Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group
Maddalena Benetton,
Pietro Merli,
Christiane Walter,
Maria Hansen,
Ambra Da Ros,
Katia Polato,
Claudia Tregnago,
Jonas Abrahamsson,
Luisa Strocchio,
Edwin Sonneveld,
Linda Fogelstrand,
Nils Von Neuhoff,
Dirk Reinhardt,
Henrik Hasle,
Martina Pigazzi,
Franco Locatelli
Affiliations
Maddalena Benetton
Department of Women’s and Children’s Health, Haematology-Oncology Clinic and Lab, University of Padova, 35128 Padova, Italy
Pietro Merli
Department of Pediatric Hematology and Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza University of Rome, 00165 Rome, Italy
Christiane Walter
Department of Pediatric Hematology and Oncology, University Hospital Essen, 45147 Essen, Germany
Maria Hansen
Department of Pediatrics, Aarhus University Hospital, 8000 Aarhus, Denmark
Ambra Da Ros
Department of Women’s and Children’s Health, Haematology-Oncology Clinic and Lab, University of Padova, 35128 Padova, Italy
Katia Polato
Department of Women’s and Children’s Health, Haematology-Oncology Clinic and Lab, University of Padova, 35128 Padova, Italy
Claudia Tregnago
Department of Women’s and Children’s Health, Haematology-Oncology Clinic and Lab, University of Padova, 35128 Padova, Italy
Jonas Abrahamsson
Department of Pediatrics, Institute of Clinical Sciences, “Sahlgrenska Academy” University of Gothenburg, 40010 Gothenburg, Sweden
Luisa Strocchio
Department of Pediatric Hematology and Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza University of Rome, 00165 Rome, Italy
Edwin Sonneveld
Princess Máxima Center for Pediatric Oncology, 1013 GM Utrecht, The Netherlands
Linda Fogelstrand
Department of Clinical Chemistry, Sahlgrenska University Hospital, 40010 Gothenburg, Sweden
Nils Von Neuhoff
Department of Pediatric Hematology and Oncology, University Hospital Essen, 45147 Essen, Germany
Dirk Reinhardt
Department of Pediatric Hematology and Oncology, University Hospital Essen, 45147 Essen, Germany
Henrik Hasle
Department of Pediatrics, Aarhus University Hospital, 8000 Aarhus, Denmark
Martina Pigazzi
Department of Women’s and Children’s Health, Haematology-Oncology Clinic and Lab, University of Padova, 35128 Padova, Italy
Franco Locatelli
Department of Pediatric Hematology and Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza University of Rome, 00165 Rome, Italy
Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22)RUNX1::RUNX1T1, or inv(16)(p13q22)CBFB::MYH11, or t(9;11)(p21;q23)KMT2A::MLLT3, or FLT3-ITD genetic markers. We calculated an ROC cut-off of 2.1 × 10−4 that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 × 10−4 and one lower cut-off of 1 × 10−2, and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management.
