AUTHORS
Brianna Nicole Smith, MD, MS, Robert B. Gerbing, Ph.D2, Todd A. Alonzo, PhD3, Matthew A. Kutny, MD4, Betsy A. Hirsch, PhD5, Gordana Raca, MD, PhD6, Samir Kahwash7, Karen Chisholm, MD, PhD8, Joseph Chewning, MD9, John Horan, MD10, Richard Aplenc I, MD, PhD11, Katherine Tarlock I, MD12, Chad A. Hudson, MD, Ph.D13, Michael Loken, PhD14, Andrew J. Menssen, Ph.D., HCLD(ABB)15, Lisa Eidenschink Brodersen, PhD16, Soheil Meshinchi, MD, PhD17, E. Anders Kolb, MD18, Todd Cooper I, DO19, Maria Luisa Sulis, MD, MS20, Jessica A. Pollard I, MD21
AFFILIATIONS
1 Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States
2 Children's Oncology Group, Arcadia, California, United States
3 Children's Oncology Group, Arcadia, California, United States, University of Southern California Keck School of Medicine, Los Angeles, California, United States
4 University of Alabama at Birmingham, Birmingham, Alabama, United States
5 University of Minnesota, Minneapolis, Minnesota, United States
6 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
7 Nationwide Children's Hospital, Columbus, Ohio, United States, The Ohio State University, Columbus, Ohio, United States
8 University of Washington, Seattle, Washington, United States
9 University of Alabama at Birmingham, Birmingham, Alabama, United States
10 University of Rochester Medical Center, Rochester, New York, United States
11 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States
12 Seattle Children's Hospital, Seattle, Washington, United States
13 Hematologics, Inc., Seattle, Washington, United States
14 Hematologics, Inc., Seattle, Washington, United States
15 Hematologics, Inc., Seattle, Washington, United States
16 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
17 Fred Hutchinson Cancer Center, Seattle, Washington, United States
18 Blood Cancer United, Washington, District of Columbia, United States
19 Seattle Children's Hospital, Seattle, Washington, United States
20 Memorial Sloan Kettering Cancer Center, New York, New York, United States
21 Dana Farber Institute/Boston Children's Cancer Center and Blood Disorders Center, Boston, Massachusetts, United States, Harvard Medical School, Boston, Massachusetts, United States
ABSTRACT
Introduction
The World Health Organization (WHO) European Leukemia Net (ELN) and the International Consensus Classification (ICC) panels recently revised cytogenetic and molecular criteria that define AML with myelodysplasia related changes (AML-MR), a subtype with higher rates of measurable residual disease (MRD), and lower event free and overall survival (EFS and OS) in adults. AML-MR is not part of the pediatric AML 2022 WHO classification. We report the prevalence, characteristics and outcomes of AML-MR in a cohort of pediatric patients (MRp) enrolled on Children’s Oncology Group study AAML1831, a randomized trial of induction chemotherapy with cytarabine/daunorubicin and gemtuzumab ozogamicin (GO; Arm A) vs. Vyxeos (liposomal cytarabine/daunorubicin) and GO (Arm B). Clinical characteristics and outcome data were compared to the non-MRp patients (pts) treated on study.
Methods
AAML1831 patient samples were screened for the composite MR abnormalities which include mutations in BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2, ASXL1, RUNX1; complex karyotype (>/= 3 abnormalities/clone), del(5q)/t(5q)/add(5q), -7/del(7q), +8, del(12p)/t(12p)/add(12p), i(17q), -17/add(17)/del(17p), del(20q), idic(X)(q13)),del(11q),-13,del(13q) and absence of co-occurring favorable cytomolecular abnormalities or risk associated FLT3 mutations. MRD was defined as >0.05% disease by flow cytometry and complete remission (CR) as <1% disease and absence of extramedullary disease after induction 2 (EOI2). The Kaplan-Meier method was used to determine 3-yr EFS, OS, disease free survival (DFS) and cumulative incidence of relapse (CIR).
Results
One hundred and ninety-eight (27.5%) of 720 eligible pts met the definition of AML-MRp; 522 (72.5%) had non-MRp AML. Of the former, 173 had karyotypic abnormalities, the most common being +8 (26.8%), complex karyotype (19.2%) and -7 or del7q (12.6%). All AML-MR defining somatic mutations were detected (n=91/198 pts); ASXL1 (10.6%), RUNX1 (10.1%) and EZH2 (8.6%) were the most common. Age, gender, race, ethnicity and CNS status were similar in both groups. Pts with MRp had lower WBC count at diagnosis (median 8.1 vs. 17.3, p<0.001) and were more often risk stratified to “High-Risk” (HR) (62% vs. 26%, p<0.001) thereby receiving stem cell transplant (SCT) more frequently (28% vs. 12%, p<0.001). Rates of CR at EOI2 for MRp vs. non-MRp cohorts were similar (85% vs. 90%, p=0.059), however rates of MRD positivity at EOI1 and EOI2 and of refractory disease (RD) were higher for MRp pts (EOI1 36% vs. 17%, p=0.001; EOI2: 20% vs.10%, p=0.002; RD: 11% vs. 5%, p=0.013).
Pts with MRp had significantly lower 3-yr EFS and OS (43.4% vs. 64% p=<0.001, 63.8% vs. 79.1%, p=<0.001) and higher CIR from study entry (47.1% vs. 31.1%, p=<0.001) compared to the non-MRp cohort. Outcomes for MRp vs. non-MRp pts by treatment arm were also inferior for the MRp subset (Arm A: 3-yr EFS 48.1% vs. 68.4% p=<0.001; OS 63.2% vs. 81% p=<0.001, CIR 44.9% vs. 27% p=0.001, Arm B: 3-yr EFS 39.7% vs. 59.4% p=<0.001, OS 64.4% vs. 77.2% p=0.001, CIR 48.8% vs. 35.3% p=0.022). MRp pts treated on Arm A vs. B had similar outcomes (data not shown). There was no significant difference in 3-yr DFS or CIR for HR pts (who received SCT as consolidation) but OS was significantly lower for the MRp subset (MRp 60.7% vs. non MRp 76.6%, p=0.024). A trend towards higher treatment related mortality was observed for MRp pts treated with SCT (8.4% vs. 2.1%, p=0.061). Among pts assigned to 5 cycles of chemotherapy/no SCT, MRp pts treated on Arm A had lower 3-yr DFS and OS and higher CIR from EOI1 than non MRp pts (DFS 43.5 % vs. 75.2% p<0.001; OS 65.5% vs. 86.5%, p=0.003; CIR 50.2% vs. 23.6%, p=0.002). Outcomes on Arm B were similar for both disease subsets and lower than Arm A outcomes for both groups (data not shown).
Conclusions
Our analysis demonstrates that MR genetic alterations in pediatric AML confer inferior outcome overall. DFS was similar for MRp vs. non MRp treated with SCT although OS was significantly worse for MRp pts. Outcomes were also inferior for MRp pts assigned to the chemotherapy alone risk group. Our analysis did not demonstrate a benefit of Vyxeos for this disease subset, both overall and in those treated with chemotherapy alone. Future pediatric trials should consider designating MRp as a HR subtype for which novel therapies are needed.
DISCLOSURES
Brianna Nicole Smith, MD, MS: No relevant conflicts of interest to declare.