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Abstract
Abstract: LB618

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
Proof of concept for TFR in CML-CP was demonstrated in the STIM trial, which enrolled pts with sustained deep molecular response (MR) on long-term imatinib (IM; median duration of 59 mo); ≈ 40% of pts enrolled in STIM maintained TFR (no loss of deep MR) after stopping IM. Similar results were observed in subsequent tyrosine kinase inhibitor (TKI) TFR studies, although differences in design (eg, pt population, monitoring requirements, criteria for reinitiation of therapy) preclude direct comparison of results across studies. Several studies have shown an association between maintaining TFR and longer TKI treatment duration.  

Aims
To present results from the single-arm phase 2 ENESTfreedom study (NCT01784068) evaluating the ability to stop NIL and maintain TFR in pts who achieved a sustained deep MR on frontline NIL.

Methods
Eligible pts had CML-CP, typical b2a2 and/or b3a2 BCR-ABL1 transcripts, and ≥ 2 y frontline NIL, and had achieved MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [IS]) on treatment. All pts provided informed consent. On study, pts continued NIL for 1 y (consolidation phase; RQ-PCR assessments every 12 wk); pts meeting response criteria during the consolidation phase (no assessment worse than MR4 [BCR-ABL1IS ≤ 0.01%], ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment) were eligible to stop NIL (TFR phase; RQ-PCR assessments every 4 wk for the first 48 wk). NIL reinitiation (ReRx phase) was triggered by loss of major MR (MMR [BCR-ABL1IS ≤ 0.1%]). 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, 30 Nov 2015).

Results
A total of 215 pts were enrolled and entered the consolidation phase; 190 of these pts stopped NIL and entered the TFR phase. Median age at enrollment was 55 y, and median NIL duration prior to TFR was 43 mo (range, 33-89 mo). At wk 48 of the TFR phase, 51.6% (95% CI, 44.2-58.9%) of 190 pts remained in MMR without reinitiation of treatment (primary endpoint), and 47.4% (95% CI, 40.1-54.7%) were in MR4.5 without reinitiation of treatment. A total of 86 pts lost MMR and reinitiated NIL. Of these 86 pts, 85 pts regained MMR, and 76 pts regained MR4.5 (1 pt discontinued from the study without regaining MMR [pt decision] 7.1 wk after entering the ReRx phase). The median time to regain MMR was 7.9 wk. No new safety signals were observed with NIL treatment. Fewer pts developed adverse events (AEs) in the TFR phase (65.8%) vs the consolidation phase (83.2%). Myalgia has been reported as part of an IM withdrawal syndrome in prior studies. Here, in the first 48 wk of the TFR phase, 47 pts (24.7%; grade 3/4 in 1.1%) stopping NIL reported AEs in the musculoskeletal pain grouping (defined as musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain, and/or spinal pain), of whom 32 had no previous such events. Most of these events occurred early in the TFR phase (39 pts had an event within the first 24 wk; median duration, 24.0 wk).

Conclusion
In ENESTfreedom, over 50% of pts remained in TFR 48 wk after stopping NIL, a clinically meaningful rate for pts with a relatively short duration of NIL therapy (≈ 3.6 y). Among pts who did not remain in TFR, all who remained on study regained MMR, and most regained MR4.5 with NIL reinitiation.

Session topic: Chronic myeloid leukemia - Clinical 2

Keyword(s): Chronic myeloid leukemia, Clinical trial
Abstract: LB618

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
Proof of concept for TFR in CML-CP was demonstrated in the STIM trial, which enrolled pts with sustained deep molecular response (MR) on long-term imatinib (IM; median duration of 59 mo); ≈ 40% of pts enrolled in STIM maintained TFR (no loss of deep MR) after stopping IM. Similar results were observed in subsequent tyrosine kinase inhibitor (TKI) TFR studies, although differences in design (eg, pt population, monitoring requirements, criteria for reinitiation of therapy) preclude direct comparison of results across studies. Several studies have shown an association between maintaining TFR and longer TKI treatment duration.  

Aims
To present results from the single-arm phase 2 ENESTfreedom study (NCT01784068) evaluating the ability to stop NIL and maintain TFR in pts who achieved a sustained deep MR on frontline NIL.

Methods
Eligible pts had CML-CP, typical b2a2 and/or b3a2 BCR-ABL1 transcripts, and ≥ 2 y frontline NIL, and had achieved MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [IS]) on treatment. All pts provided informed consent. On study, pts continued NIL for 1 y (consolidation phase; RQ-PCR assessments every 12 wk); pts meeting response criteria during the consolidation phase (no assessment worse than MR4 [BCR-ABL1IS ≤ 0.01%], ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment) were eligible to stop NIL (TFR phase; RQ-PCR assessments every 4 wk for the first 48 wk). NIL reinitiation (ReRx phase) was triggered by loss of major MR (MMR [BCR-ABL1IS ≤ 0.1%]). 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, 30 Nov 2015).

Results
A total of 215 pts were enrolled and entered the consolidation phase; 190 of these pts stopped NIL and entered the TFR phase. Median age at enrollment was 55 y, and median NIL duration prior to TFR was 43 mo (range, 33-89 mo). At wk 48 of the TFR phase, 51.6% (95% CI, 44.2-58.9%) of 190 pts remained in MMR without reinitiation of treatment (primary endpoint), and 47.4% (95% CI, 40.1-54.7%) were in MR4.5 without reinitiation of treatment. A total of 86 pts lost MMR and reinitiated NIL. Of these 86 pts, 85 pts regained MMR, and 76 pts regained MR4.5 (1 pt discontinued from the study without regaining MMR [pt decision] 7.1 wk after entering the ReRx phase). The median time to regain MMR was 7.9 wk. No new safety signals were observed with NIL treatment. Fewer pts developed adverse events (AEs) in the TFR phase (65.8%) vs the consolidation phase (83.2%). Myalgia has been reported as part of an IM withdrawal syndrome in prior studies. Here, in the first 48 wk of the TFR phase, 47 pts (24.7%; grade 3/4 in 1.1%) stopping NIL reported AEs in the musculoskeletal pain grouping (defined as musculoskeletal pain, myalgia, pain in extremity, arthralgia, bone pain, and/or spinal pain), of whom 32 had no previous such events. Most of these events occurred early in the TFR phase (39 pts had an event within the first 24 wk; median duration, 24.0 wk).

Conclusion
In ENESTfreedom, over 50% of pts remained in TFR 48 wk after stopping NIL, a clinically meaningful rate for pts with a relatively short duration of NIL therapy (≈ 3.6 y). Among pts who did not remain in TFR, all who remained on study regained MMR, and most regained MR4.5 with NIL reinitiation.

Session topic: Chronic myeloid leukemia - Clinical 2

Keyword(s): Chronic myeloid leukemia, Clinical trial

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