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1076 Outcome of (Novel) Subgroups in 1257 Pediatric Patients with KMT2A-Rearranged Acute Myeloid Leukemia (AML) and the Significance of Minimal Residual Disease (MRD) Status: A Retrospective Study By the I-BFM-SG

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
AML, Diseases, Pediatric, cytogenetics, Study Population, Myeloid Malignancies, Clinically relevant
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Romy E. Van Weelderen1,2*, Kim Klein, MD3,4*, Bianca F. Goemans, MD, PhD5, Christian M. Zwaan, MD, PhD5,6, Hester A. De Groot-Kruseman, PhD5,7*, Jonas Abrahamsson, MD, PhD8*, Nira Arad-Cohen, MD, PhD9*, Emmanuelle Bart-Delabesse, PharmD, PhD10*, Barbara Buldini, MD, PhD11*, Barbara De Moerloose, MD, PhD12*, Michael Dworzak, MD, PhD13*, Sarah Elitzur, MD14*, José M. Fernández Navarro, MD15*, Robert B. Gerbing, MA16*, Erin Guest, MD17, Shau-Yin Ha, MD, PhD18*, Christine J. Harrison, PhD, FRCPath19, Henrik Hasle, MD20, Kathy Jackson, MD, PhD21*, Charikleia Kelaidi, MD22*, Hélène Lapillonne, MD, PhD23*, Guy Leverger, MD, PhD24*, Franco Locatelli, MD, PhD25, Takako Miyamura, MD, PhD26, Sophia Polychronopoulou, MD, PhD22*, Mareike Rasche, MD27*, Jeffrey E. Rubnitz, MD28, Jan Stary, MD, PhD29*, Daisuke Tomizawa, MD, PhD30, Femke Verwer2,7* and Gertjan J.L. Kaspers, Prof. MD, PhD3,5

1Department of Pediatric Hematology and Oncology, Emma Children’s Hospital, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
2Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
3Department of Pediatric Hematology and Oncology, Emma Children's Hospital, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
4Wilhelmina Children’s Hospital/University Medical Center Utrecht, Utrecht, Netherlands
5Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
6Department of Pediatric Oncology/Hematology, Erasmus University Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands
7Dutch Childhood Oncology Group, Utrecht, Netherlands
8Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden
9Pediatric Hematology Oncology Department, Ruth Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel
10Laboratoire d'Hématologie secteur Génétique des Hémopathies, IUC Toulouse-Oncopole, Toulouse, France
11Pediatric Hematology-Oncology, Department of Women's and Children's Health, University of Padova, Padova, Italy
12Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
13St. Anna Children's Hospital and Cancer Research Institute, Medical University of Vienna, Vienna, Austria
14Pediatric Hematology and Oncology, Schneider Children's Medical Center and Tel Aviv University, Tel Aviv, Israel
15Pediatric Oncohematology Unit, Hospital Universitari i Politècnic la Fe, Valencia, Spain
16Children's Oncology Group, Monrovia, CA
17Division of Hematology/Oncology/Bone Marrow Transplantation, Children's Mercy, Kansas City, MO
18Department of Pediatrics, Queen Mary Hospital, Hong Kong, Hong Kong
19Leukaemia Research Cytogenetics Group, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, ENG, United Kingdom
20Pediatrics, Aarhus University Hospital, Aarhus, Denmark
21St. Jude Children’s Research Hospital, Memphis, TN
22Department of Pediatric Hematology and Oncology, Aghia Sophia Children’s Hospital, Athens, Greece
23Pediatric Hematology and Oncology Department, Hôpital Armand Trousseau, Paris, France
24Pediatric Hematology and Oncology Department, Hôpital Armand-Trousseau, Paris, France
25Department of Pediatric Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
26Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
27Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
28Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
29Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic
30Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan

Introduction

Outcome of KMT2A-rearranged (KMT2A-r) pediatric AML (pAML) is in general poor with a 5-year probability of event-free survival (5y-pEFS) and overall survival (5y-pOS) of 44% and 56%, respectively (Balgobind et al., 2009). However, over the past decades, the heterogeneity of KMT2A-r pAML has emerged, showing differences in outcome between subgroups based on translocation partners. The predictive value of MRD in KMT2A-r pAML is undefined. This retrospective study aimed to confirm the outcome of pediatric KMT2A subgroups (Balgobind et al., 2009) in a more recent era and to study the significance of MRD status during and after induction.

