Philadelphia Chromosome Negative (Ph-) Very High Risk (VHR) Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents: The Impact of Intensified Chemotherapy on Early Event Free Survival (EFS) in Children’s Oncology Group (COG) Study AALL0031.
Bibliographic record
Abstract
Abstract Background: VHR patients eligible for COG AALL0031 had an expected 5-year EFS ≤ 40% and consisted of those with Ph+ ALL, severe hypodiploidy (<44 chromosomes), and induction failure (IF) with >25% blasts at the end of standard induction therapy. Patients with hypodiploidy and IF are the subject of this report. Ph+ patients were reported previously (Blood Schultz KR, et. al. Blood2006; 108:87a.). Methods: Between 10/14/02 and 10/20/06, 63 evaluable patients (41 hypodiploidy and 22 IF) were enrolled in AALL0031 after completion of a 3- or 4-drug induction, and begun on an intensive chemotherapy regimen. Induction failure patients not entering complete remission (CR) after the first two chemotherapy cycles, ifosfamide and etoposide (cycle 1) and IV cyclophosphamide, IV etoposide) followed by high dose methotrexate and high dose cytarabine (cycle 2), were removed from study. Remission patients were assigned to 8 cycles of standard maintenance. All patients received triple intrathecal chemotherapy followed by cranial irradiation. An HLA-identical blood and marrow transplantation (BMT), by donor availability or to an intensive ~2.2 year chemotherapy regimen. The intensive chemotherapy regimen included a reinduction block (daunomycin, cyclophosphamide, vincristine, L-asparaginase, dexamethasone), intensification block [IV methotrexate (Mtx), etoposide, cyclophosphamide, high dose cytarabine, L-asparaginase], with each block repeated followed by 4 cycles of intensive maintenance (high dose Mtx, PO Mtx, IV vincristine, PO 6-MP). Unrelated donor BMT was not an option on AALL0031. Results: Twenty-one of 22 (95%) IF patients achieved CR after two cycles of therapy. Of these, 12 continued chemotherapy, 2 underwent BMT, and 7 were taken off protocol for an unrelated donor BMT. At 2-years, the EFS for IF patients was chemotherapy (46±17%) or related/unrelated donor BMT (67±17%; p = 0.50). Twenty-eight hypodiploidy patients continued chemotherapy, 12 underwent related donor BMT and 1 was taken off protocol for an unrelated donor BMT. For hypodiploid patients, the 2 year EFS was 57±10% for those receiving chemotherapy compared to related/unrelated donor BMT (67±14%, p=0.74). These outcomes compared favorably with COG historical controls (n=16, 44±12%; p=0.30). We lack a COG historical control for a comparison with IF patients. We examined minimal residual disease (MRD) at the end of cycle 2 in patients undergoing related/unrelated BMT and those receiving chemotherapy. With MRD > 0.01% (n=9) and < 0.01% (n=6), 2-year EFS was 56±19% and 83±15% (p=0.27), respectively. Chemotherapy groups showed a 2 year EFS for > 0.01% of 57±22% (N = 7) compared to 53±12% for ≤ 0.01% (N=19; p =0.83). Conclusions: The AALL0031 regimen attained a very high CR (95%) for IF patients. Small number severely limited statistical power. We found better outcomes for AALL0031 versus historical data, for allogeneic BMT versus chemotherapy, and MRD negativity versus positivity in BMT patients, although none were statistically significant. Future strategies focused on inducing lower MRD early in therapy may improve outcomes for both chemotherapy and BMT. International collaborations to allow for higher patient accrual should be considered.
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".