 15 had discontinued the study. At 5 years, the TFR rate was 42.9% (54/126; 95% CI, 34.1-52.0). Compared with pts in TFR at the end of the 3.7-year follow-up, an additional 4 pts were not in TFR at the 5-year follow-up, none due to loss of response: 2 pts discontinued TFR due to pt/guardian decision, 1 pt had an ischemic stroke and died in the post-treatment follow-up phase, and 1 pt was lost to follow-up. The MR4.5 rate at 5 years after starting TFR was 37.3% (47/126, 95% CI: 28.9-46.4). 11 pts with MR4.5 at 5 years had a temporary loss of MR4.5 while 36/126 (28.6%) maintained stable MR4.5 for 5 years. The estimated treatment-free survival (TFS) rate at 5 years was 49.4% (95% CI: 40.3-57.9). Of the 59 pts who resumed NIL, 58 (98.3%) regained MMR. The only pt who did not regain MMR stopped retreatment at 20 weeks and withdrew from the study. 56 (94.9%) pts regained MR4.0 and 55 (93.2%) regained MR4.5 (Figure). The median time to regain MR4.5 was 2.9 months (range: 0.9-22.5). Baseline characteristics between pts who resumed NIL due to loss of MMR (n=34) or confirmed loss of MR4.0 (n=25)were similar; more pts with loss of MMR had a low Sokal relative risk score at diagnosis (44.1% vs 16.0%) and pts with loss of MMR had a shorter median time from achievement of MR4.5 until TFR entry (27.9 vs 40.1 months). In pts with confirmed loss of MR4.0, 25/25 (100.0%) and 24/25 (96.0%) regained MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. In pts with loss of MMR, 33/34 (97.1%), 31/34 (91.2%) and 30/34 (88.2%) regained MMR, MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. The median time to regain MR4.5 for pts who resumed NIL due to confirmed loss of MR4.0 or loss of MMR was 2.0 months (range: 0.9-4.6) and 3.6 months (range: 1.6-22.5), respectively. There were no cases of disease progression or death due to underlying CML. For pts remaining in TFR &gt;3.7 years (n=58), the rates of all-grade adverse events (AEs) were 50.0% in the fifth 48 weeks of TFR compared with 55.2% in the fourth 48 weeks. The musculoskeletal pain AE rate was high during the first 48 weeks of TFR (53.4%) but by the fifth 48 weeks of TFR was lower (6.9%) than during CONS (10.3%). In pts who resumed NIL (n=59), the rate of all-grade AEs was higher (94.9%) than during CONS (77.9%, n=163). Overall all-grade AE rates were similar between pts re-initiating NIL due to loss of MMR (94.1%) or confirmed loss of MR4.0 (96.0%), with the most common AEs being hypertension (26.5% vs 32.0%), arthralgia (20.6% vs 8.0%), constipation (11.8% vs 20.0%) and hyperglycemia (26.5% vs 0%).
Conclusions: These results illustrate the long-term (up to 5 years) durability and safety of TFR in pts with CML-CP following 2L NIL. The majority of pts requiring NIL re-treatment rapidly regained MMR, MR4.0 or MR4.5. The faster rate of regain in pts resuming NIL due to confirmed loss of MR4.0 likely reflects earlier intervention but could also suggest a slower tempo of relapse and possibly more favorable biology. Subgroup analysis should be interpreted with caution due to small base sizes. No new or unexpected safety signals were observed.

Disclosures
Mahon: ARIAD: Honoraria; Novartis Pharma: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Honoraria. Clementino:EMS: Other: Financial support for congress. Fominykh:Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kim:Sun Pharma.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Current Employment, Current equity holder in publicly-traded company, Research Funding. Tiwari:Novartis: Current Employment. Bouard:Novartis: Current Employment. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.