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Abstract
Abstract: LB237

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Prior clinical studies of imatinib (IM) have demonstrated proof of concept for TFR; in the STIM trial, TFR (no loss of deep molecular response [MR]) was maintained 1 y after treatment discontinuation by ≈ 40% of pts with sustained deep MR on long-term frontline IM. In ENESTcmr, pts who did not achieve deep MR (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [IS]) with IM were more likely to achieve this response with a switch to NIL.

Aims
To present results from the single-arm phase 2 ENESTop study (NCT01698905) evaluating the ability to maintain TFR in pts who achieve and sustain MR4.5 on NIL following a switch from IM to NIL treatment.

Methods
Eligible pts had CML-CP, received prior tyrosine kinase inhibitor (TKI) treatment for ≥ 3 y (including IM for > 4 wk followed by NIL for ≥ 2 y), and achieved MR4.5 with NIL. All pts provided informed consent. Upon enrollment, pts continued NIL for 1 y (consolidation phase; RQ-PCR assessments every 12 wk). Pts without confirmed loss of MR4.5 (consecutive BCR-ABL1IS > 0.0032%) during the consolidation phase were eligible to stop NIL (TFR phase; RQ-PCR assessments every 4 wk for the first 48 wk). NIL was reinitiated (ReRx phase) upon confirmed loss of MR4 (consecutive BCR-ABL1IS > 0.01%) or loss of MMR (BCR-ABL1IS > 0.1%). The primary endpoint was the proportion of pts with ongoing TFR 48 wk after stopping NIL. This analysis was conducted when all pts who entered the TFR phase had completed 48 wk of TFR, entered the ReRx phase, or discontinued from the study (data cutoff, 26 Nov 2015).

Results
A total of 163 pts were enrolled and entered the consolidation phase; 126 entered the TFR phase. Median age at baseline was 56 y; prior to entering the TFR phase, median durations of TKI and NIL treatments were 88 (range, 49-171) and 53 (range, 37-109) mo, respectively. Of 126 pts, 57.9% (95% CI, 48.8-66.7%) remained in TFR at wk 48 (primary endpoint); 53.2% (95% CI, 44.1-62.1%) of pts had MR4.5 at wk 48. Of 53 pts who discontinued from the TFR phase, 51 entered the ReRx phase (loss of MMR, n = 34; confirmed loss of MR4, n = 17), and 2 permanently discontinued from the study (1 with confirmed MR4 loss did not enter ReRx phase due to investigator decision; 1 was found to have atypical transcripts). In the ReRx phase, 50 pts (98.0%) regained MMR or better by the data cutoff, and 48 (94.1%) and 47 (92.2%) regained MR4 and MR4.5, respectively; median times to regain MR4 and MR4.5 were 12.0 and 13.1 wk, respectively. No new safety signals were observed with NIL. Adverse event rates were 77.0% vs 73.8% in the consolidation vs the TFR phase (full analysis set). Events in the musculoskeletal pain grouping (defined as musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain, and/or spinal pain) were reported in 42.1% (n = 53) of pts (grade 3/4, 1.6%) in the first 48 wk of the TFR phase; most of these pts (37 of 53; 69.8%) had no history of musculoskeletal pain. In the TFR phase, the majority of events (46 of 54) in this grouping occurred during the first 24 wk; most events were still ongoing.

Conclusion
ENESTop provides the largest set of prospective TFR data to date in pts with CML-CP who achieved sustained deep MR after switching from IM to NIL. After stopping NIL, 58% of pts remained in TFR at 48 wk. The results of ENESTop, together with those from ENESTcmr showing that a higher proportion of pts switching to NIL reach deep MR, suggest that a higher proportion of pts switching to NIL will achieve TFR compared with pts continuing on IM.

Session topic: Chronic myeloid leukemia - Clinical 1

Keyword(s): Chronic myeloid leukemia, Clinical trial
Abstract: LB237

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Prior clinical studies of imatinib (IM) have demonstrated proof of concept for TFR; in the STIM trial, TFR (no loss of deep molecular response [MR]) was maintained 1 y after treatment discontinuation by ≈ 40% of pts with sustained deep MR on long-term frontline IM. In ENESTcmr, pts who did not achieve deep MR (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [IS]) with IM were more likely to achieve this response with a switch to NIL.

Aims
To present results from the single-arm phase 2 ENESTop study (NCT01698905) evaluating the ability to maintain TFR in pts who achieve and sustain MR4.5 on NIL following a switch from IM to NIL treatment.

Methods
Eligible pts had CML-CP, received prior tyrosine kinase inhibitor (TKI) treatment for ≥ 3 y (including IM for > 4 wk followed by NIL for ≥ 2 y), and achieved MR4.5 with NIL. All pts provided informed consent. Upon enrollment, pts continued NIL for 1 y (consolidation phase; RQ-PCR assessments every 12 wk). Pts without confirmed loss of MR4.5 (consecutive BCR-ABL1IS > 0.0032%) during the consolidation phase were eligible to stop NIL (TFR phase; RQ-PCR assessments every 4 wk for the first 48 wk). NIL was reinitiated (ReRx phase) upon confirmed loss of MR4 (consecutive BCR-ABL1IS > 0.01%) or loss of MMR (BCR-ABL1IS > 0.1%). The primary endpoint was the proportion of pts with ongoing TFR 48 wk after stopping NIL. This analysis was conducted when all pts who entered the TFR phase had completed 48 wk of TFR, entered the ReRx phase, or discontinued from the study (data cutoff, 26 Nov 2015).

Results
A total of 163 pts were enrolled and entered the consolidation phase; 126 entered the TFR phase. Median age at baseline was 56 y; prior to entering the TFR phase, median durations of TKI and NIL treatments were 88 (range, 49-171) and 53 (range, 37-109) mo, respectively. Of 126 pts, 57.9% (95% CI, 48.8-66.7%) remained in TFR at wk 48 (primary endpoint); 53.2% (95% CI, 44.1-62.1%) of pts had MR4.5 at wk 48. Of 53 pts who discontinued from the TFR phase, 51 entered the ReRx phase (loss of MMR, n = 34; confirmed loss of MR4, n = 17), and 2 permanently discontinued from the study (1 with confirmed MR4 loss did not enter ReRx phase due to investigator decision; 1 was found to have atypical transcripts). In the ReRx phase, 50 pts (98.0%) regained MMR or better by the data cutoff, and 48 (94.1%) and 47 (92.2%) regained MR4 and MR4.5, respectively; median times to regain MR4 and MR4.5 were 12.0 and 13.1 wk, respectively. No new safety signals were observed with NIL. Adverse event rates were 77.0% vs 73.8% in the consolidation vs the TFR phase (full analysis set). Events in the musculoskeletal pain grouping (defined as musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain, and/or spinal pain) were reported in 42.1% (n = 53) of pts (grade 3/4, 1.6%) in the first 48 wk of the TFR phase; most of these pts (37 of 53; 69.8%) had no history of musculoskeletal pain. In the TFR phase, the majority of events (46 of 54) in this grouping occurred during the first 24 wk; most events were still ongoing.

Conclusion
ENESTop provides the largest set of prospective TFR data to date in pts with CML-CP who achieved sustained deep MR after switching from IM to NIL. After stopping NIL, 58% of pts remained in TFR at 48 wk. The results of ENESTop, together with those from ENESTcmr showing that a higher proportion of pts switching to NIL reach deep MR, suggest that a higher proportion of pts switching to NIL will achieve TFR compared with pts continuing on IM.

Session topic: Chronic myeloid leukemia - Clinical 1

Keyword(s): Chronic myeloid leukemia, Clinical trial

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