Morphologic leukemia-free state (MLFS) is associated with inferior outcomes in patients with Acute Myeloid Leukemia (AML) treated with front-line azacitidine plus venetoclax
Bibliographic record
Abstract
Abstract Background Azacitidine plus venetoclax (Aza-Ven) is now standard of care for newly diagnosed acute myeloid leukemia (AML) in patients (pts) ineligible for intensive chemotherapy. Whilst this is better tolerated than intensive induction therapy, myelosuppression is common and can be severe. In this study, we sought to investigate the impact of incomplete hematological recovery after Aza-Ven on long-term survival. Methods We conducted a retrospective study of pts diagnosed with AML, who received front-line treatment with Aza-Ven at the Princess Margaret Cancer Centre between 2017 and 2024. Reponses were categorised based on the 2022 European Leukemia Network (ELN) recommendations for AML. We defined composite complete remission (CRc) rate as a combination of complete remission (CR) and CR with incomplete hematological recovery (CRi). We defined morphologic composite remission (mCR) as achievement of < 5% bone marrow blasts including CR, CRi and morphologic leukemia-free state (MLFS). The primary outcome was overall survival (OS). Results Our cohort consisted of 132 cases, with 82 (62%) male pts. The median age was 74 years (range, 34 – 90). Based on the International Consensus Classification (ICC), 127 (96%) pts met the diagnostic criterion for AML; five (4%) pts were classified as myelodysplastic syndrome/AML (MDS/AML). In this real-world cohort, 83 (63%) pts met VIALE-A eligibility criteria. Most pts received 28 days of venetoclax (n=106, 80%) with cycle 1. Bone marrow assessments (BMA) were performed in 117 (89%) pts after cycle 1. In evaluable pts with BMA after cycle 1, 59 (50%) achieved CRc, including 31 (26%) in CR and 28 (24%) in CRi. A total of 82 (70%) achieved mCR, including pts in CRc plus 23 (20%) pts in MLFS. Nine (8%) pts had partial response (PR) and 24 (21%) pts had no response (NR). From initiation of cycle one, 30-day and 60-day mortality were 2% and 8%, respectively. The median OS in our whole cohort was 13 months (95% CI: 11 – 16 months). To better characterise the heterogeneity within pts achieving mCR (n=82), subgroup analysis was performed. Pts who achieved MLFS were more likely to have had previous exposure to hypomethylating agents (HMA) (13% vs 0%, p<0.01) as well as mutations in ASXL1 (42.9% vs 19%, p=0.03), STAG2 (23.8% vs 3.4%, p<0.01) and TET2 (38.1% vs 15.5%, p=0.03). Pts achieving CR/CRi also more commonly had favourable risk disease as per ELN 2024 (49.2% vs 26.1%, p=0.03), compared to those who achieved MLFS. There was no significant association between achievement of MLFS, and prior history of MDS or MDS/MPN (p=0.11) or previous cytotoxic therapy (p=0.12). Mutations in FLT3-TKD (p=0.04) and STAG2 (p=0.03) were more common among pts with delayed neutrophil recovery (≥42 days from cycle 1 day 1). Conversely, mutations in FLT3-ITD (p=0.02), RUNX1 (p=0.03), and STAG2 (p=0.03) were more frequent in pts with delayed platelet recovery (≥28 days from cycle 1 day 1). There was no significant difference in measurable residual disease (MRD) positivity assessed by flow cytometry between pts who achieved CRc versus MLFS (38% vs 53%, p=0.26) and MRD status was not associated with OS (HR 0.89, 95% CI 0.42-1.89, p=0.77) among pts achieving mCR. There was no significant relationship between reduced duration of venetoclax (<25 days), MLFS, neutrophil or platelet recovery. However, due to the relatively small number of pts who received the shorter course (n=22/132), definitive conclusions cannot be drawn. Pts achieving CRc (n=59) after cycle 1 had significantly longer median OS at 22.5 months, compared to those who achieved MLFS (n=23) at 6.6 months (HR 0.45, 95% CI: 0.24 – 0.85, p=0.01). The 2-year OS rates in pts achieving CRc and MLFS were 46% and 27%, respectively. Median relapse-free survival (RFS) in pts achieving CRc and MLFS were 25.0 months and 7.9 months respectively (HR 0.62, 95% CI: 0.29 – 1.32, p=0.22). The 2-year RFS in pts achieving CRc and MLFS were 52% and 38%, respectively.Conclusion: Patients who achieve MLFS after Aza-Ven have significantly worse OS compared with those who achieve CRc. There was no significant difference in MRD positivity between pts achieving CRc or MLFS, but mutational profile may identify pts at risk of delayed or deficient hematological recovery. Future research should focus on identifying strategies to improve bone marrow failure beyond the achievement of bone marrow blast reduction.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".