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730 Results in Pediatric T-ALL Patients Treated in Trial AIEOP-BFM ALL 2009: Exploring Prognostic Factors in the Context of Modern Risk Adapted Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Look into the Crystal B-ALL: Genetic, Phenotypic and Dynamic Outcome Predictors in Lymphoblastic Leukemia
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Pediatric, Young adult , Study Population, Human, Measurable Residual Disease
Monday, December 9, 2024: 11:15 AM

Gunnar Cario, MD1*, Maria Grazia Valsecchi, PhD2*, Valentino Conter, MD3*, Giacomo Gotti, MD4*, Anja Möricke, MD1*, Martin Stanulla, MD5*, Michaela Vossen-Gajcy1*, Lennart Lenk, PhD6*, Jan Stary, MD, DSc7*, Michael Dworzak, MD8*, Andishe Attarbaschi, MD9,10*, Draga Barbaric, MD11*, Franco Locatelli, MD12, Nicole Bodmer, MD13*, Sarah Elitzur, MD14, Daniela Silvestri3*, Luciano Dalla-Pozza, MD15, Andreas E. Kulozik, MD, PhD16, Shai Izraeli, MD17,18, Carmelo Rizzari, MD, PhD4*, Barbara Buldini, MD, PhD19, Jean-Pierre Bourquin, MD, PhD20, Francesca Graziano21*, Martin Zimmermann, PhD22*, Martin Schrappe, MD1 and Andrea Biondi4

1Department of Pediatrics I, Pediatric Hematology and Oncology, ALL-BFM Study Group, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
2School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
3Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
4Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
5Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
6Department of Pediatrics I, Pediatric Hematology and Oncology, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany, Kiel, Germany
7Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
8Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, St. Anna Children's Hospital, Vienna, Austria
9Department of Pediatric Hematology and Oncology, St. Anna Kinderspital, Vienna, Austria
10St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria
11Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick NSW, AUS
12Department of Hematology-Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
13Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
14Schneider Children's Medical Center, Petah Tikva, Israel
15Cancer Center for Children, Sydney, Australia
16Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University, Heidelberg, Germany
17The Dora and Gregorio Chair of Hematological Malignancies Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
18Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Tel Aviv University, Petah Tikva, Israel
19University of Padova, Padua, Italy
20Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland
21Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
22Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany

Introduction

The prognosis of children with T-cell acute lymphoblastic leukemia (T-ALL) has dramatically improved over time, but the outcome of relapsed and refractory patients remains dismal. Trial AIEOP-BFM ALL 2000 showed the benefit of dexamethasone (DXM) during induction in patients with prednisone good response (PGR) and that high level of bone marrow disease (≥10% blasts) by flowcytometry at induction day 15 (d15 FCM-MRD HR) was associated with poor prognosis. The subsequent AIEOP-BFM ALL 2009 trial included these interventions for T-ALL: (1) use of d15 FCM-MRD HR as new high risk (HR) criterion for stratification, (2) DXM for PGR patients in induction, (3) addition of cyclophosphamide (1 g/m2) on induction day 10 in patients with prednisone poor response (PPR), (4) substitution of native asparaginase with PEG-ASNASE, (5) a randomized study to receive or not 4 doses of PEG-ASNASE (2500 IU/m2) during Consolidation Phase IB in patients classified as HR by end of induction (EOI). Patients were stratified as HR if they had one of the following: PPR, d15 FCM-MRD HR, no EOI-CR or MRD ≥5×10-4 at end of consolidation (EOC). Here we describe the outcome of T-ALL patients into this protocol and explore the prognostic factors for future refinement of risk group classification.

Methods

Between 06/2010 and 02/2017, this trial enrolled 6136 patients, aged 1-17, of whom 872 (14.2%) with T-ALL. The Cox regression model on event-free survival (EFS) evaluated the effect of factors in terms of Estimated Hazard Ratios (EHR) in different scenarios for patient stratification (significance was p<0.05).

