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807 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)Clinically Relevant Abstract

Acute Lymphoblastic Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis
Program: Oral and Poster Abstracts
Type: Oral
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: Prognostic Factors in Adult and Pediatric Acute Lymphoblastic Leukemia
Monday, December 7, 2015: 5:00 PM
W331, Level 3 (Orange County Convention Center)

Elizabeth Raetz, MD1, Mignon L. Loh, MD2, Meenakshi Devidas, PhD3, Kelly Maloney, MD4, Eric C. Larsen, MD5*, Leonard A. Mattano Jr., MD6, Michael J. Borowitz, MD, PhD7, Brent L Wood, MD, PhD8, Andrew J. Carroll, PhD9, Nyla A. Heerema, PhD10, I-Ming Chen, DVM, MS11*, Alison M. Friedmann, MD, MSC12*, Kirk R. Schultz, MD13, Mary V. Relling, PharmD14, Richard C Harvey, PhD15, Julie Gastier-Foster, PhD16*, Cheryl L. Willman, MD17, Naomi J. Winick, MD18, Stephen P Hunger, MD19 and William L. Carroll, MD20

1Department of Pediatrics, Huntsman Cancer Institute and Primary Children's Hospital, University of Utah, Salt Lake City, UT
2Department of Pediatrics, Benioff Children’s Hospital, University of California at San Francisco, San Francisco, CA
3Department of Biostatistics, Colleges of Medicine, Public Health & Health Profession, University of Florida, Gainesville, FL
4The Childrens' Hospital Colorado, Aurora, CO
5Maine Children's Cancer Program, Scarborough, ME
6HARP Pharma Consulting, Mystic, CT
7Hematologic Pathology, Johns Hopkins University, Baltimore, MD
8Seattle Cancer Care Alliance, Seattle, WA
9Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
10Pathology, The Ohio State University, Columbus, OH
11Department of Pathology, University of New Mexico, Albuquerque, NM
12Pediatric Hematology/Oncology, Massachusetts General Hosp., Boston, MA
13B.C. Children's Hospital, University of British Columbia, Vancouver, BC, Canada
14Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
15Pathology, University of New Mexico Cancer Center, Albuquerque, NM
16Department of Pathology, Nationwide Children's Hospital, Columbus, OH
17UNM Cancer Research Facility, University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM
18University of Texas Southwestern Medical Center, Dallas, TX
19Department of Pediatrics, Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
20Department of Pediatrics, Perlmutter Cancer Center,, New York University Medical Center, New York, NY

Overall improvements in ALL outcomes have been attributed in part to refinements in risk classification that affect treatment intensity.  The COG developed a real-time disease classification protocol utilizing clinical, biologic and early disease response measures from local and central reference laboratories.

Patients between 1-30 years were enrolled on 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 underwent standardized testing at approved or central laboratories to detect favorable (triple trisomies of chromosomes 4, 10 and 17 [TT] or ETV6-RUNX1 fusion) and unfavorable (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 WBC, extramedullary disease status, blast cytogenetics and early treatment response based on bone marrow morphology and day 29 marrow minimal residual disease (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).

 

From December 2003 – September 2011, 11,196 (11,144 eligible) patients enrolled on AALL03B1; 89% enrolled on a frontline ALL therapeutic trial, 96% of whom were evaluable for post-induction treatment assignment. Among these patients, 5104 and 2791 respectively, were treated on companion clinical trials for NCI SR (AALL0331, 65%) or HR (AALL0232, 35%) B-ALL.  Patients with very high risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) 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 (EFS) and overall survival (OS) rates of 89.3% and 95.2%, respectively for RERs and 67.9% and 84.3%, respectively for SERs.  Five-year EFS and OS rates for SR and HR patients combined according to cytogenetic subtype are summarized in the Table.  The overall frequencies for the genetic subsets were:  ETV6-RUNX1 26%; TT 21%; hypodiploidy 1.5%; MLL 2%; BCR-ABL1 2.6% and iAMP21 2%.  Five-year EFS varied according to cytogenetic subset ranging from 70% (unfavorable) to 95% (favorable).  Notably, 5-year OS was over 98% for the favorable 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 favorable cytogenetics who were CNS1 had 5-yr EFS and OS of 94.9% and 98.1% (n=243), respectively.

In conclusion, real-time classification was feasible in close to 10,000 patients enrolled on COG ALL trials and identified patients with varying outcomes for risk-based treatment allocation.  While the COG has not previously utilized favorable 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.

Table

Favorable

 

5-year EFS (SE)*

5-year 0S (SE)*

ETV6-RUNX1

 

 

Positive (n=1928)

93.2% (0.7%)

98.3% (0.3%)

Negative (n=5578)

83.5% (0.6%)

92% (0.4%)

Triple Trisomy 4/10/17

 

 

Positive (n=1483)

94.7% (0.7%)

98.7% (0.3%)

Negative (n=5603)

83.6% (0.6%)

92.2% (0.4%)

Unfavorable

MLL rearrangement

 

 

Positive (n=145)

73.9% (4.2%)

83.1% (3.6%)

Negative (n=6649)

85.9% (0.5%)

93.6% (0.3%)

iAMP21

 

 

Positive (n=156)

69.5% (4.3%)

90.1% (2.8%)

Negative (n=7739)

86.1% (0.5%)

93.4% (0.3%)

* P < 0.0001 for all EFS and OS comparisons between positive and negative cytogenetic subsets except P = 0.0026 for the OS comparison for iAMP21.

 

 

Disclosures: Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding . Hunger: Spectrum Pharmaceuticals: Consultancy ; Jazz Pharmaceuticals: Consultancy ; Merck: Equity Ownership ; Sigma Tau: Consultancy .

*signifies non-member of ASH