Allogeneic Stem Cell Transplantation Can Overcome the Adverse Prognostic Impact of TP53 Mutation In Chronic Lymphocytic Leukemia (CLL): Results From the GCLLSG CLL3x Trial
Bibliographic record
Abstract
Abstract Abstract 2357 There is ample evidence that poor-risk CLL, as defined by fludarabine refractoriness or the presence of deletion 17p-, can be successfully treated by allogeneic stem cell transplantation (alloSCT). It is unknown, however, whether alloSCT can also overcome the treatment resistance associated with TP53 mutations seen under conventional fludarabine combination therapy. Therefore we have assessed the impact of TP53 mutations on the outcome of alloSCT with the patient cohort enrolled on the CLL3X trial of the German CLL Study Group. Patients and Methods: The CLL3X trial included 90 patients with poor-risk CLL who were allografted with unmanipulated blood stem cells from related or unrelated donors after nonmyeloablative conditioning. With a median follow-up of 46 months, 4-year event-free (EFS) and overall survival (OS) was 42% and 65%, respectively (Blood July 1, 2010). PFS and OS of 13 patients with deletion 17p- were similar to that of patients without this abnormality. TP53 mutations were identified by denaturating high-performance liquid chromatography (DHLPC) (exons 4–10). In addition, cases with deletion 17p- where no TP53 mutation was detected were also directly sequenced. Results: The TP53 mutational status could be obtained in 72 of 90 patients who had informative DNA samples from the time of study entry available. Of these, 19 (26%) showed TP53 mutations; 7 (10%) with a concurrent deletion 17p-, and 9 (12%) in the absence of deletion 17p-. 17p- status was not available in three TP53-mutated patients (4%). Three additional patients (4%) had 17p- without TP53 mutation. Four-year EFS and OS was 46% and 56% with TP53 mutation vs 38% and 66% without TP53 mutation (Figure). Within the TP53-mutated group, 4-year EFS and OS was 44% and 56% for patients without deletion 17p- vs 38% and 50% for patients with concurrent deletion 17p-. None of these differences were statistically significant. Among the patients who were event-free 12 months post alloSCT and had results of minimal residual disease (MRD) assessment available, the probability of being MRD-negative at this landmark was 71% with TP53 mutations and 63% without (p = 1.0). Finally, multivariate analysis using Cox regression modeling (adjusting for age, deletion 17p-, remission status at alloSCT, and T cell depletion) did not show a significant impact of TP53 mutations on EFS (Hazard ratio (HR) 0.71; 95%CI 0.31–1.61) and OS (HR 1.13; 95%CI 0.41–3.12). Conclusions: AlloSCT can provide long-term EFS in about 40% of patients with poor-risk CLL with TP53 mutation independent from the presence of concurrent deletion 17p-. Disease control appears to be similar in patients with and without TP53 mutation, suggesting that alloSCT can overcome the treatment resistance associated with this abnormality. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".