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Real-time protocol identifies high-risk pediatric B-ALL patients with favorable outcomes
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ORLANDO, Fla. — A real-time classification protocol based on genetics and treatment response identified patients with high-risk childhood B-lymphoblastic leukemia who achieved favorable outcomes, according to multi-institutional Children’s Oncology Group (COG) study results presented at the ASH Annual Meeting and Exposition.
The protocol, thus, may identify high-risk patients who may not need further intensification of chemotherapy, according to researchers.
Elizabeth Ann Raetz, MD, professor in the division of pediatric hematology-oncology at Huntsman Cancer Institute and Primary Children’s Hospital of University of Utah, and colleagues sought to determine the feasibility of real-time classification with the COG protocol, which uses biologic, clinical and early disease response measures. Researchers used these protocol measures, which were based on cytogenetics and minimal residual disease (MRD) assessments, to evaluate outcomes of patients within National Cancer Institute (NCI) risk categories.
The analysis included data from 11,144 eligible patients enrolled on the AALL03B1 study between December 2003 and September 2011. Patients were aged 1 to 30 years at the time of B-lymphoblastic leukemia (B-ALL) diagnosis and received a three-drug induction regimen if they were NCI standard risk or a four-drug regimen if they were NCI high risk.
Under the real-time protocol, patients underwent standardized testing to detect favorable cytogenetics — such as triple trisomies of chromosomes 4, 10 and 17 (TT) or ETV6-RUNX1 fusion — and unfavorable cytogenetics, including hypodiploidy (DNA index ˂ 0.81 or chromosomes ˂ 44), MLL rearrangements, BCR-ABL1 or iAMP21.
At the conclusion of their induction therapy, patients were classified into one of four NCI risk groups for treatment allocation — low, standard, high or very high risk — based on age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on more marrow morphology and day 29 marrow MRD.
“Early response by marrow morphology was not prognostic when MRD response was used and therefore is no longer used in our current generation of protocols,” Raetz said at a press conference.
Ninety-six percent of patients were available for post-induction treatment assignment, of whom 5,104 were treated on companion trials for NCI standard-risk disease and 2,791 for NCI high-risk disease. Patients with very high-risk features — such as BCR-ABL1, hypodiploidy, induction failure or poor response at day 43 — did not continue on the companion trials post-induction, but their outcome data were included in the analysis.
As part of the real-time protocol, researchers evaluated rapid early response — defined as less than 5% blasts (M1) in bone marrow by day 15 plus flow cytometry-based MRD less than 0.1% on day 29 of induction — as well as slow early response, or 5% or more blasts (M2/M3) in day 15 bone marrow or MRD of 0.1% or greater on day 29.
Eighty-four percent of patients demonstrated a rapid early response, and the other 16% were slow early responders.
The patients with a rapid response had a 5-year EFS rate of 89.3% and a 5-year OS of 95.2%. Patients with a slow response had a 5-year EFS rate of 67.9% and a 5-year OS rate of 84.3%.
Five-year EFS and OS varied according to patient cytogenetics, which included ETV6-RUNX1 (26%), TT (21%), BCR-ABL1 (2.6%), MLL (2%), iAMP21 (2%) and hypodiploidy (1.5%).
Outcomes were superior among patients positive for the favorable cytogenetics ETV6-RUNX1 (EFS, 93.2% vs. 83.5%; OS, 98.3% vs. 92%) and TT (EFS, 94.7% vs. 83.6%; OS, 98.7% vs. 92.2%), whereas those with the unfavorable cytogenetics had worse outcomes for MLL rearrangement (EFS, 73.9% vs. 85.9%; OS, 83.1% vs. 93.6%) and iAMP21 (EFS, 69.5% vs. 86.1%; OS, 90.1% vs. 93.4%).
Researchers noted that the rate of 5-year OS was over 98% among NCI high-risk and standard-risk patients with these favorable cytogenetics, which accounted for nearly 50% of patients.
In a subsequent analysis using current Children’s Oncology Group MRD measurements — or that defined rapid early response as MRD less than 1% in day 8 blood and MRD less than 0.01% in day 29 bone marrow — NCI high-risk patients with favorable cytogenetics had a 5-year EFS of 94.9% and a 5-year OS of 98.1%.
“While favorable cytogenetic features were not prognostic in NCI high-risk B-ALL patients in prior studies, outcomes for this subgroup who have no evidence of CNS leukemia and who are rapid MRD responders are excellent with contemporary therapy and suggest that these patients will not benefit from further chemotherapy intensification,” Raetz said. – by Anthony SanFilippo
Reference:
Raetz E, et al. Abstract 807. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The researchers report research funding from Becton Dickinson Biosciences and Medimmune and consultant/advisory roles with Jazz Pharmaceuticals, Merck and Sigma Tau.
Perspective
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Wendy Stock, MD
The beauty of this study is that this was a huge study that allowed us to identify risk groups within a very large population who otherwise would probably not have been identified.
The implications are that the subset of nearly 300 patients identified here will have extraordinarily favorable outcomes despite their previously adverse risk. Based on these findings, it will be possible to not further intensify treatment.
Just as it is important in very high-risk patients to intensify treatment in order to get these incredibly good survival rates, it may also be possible to identify patients who were previously thought to be very high risk who do not need further intensification in therapy, which is equally important. The drugs that we use are not always easy to tolerate.
This careful categorization of patients as done by the Children’s Oncology Group allows for many important genetic studies to be done. It shows the power of careful classification and allocation of samples for these very important genetic risk studies so that we can further refine treatment and risk in these diseases.
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