Bibliographic record
Abstract
There is considerable current interest in discontinuing treatment in CML patients with excellent and enduring molecular responses after prolonged tyrosine kinase inhibitor (TKI) treatment.Although entry criteria and definition of molecular relapse vary across studies, most show a 40-50% molecular recurrence rate after abrupt TKI withdrawal, and all restrict entry to patients in durable MR4 (BCR-ABL1/ ABL1 transcript ratio <0.01%).Thus the role of gradual TKI withdrawal, and the effect of withdrawal in patients in stable major molecular response (MMR) but not necessarily MR4 have not been previously investigated.The De-Escalation and Stopping Treatment of Imatinib, Nilotinib and sprYcel (DESTINY) trial is examining 12 months of half dose TKI therapy followed by complete withdrawal for 24 months, in adult patients in first chronic phase with at least 3 years of TKI therapy, whose PCR results in the previous 12 months have been either all <0.01%(the 'MR4' group) or some/all between 0.1 and 0.01% (the 'MMR' group).Central molecular monitoring is carried out monthly for the first 2 years and alternate months thereafter; molecular recurrence is defined as the first of 2 consecutive PCR results >0.1%.Throughout the study period patients were asked to complete a monthly symptoms diary.Complete data on 2 years follow up are presented here.Between 12/2013 and 5/2015, 174 (98 male) patients were recruited across 20 sites.During the initial 12 months of half dose therapy, 3 (2%) of 121 evaluable MR4 and 9 (19%) of 49 MMR patients underwent molecular recurrence.During the subsequent 12 months of complete cessation of TKI therapy, 26 (22%) of 117 evaluable MR4 and 20 (51%) of 39 MMR patients underwent molecular recurrence.The overall 2-year freedom from molecular recurrence of 76% for the MR4 group is therefore significantly superior to the 39% for the MMR group (p < 0.001), and in multivariate analysis, the duration of TKI therapy prior to study entry was also predictive of molecular recurrence, though age, gender or choice of prior TKI had no predictive value.All 58 patients experiencing molecular recurrence returned to at least MMR within 5 months (median 3 months) of resuming their TKI at full dose.No patient progressed to advanced phase.In both the MR4 and MMR groups, patientreported symptoms declined sharply in the first 3 months of dose de-escalation and again further in the 3 months following complete TKI cessation.For the MR4 group, freedom from molecular recurrence after 12 months TKI cessation is higher in DESTINY (76%) than in the contemporary EUROSKI study (56%) despite ~identical entry criteria and recurrence definition.Thus, the initial 12 months of half dose treatment in DESTINY may improve the success of subsequent treatment discontinuation, though the mechanism of this is unclear.Also, in MMR patients, a group not previously studied, 39% of patients remain recurrence free after 12 months cessation, suggesting that treatment discontinuation may not be unreasonable in stable MMR where there is a strong clinical case.Both dose reduction and treatment cessation are associated with overall reduction in TKI-associated symptoms, though current data suggest that musculoskeletal symptoms may occur on TKI withdrawal in 30% of patients.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.012 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.004 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.752 | 0.583 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".