Results

The 5-year EFS and overall survival for T-ALL patients were 79.9±1.4% and 84.9±1.2%, respectively, and the cumulative incidence of relapse (CIR) and death were 13.7±1.2% and 6.3±0.9%, respectively.

Non-HR patients (n=470) had an EFS of 86.8±1.6% and CIR of 8.7±1.3%, respectively, with excellent outcome in those MRD negative at EOI (n=137, EFS 91.1±2.5%). For HR patients (n=402), EFS and CIR were 71.9±2.3% and 18.0±1.9%, respectively, with a markedly inferior outcome in those assigned to HR group due, in hierarchical order, to EOC-MRD ≥5x10-4 (n=79, EFS 58.7±5.6%) or no EOI-CR (n=26, EFS 57.4±9.7%) compared to those assigned to HR due to PPR (n=228, EFS 75.8±2.9%) or d15 FCM-MRD HR only (n=65, 83.0±4.7%). The randomized intensification with PEG-ASNASE did not improve outcome, as already reported (Rizzari C, Hemasphere 2023). Other interventions adopted in this study contributed to the improved outcome compared to trial AIEOP-BFM ALL 2000 (EFS 76.3%±2.0%, Schrappe M, Blood 2011).

In univariate analysis, WBC count ≥300 x109/L (n=155, EFS 70.2±3.7%), central nervous system disease (CNS3, n=78, EFS 63.6±5.7%), PPR, d15 FCM-MRD HR or no EOI-CR were associated with worse prognosis. Poor outcome was also observed for patients with EOI-MRD ≥5x10-2 (n=90, EFS 64.5±5.2%) compared to those with lower levels or negative (n=656, EFS 78.5±3.9% – 92.3±2.3%). Similarly, the outcome was worse for patients with EOC-MRD ≥5x10-4 (n=79, EFS 58.7±5.6%) compared to those with lower levels or negative (n=667, EFS 79.6±2.5% - 88.1±1.6%).

A Cox model investigated if factors for optimizing stratification could be identified at EOI. In this model, CNS3 (EHR 2.36), PPR (EHR 1.77) and high level of EOI-MRD (EHR 4.75 for ≥5x10-2 compared to negative) retained a significant impact on EFS. A 2nd model included also EOC-MRD, with a significant impact of levels ≥5x10-4 and <5x10-3 (EHR 2.52) and of ≥5x10-3 (EHR 6.28); here EOI-MRD lost significance, while CNS3 and PPR retained their prognostic value. A 3rd model investigating the dynamic of MRD showed an increased hazard for patients maintaining a high level at EOC (≥5x10-4) regardless of EOI level, and similar results for CNS3 and PPR. Age, WBC count, d15 FCM-MRD HR did not significantly affect outcome in these 3 models.

Conclusions

Results of T-ALL patients in AIEOP-BFM ALL 2009 were favorable, yet future patient stratification can be optimized. Although EOC-MRD remains the strongest prognostic factor, PPR remains a risk factor and CNS3 disease is identified as a novel HR factor for stratification. EOI-MRD alone has prognostic value, with increasing levels associated with worsening outcome, and identifies two patient subgroups, those with levels ≥5x10-4 and <5x10-2 with a poor prognosis and those with MRD ≥5x10-2 with a dismal prognosis, that could be the targets for early experimental interventions.

Disclosures: Cario: Jazz Pharmaceuticals: Other: travel support. Lenk: OSE Immunotherapeutics: Research Funding. Dalla-Pozza: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; JazzPharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulozik: Vertex: Honoraria. Rizzari: AMGEN, CLINIGEN, JAZZ, SERVIER, SERB: Consultancy, Honoraria, Speakers Bureau. Schrappe: JazzPharma, Servier, Amgen: Honoraria, Research Funding, Speakers Bureau. Biondi: CoImmune, Galapagos, Amgen, Novartis, BMS: Consultancy, Research Funding, Speakers Bureau.

*signifies non-member of ASH