Methods

Outcome and MRD data of 1257 KMT2A-r de novo pAML patients from 15 AML groups affiliated with the I-BFM-AML study group, diagnosed between 2005 and 2016 were retrospectively collected. Patients were assigned to KMT2A subgroups, or to the KMT2A-other group in case of unknown translocation partner. Flow cytometry MRD levels <0.1% were considered negative, and levels ≥0.1% positive. Kaplan-Meier methods were used to estimate probabilities of disease-free survival (pDFS), pEFS and pOS. Cox regression analyses were performed to study the independent impact of KMT2A subgroups and potentially prognostic factors: white blood cell count (WBC), age and MRD status.

Results

The 1257 patients were assigned to 13 KMT2A subgroups, or the KMT2A-other group. Two novel subgroups were identified: t(X;11)(q24;q23) (n=21, 2%) and t(1;11)(p32;q23) (n=12, 1%). The median age was 2.5 years (range, 0-18.9). The median WBC was 21.4 x 109/L (range, 0.2-727). Overall complete remission rate was 91%. The 5y-pEFS was 46% [SE, 2%] and the 5y-pOS was 62% [SE, 2%]. Differences across subgroups in 5y-pEFS (Figure 1) ranged from 24% [SE, 5%] to 76% [SE, 9%], and in 5y-pOS from 25% [SE, 13%] to 92% [SE, 8%] (both p<0.0001). The median follow-up time of patients at risk was 5 years.

The subgroups t(10;11)(p12;q23) (HR 1.7, p<0.0001), t(6;11)(q27;q23) (HR 1.9, p<0.0001), t(4;11)(q21;q23) (HR 2.9, p=.003) and t(10;11)(p11.2;q23) (HR 2.7, p<0.0001), WBC of >100 x 10^9/L (HR 1.3, p=.006), and age >10y (HR 1.3, p=.005) were revealed as independent predictors of poor EFS. These factors also predicted OS.

MRD data after induction course one were available for n=635 (MRD-positivity (range, 0.1-94) n=126, 20%) and after course two for n=527 (MRD-positivity (range, 0.1-88) n=51, 10%). In the four KMT2A poor-risk subgroups, MRD-positivity was not significantly more common after induction course one (p=.0232) or two (p=.066), compared with the other subgroups.

MRD-positivity was associated with inferior 5y-pDFS after both induction course one (36% [SE, 4%] vs 48% [SE, 2%]; p=.002) and course two (28% [SE, 6%] vs 49% [SE, 2%]; p<0.0001) (Figure 2). Within the t(9;11)(p22;q23) subgroup, MRD-positivity after induction course one, and within the t(10;11)(p12;q23) subgroup after course two, was associated with inferior 5y-pDFS (36% [SE, 8%] vs 56% [SE, 4%]; p=.004, and 0% [SE, 0%] vs 35% [SE, 5%]; p<0.0001, respectively). After induction course one, the subgroups t(10;11)(p12;q23) (HR 1.7, p<0.0001) and t(10;11)(p11.2;q23) (HR 4.0, p<0.0001), and MRD-positivity (HR 1.5, p=.003) were revealed as independent predictors of poor DFS. After induction course two, the subgroups t(10;11)(p12;q23) (HR 1.8, p<0.0001), t(4;11)(q21;q23) (HR 4.9, p=.008) and t(10;11)(p11.2;q23) (HR 3.2, p<0.0001), MRD-positivity (HR 2.0, p<0.0001), and age >10y (HR 1.5, p=.002) were revealed as independent predictors of poor DFS.

Within the group of patients with MRD-negativity after induction course two, the subgroups t(10;11)(p12;q23) and t(10;11)(p11.2;q23) were independent predictors of poor EFS (5y-pEFS 35%, HR 1.7, p=.003 and 5y-pEFS 18%, HR 2.7, p=.004, respectively).

Conclusion

Outcome for KMT2A-r pAML patients has improved slightly, but similar subgroups were identified as poor risk (Balgobind et al., 2009), including t(10;11)(p12;q23), t(10;11)(p11.2;q23) and t(6;11)(q27;q23). In our study, t(4;11)(q21;q23) was poor risk as well. These subgroups should be considered for high-risk pAML therapy protocols. The favorable risk of t(1;11)(q21;q23) could not be confirmed in our cohort. MRD status is highly predictive of outcome within KMT2A subgroups. In MRD-negative patients after induction course two, both t(10;11) KMT2A subgroups were associated with poor outcome.

Disclosures: Guest: Syndax Pharmaceuticals: Consultancy. Locatelli: Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Rubnitz: AbbVie Inc.: Research Funding. Kaspers: Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months; AbbVie: Ended employment in the past 24 months.

*signifies non-member of ASH