Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Children and Young Adults with T-Cell Acute Lymphoblastic Leukemia (T-ALL) Treated at Investigator Discretion: A Report from Children's Oncology Group (COG) AALL0434
Bibliographic record
Abstract
Abstract Introduction: Salvage therapies in children and young adults with relapsed T-ALL are successful in <10% of patients, thus relapse prevention is a first priority. Contemporary strategies have included the use of intensified multi-agent regimens, novel therapies, and alloHSCT. COG AALL0434 did not include an alloHSCT treatment arm. To mitigate the risk of relapse, some patients were taken off study and, at investigator discretion, referred for alloHSCT. We retrospectively collected data to identify which patients were taken off study, either during induction, or after end-induction risk assignment to receive alloHSCT, for reasons other than relapse. In particular, it was unknown how alloHSCT affected the outcomes for patients with specific subsets of disease, such as induction failure (IF) or with the early thymic precursor (ETP) phenotype. Patients and Methods: From 2007-2014, AALL0434 enrolled 1,895 patients (1,596 T-ALL) and included a 2 x 2 pseudo-factorial randomization using a COG-modified BFM regimen. Patients were randomized to receive escalating dose methotrexate without leucovorin rescue plus pegaspargase (CMTX) or High Dose MTX (HDMTX) with leucovorin rescue in a single Interim Maintenance phase, with or without six 5-day courses of nelarabine. No patients were risk stratified on the basis of ETP. Participants with ≥ 25% marrow blasts on day 29 of induction (IF) were assigned to receive HDMTX with nelarabine. All patients with intermediate risk (IR), high risk (HR) or IF received cranial irradiation. Results: Among 1385 eligible, evaluable T-ALL patients for whom survey information was available, 333 (24%) were taken off therapy during induction prior to randomization. Thirty-two (9.6%) of these 333 subsequently underwent alloHSCT (19 with M1, 9 with M2 and 4 with unknown Day 29 marrow status). At the end of induction, 1052 patients were risk stratified and consented to randomization. Of these, 43 patients (4.3%) were subsequently taken off protocol therapy for alloHSCT [0 low risk (LR), 2 IR, 21 HR and 20 IF]. For the 75 patients who were taken off protocol therapy during or after induction and underwent alloHSCT, time to transplantation from end induction ranged from 1 to 9 months (median 5) for the 20 IF patients, and from 1 to 30 months (median 4) for the 55 patients who achieved CR1. A variety of conditioning regimens were used, but most (80%) included total body irradiation. Five types of alloHSCTs were employed: matched unrelated in 37 (50%), matched related in 28 (38%), mismatched unrelated in 7 (10%), and mismatched related and unknown (1 each (1.4%)). Stem cells sources were bone marrow in 50 (67%), umbilical cord blood in 14 (19%) and peripheral blood in 11 (15%). Multivariate analyses on all 75 patients (adjusting for treatment arm and risk group, and using time-dependent covariates for time to HSCT) showed worse outcomes for those who received alloHSCT versus chemotherapy [Hazard ratio 3.46 (95% Confidence Interval 1.39 - 8.60); P = 0.008]. For IF patients, there was no difference in outcome for those receiving chemotherapy versus alloHSCT [Hazard Ratio 0.75 (95% CI 0.27-2.14); P = 0.60]. Centrally determined ETP status was available for 1123 (81%) of the subjects (Table), which were categorized as ETP (11%), Near ETP (17%) and Not ETP (72%) (Wood, BL: Blood 2014: [21]1). Most patients were not taken off therapy during induction, but among those who were and had ETP/Near ETP, 21 of 28 (75%) received alloHSCT versus 71 of 251 (28%) who received chemotherapy alone (Fischer's exact test, P <0.001). In multivariate analyses adjusting for ETP status, alloHSCT (n=66) was associated with inferior EFS compared to chemotherapy [Hazard ratio 2.81 (95% CI of 1.49-5.31); P = 0.001], and ETP status did not have a statistically significant impact on EFS [Hazard Ratio 1.36 (95% CI of 0.87-2.120; P = 0.18]. Conclusions: Our findings showed that only ~5% of participants in AALL0434 received alloHSCT, and that alloHSCT was employed in about half of those patients with IF. There was no EFS advantage for patients who failed induction and subsequently received alloHSCT. Patients were taken off protocol therapy and transplanted for a variety of reasons, which introduced heterogeneity. However, compared to those who received alloHSCT off therapy, we found that survival advantages favored those who received chemotherapy, regardless of ETP status. Table. Table. Disclosures No relevant conflicts of interest to declare.
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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 | 0.001 | 0.001 |
| 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 | 0.000 |
| 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".