Prognostic Factors for Outcome of Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) in Poor-Risk Chronic Lymphocytic Leukemia (CLL): Final Results from a Prospective Multicenter Trial (GCLLSG CLL3X study)
Bibliographic record
Abstract
Abstract In order to refine the indications for NST in CLL, we analyzed prognostic factors for various endpoints of the CLL3X trial. CLL3X was a phase-2 trial investigating in a multicenter setting feasibility, toxicity and efficacy of NST in patients with poor-risk CLL. Patients <65 years were eligible if they had progressive disease in the presence of an unfavorable VH status, were fludarabine refractory, or had failed autoSCT. Central genetic work-up including FISH karyotyping was mandatory. Conditioning was based on fludarabine and cyclophosphamide. Centers could opt for routine addition of in-vivo T-cell depletion with alemtuzumab (TCD). Donors were HLA-matched (6/6) siblings or unrelated volunteers. Prospective longitudinal monitoring of minimal residual disease (MRD) was done centrally by MRD-flow or RQ-PCR. MRD results were communicated to the investigators for preemptive immunomodulation (restriction of immunosuppression or donor lymphocyte infusions). Results: Between June 2001 and March 2007, 113 patients were accrued in 16 centers. Thirteen patients had to be excluded due to ineligibility, and 10 patients did not proceed to NST because they lacked a donor, died or developed Richter’s transformation prior to NST, or refused NST. The 90 patients remaining had received 4 (1–11) pre-transplant regimens. 39/71 (55%) had an unfavorable FISH karyotype (del 11q- (37%) or del 17p- (18%)). 42/90 (47%) were fludarabine refractory, but only 24% had uncontrolled disease at NST. Allografts were obtained from related (39%) or unrelated donors (61%). TCD was performed in 12 patients. Due to logistical reasons, continuous sampling for prospective MRD monitoring was possible in only 4 centers representing 58% of the patients. With a median follow-up of 28 (6–80) months, 3-year non-relapse mortality, relapse incidence (REL), event-free survival (EFS) and overall survival (OS) from NST was 23% (95%CI 12%–34%), 42% (29%–56%), 42% (30%–54%), and 66% (55%–78%), respectively. Univariate log rank comparisons identified refractory disease at NST and TCD; but not age, fludarabine resistance, donor, and del 17p- as adverse factors for EFS. Three-year EFS was 43% (95%CI 14%–71%) with del 17p- vs 41% (27%–55%) without del 17p-. Cox regression models (adjusting for age, del 17p-, fludarabine resistance, remission status at NST, TCD, and donor) confirmed younger age (hazard ratio (HR)/year 0.94 (95%CI 0.89–0.99) and TCD (HR 3.68 (1.36–9.92)) as significant prognostic variables for REL; refractory disease at NST (HR 4.08 (1.9–8.74)) and TCD (HR 3.26 (1.53–6.94)) for EFS; and refractory disease at NST (HR 3.87 (1.62–9.25)) for OS. Three-year EFS was 57% (43%–72%) in patients who had sensitive disease at NST and no TCD employed, with no relapse occurring after the 3-year landmark. Only one relapse was observed in 25 patients (5 with del 17p-) who were MRD negative at month +12; and 15 out of 16 patients event-free more than 3 years after NST with MRD values available were MRD negative at last assessment. Conclusions: T-replete NST from related or unrelated donors results in sustained MRD-negative EFS in a significant proportion of patients with poor-risk CLL including those with del 17p-. NST should be performed before disease has become refractory. The potential benefit of preemptive post-transplant immunomodulation guided by real-time MRD monitoring remains to be settled.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.000 |
| 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".