Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML).
Bibliographic record
Abstract
7042 Background: Ivosidenib (IVO; AG-120) and enasidenib (ENA; AG-221) are oral inhibitors of mIDH1 and mIDH2 proteins. In vitro, mIDH inhibitor + AZA combinations enhance cell differentiation and apoptosis. We report results of an ongoing phase 1b/2 study of mIDH inhibitors + AZA in patients (pts) with newly diagnosed (ND) AML (NCT02677922). Methods: Adult pts with mIDH ND-AML ineligible for intensive treatment (Tx) receive continuous IVO (mIDH1) 500 mg or ENA (mIDH2) 100 or 200 mg QD, plus SC AZA 75 mg/m2 x 7d, in repeated 28d cycles. Response is defined by IWG 2003 AML criteria. Results: At data cutoff (Sep 1, 2017) 17 pts had received IVO 500 mg (n = 11) or ENA 100 mg (3) or 200 mg (3) + AZA in the phase 1b portion of the study; 11 were ongoing. IVO: Median age was 76 yrs. Median number of Tx cycles was 3 (range 1-13).Three pts discontinued Tx, 2 due to progressive disease (PD).AEs in ≥4 pts (any grade) were nausea (n = 8), constipation (6), fatigue (5) and diarrhea (4). Grade 3-4 hematological AEs (Table) occurred at similar frequency to what has been reported for AZA alone. Serious AEs in > 1 pt were pneumonia, febrile neutropenia (n = 2 each). Eight of 11 pts responded, including 4 complete remissions (CRs). ENA:Median age was 68 yrs. Median number of Tx cycles was 9 (1-13). Three pts discontinued Tx, 2 due to PD. Most common AEs (any grade) were nausea and hyperbilirubinemia (n = 4 each). Serious AEs in > 1 pt were pyrexia, bilirubin increase, pneumonia (n = 2 each). Four of 6 pts responded, including 2 CRs. Conclusions: mIDH inhibitor + AZA regimens were generally well tolerated in pts with ND-AML. Most AEs were grade 1-2 GI events and ENA-related indirect bilirubin elevations due to off-target UGT1A1 inhibition. Response rates are encouraging. Phase 1b enrollment completed in late 2017; updated data for all 23 IVO and 6 ENA pts will be presented, as well as longitudinal changes in mIDH variant allele frequencies. Enrollment continues in the phase 2 portion of this study (ENA + AZA) and the phase 3 AGILE study of IVO + AZA (NCT03173248). Clinical trial information: NCT02677922.Grade 3-4 hematological AEs. IVO 500 mg + AZA (n = 11) ENA 100 mg + AZA (n = 3) ENA 200 mg + AZA (n = 3) n Thrombocytopenia 1 0 1 Anemia 2 0 1 Febrile neutropenia 2 0 1 Neutropenia 1 0 2 Lymphocyte decrease 0 0 1 WBC decrease 0 0 1
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".