Real-time classification system based on cytogenetics and treatment response identifies leukemia patients with an excellent outcome despite high-risk clinical features

A real-time classification system incorporating clinical features, blast cytogenetics and early response data was used in close to 10,000 patients enrolled into COG acute lymphoblastic leukemia (ALL) trials and identified a subgroup of patients with a very high likelihood of being alive at 5 years, despite having high-risk clinical features. As such, this classification identified a previously unrecognized subset of high-risk patients with excellent chances for cure without further intensification of treatment.

The overall improvements in the outcome of ALL patients can partly be attributed to refinements in risk classification that affect treatment intensity. During ASH 2015, a Children’s Oncology Group (COG) study was presented that systematically assessed minimal residual disease (MRD) at the end of induction therapy and used this, in concert with clinical and biological data, for risk stratification and treatment assignment.

Newly diagnosed B-cell ALL patients between 1 and 30 years of age were enrolled into the COG AALL03B1 classification study at the time of B-ALL diagnosis and subsequently initiated a 3-drug (standard risk; SR) or 4-drug induction (HR) based on NCI risk group. All patients in the study underwent standardized testing at approved or central laboratories to detect favourable (triple trisomies of chromosomes 4, 10, and 17 [TT] or ETV6-RUNX1 fusion) and unfavourable (hypodiploidy [DNA index < 0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1 or iAMP21) cytogenetic abnormalities. At the end of induction therapy, patients > 1 year of age with B-ALL were classified into low, standard, high or very high risk groups for treatment allocation. Variables used for risk classification included age, initial white blood cells, extramedullary disease status, blast cytogenetics and early treatment response based on bone marrow morphology and day 29 marrow MRD. Rapid early response (RER) was defined as M1 (< 5% blasts) bone marrow by day 15 plus flow cytometry-based MRD < 0.1% on day 29 of induction. Those with either M2/M3 (≥ 5% blasts) day 15 marrow or MRD ≥ 0.1% at day 29 were deemed slow early responders (SER).

In total, 11,196 patients were enrolled into AALL03B1; 89% enrolled on a frontline ALL therapeutic trial, and 96% of patients was evaluable for post-induction treatment assignment. Among these patients, 5,104 and 2,791 patients respectively, were treated on companion clinical trials for NCI SR (AALL0331, 65%) or HR (AALL0232, 35%) B-ALL. Patients with very high risk features did not continue on AALL0232/AALL0331 post induction, but did have outcome data captured for analysis.

The distribution of induction response was 84% RER and 16% SER with 5-year event-free survival (EFS) and overall survival (OS) rates of 89.3% and 95.2% respectively for RERs, and 67.9% and 84.3% for SERs. Five-year EFS and OS rates for SR and HR patients according to cytogenetic subtype are summarized in the Slide 3 attached to this article. The five-year EFS varied according to cytogenetic subset ranging from 70% (unfavourable) to 95% (favourable). Of note, the 5-year OS was over 98% for the favourable cytogenetic subsets of combined SR and HR patients that accounted for almost half of all patients. In a subsequent analysis using current COG MRD response measures (RER = day 8 blood MRD < 1% and day 29 marrow MRD < 0.01%), HR patients with favourable cytogenetics who were CNS1 had 5-year EFS and OS rates of 94.9% and 98.1% (n=243), respectively.

In conclusion, real-time classification was feasible in close to 10,000 patients enrolled into COG ALL trials and identified patients with varying outcomes for risk-based treatment allocation. While the COG has not previously utilized favourable cytogenetic features to risk classify NCI HR B-ALL patients, outcomes for this subgroup who also have rapid MRD responses during induction are excellent and suggest that these patients will not benefit from further chemotherapy intensification.


Raetz E, Loh M, Devidas M, et al. Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children's Oncology Group (COG). Presented at ASH 2015; Abstract #807.

Speaker Elizabeth Raetz


Elizabeth A. Raetz, MD,
Professor in the Division of Pediatric Hematology-Oncology, Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City, Utah, USA


See: Keyslides


Back to Top