Intensive Chemotherapy Vs. Azacitidine + Venetoclax for AML with Secondary Mutations
Bibliographic record
Abstract
Introduction In AML, secondary mutations (sMut) represent a group of mutations with a strong association with clinically-defined secondary AML (sAML). AML with sMut have been associated with inferior survival outcomes and have been incorporated into the updated ELN 2022 guidelines to reflect high-risk disease as AML with myelodysplasia-related gene mutations (AML-MR). Prior studies have demonstrated improved survival outcomes within AML-MR with the utilization of hypomethylating agents and venetoclax (HMA+Ven) versus hypomethylating agent monotherapy. At present, treatment-specific outcomes, including the benefit of using intensive chemotherapy (IC) versus venetoclax-based regimens, within this cohort remain understudied. Methods This study included patients diagnosed with AML harbouring sMut, first seen at PMCC from 1st Jan 2015 to April 2023. Patients were excluded from the analysis if the NGS data was unavailable or if it was performed >6 months from time of diagnosis. sMut included mutations within one or more of the following genes: SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2. Non-intensive therapy included patients treated with HMA monotherapy and venetoclax-based regimens in the first line setting. The primary objective was to compare IC with with venetoclax-based regimens within AML with sMut. A key secondary objective was to evaluate the role of allogeneic hematopoetic stem cell transplant (HSCT) in patients with AML with sMut. OS was calculated from date of AML diagnosis to date of last known follow up or date of death. Kaplan-Meier survival curves were generated for OS, and differences were tested using the log-rank test. Results A total of 665 patients were eligible for inclusion in this study with, a median follow-up of 12.39 (0.03, 108.3) months. 418 (63%) patients had de novo AML, 186 (30%) patients had an antecedent hematologic malignancy, and 51 (8%) AML had a history of cytotoxic therapy. Of the total study population, 364 (68%) patients received IC,168 (32%) patients received non-intensive chemotherapy of which 87 (17%) received HMA+Ven. Patients treated with HMA+Ven were significantly older (76.1 vs 62.7, p=<0.0001) and were less likely to have an NPM1 mutation (14% vs 17%, p=0.047). There was no significant difference in cytogenetic risk (p=0.45), TP53 status (p=0.56), or FLT3-ITD status (p=0.05). Patients with de novo AML had improved OS compared to patients with sAML and tAML with sMut (3-year OS 39.5% vs 19.9% vs 23.2%, p= <0.0001). The primary analysis of IC vs. HMA-Ven was restricted to patients 70 years old and younger to minimize bias by including only patients who would theoretically be eligible for treatment with curative intent. When comparing these patients with newly diagnosed AML with sMut who were 70 years old at diagnosis or younger, there was no significant difference in OS between those who received upfront IC vs. HMA-Ven (3-year OS 52.8% vs 48.9%, p=0.25).Among patients less than 70 years old at diagnosis who received IC, patients who underwent HSCT had significantly improved OS compared to those who did not undergo HSCT (p= <0.0001). There was no statistically significant difference in OS between patients who received IC versus HMA+Ven prior to transplant (p=0.0756). In multivariable analysis (MVA), NPM1 mutation was associated with improved OS (aHR 0.63 [0.43, 0.92]). Patients who did not undergo HSCT (aHR 3.13 [2.35, 4.18]), had sAML (aHR 1.32, [1.01, 1.73]), tAML (aHR 1.52 [1.01, 2.30]), or high-risk cytogenetics (aHR 3.03, [1.29, 7.13]) had inferior OS in MVA. There was no significant difference in OS in patients receiving IC versus HMA+Ven (p=0.055) after adjustment for confounding variables. Conclusions AML-MR represents a novel, high-risk entity with recent introduction into ICC and WHO guidelines and has been associated with inferior survival outcomes emphasizing the importance of investigating treatment-specific outcomes. When comparing IC to HMA+Ven in patients with AML and sMut up to the age of 70 years, there was no significant improvement in OS. We also found that patients with AML and sMUT who received HSCT had improved OS compared to those treated with IC alone. A limitation of this study includes potential bias from clinical factors including comorbidities and frailty that may have influenced treatment candidacy and will be addressed in future studies including matched-cohort analyses.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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) | 0.003 | 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".