Allogeneic Stem Cell Transplant in First Complete Remission Overcomes the Poor Prognosis Associated with the FLT-3 Internal Tandem Duplication in Acute Myeloid Leukemia.
Bibliographic record
Abstract
Abstract Introduction: FLT-3 internal tandem duplications (ITD) and mutations in the nucleophosmin 1 (NPM1)gene appear to have negative and positive prognostic significance, respectively, in newly-diagnosed patients with acute myeloid leukemia (AML) treated with conventional chemotherapy. The prognostic significance of the D835 point mutation in exon 20 of FLT-3 is uncertain. In this study the relative importance of these abnormalities in predicting outcome was compared between patients receiving chemotherapy-based consolidation (chemo) or allogeneic stem cell transplantation (alloSCT) for AML in first complete remission (CR1). Methods: DNA was extracted from diagnostic blood or bone marrow from 267 AML patients aged < 60 years who achieved CR1 with induction chemotherapy and then analyzed for the presence of the ITD by PCR and NPM1 exon 12 and FLT3 exon 20 mutations by direct sequencing. Diagnostic cytogenetic abnormalities were assigned prognostic significance using Medical Research Council (MRC) UK criteria. Patients with intermediate or poor prognostic abnormalities and a sibling donor received alloSCT in CR1. If more than 1 cycle of induction therapy was necessary to achieve CR1 or poor risk cytogenetics were detected, patients without a sibling donor received unrelated donor SCT. All other patients received a minimum of one cycle of chemotherapy consolidation. Most patients received high dose cytarabine and daunorubicin induction therapy with similar consolidation. Median (range) follow-up for the entire group was 870 days (90–6003 days). Results: The overall frequency of mutations was 25%, 10% and 24% for the ITD, D835 and NPM1 mutations, respectively. On analysis of the 230 patients remaining after exclusion of acute promyelocytic leukemia (APL), ITD was significantly associated with poor disease free (DFS), event free (EFS) and overall (OS) survival. The D835 mutation was associated with poor DFS only and no effect of the NPM1 mutations could be detected. The presence of the ITD correlated with normal cytogenetics and a high presenting white cell or blast count. 92 and 138 of 230 non-APL patients received alloSCT or chemo, respectively, as consolidation in CR1.Of these 68 in the alloSCT and 95 in the chemo groups had intermediate risk cytogenetics. ITD predicted a poor EFS, DFS and OS for chemo patients regardless of the NPM1 mutation status. For ITD positive patients, relapse risk was higher with chemo in CR1 vs alloSCT (p= 0.007). Among intermediate risk cytogenetic patients 10 of 37 (27%) ITD positive vs 29 of 59 (49%) ITD negative patients are alive after chemo consolidation in CR1 (p<0.05). In the alloSCT group no significant differences in outcomes were seen comparing ITD positive and negative patients. When intermediate risk cytogenetics patients only were considered 8 of 18 (44%) vs 28 of 52 (54%) of ITD positive and negative patients, respectively, who received alloSCT are alive (p>0.5). Conclusions: FLT3 ITD predicts a poor OS following chemotherapy as consolidation for AML in CR1. In contrast the results of alloSCT in CR1 are similar for pts with and without the ITD suggesting that alloSCT can overcome the poor prognosis associated with this mutation.
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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) | 0.000 | 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 | 0.000 |
| 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".