Incidence and prognostic value of central nervous system involvement in infants with B-cell precursor acute lymphoblastic leukemia treated according to the MLL-Baby protocol
Corresponding Author
Alexander Popov
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Correspondence
Alexander Popov, National Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, 1, S. Mashela St, Moscow, 117998, Russian Federation.
Email: [email protected]
Search for more papers by this authorGrigory Tsaur
Regional Children's Hospital, Ekaterinburg, Russian Federation
Ural State Medical University, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorZhan Permikin
Regional Children's Hospital, Ekaterinburg, Russian Federation
Ural State Medical University, Ekaterinburg, Russian Federation
Search for more papers by this authorVeronika Fominikh
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorTatiana Verzhbitskaya
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorTatiana Riger
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorAnna Demina
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorEgor Shorikov
PET-Technology Centre of Nuclear Medicine, Ekaterinburg, Russian Federation
Search for more papers by this authorAnatoly Kustanovich
The Sharett Institute of Oncology, Hadassah Medical Centre, Jerusalem, Israel
Search for more papers by this authorLiudmila Movchan
Belarussian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Search for more papers by this authorOlga Streneva
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorOlga Khlebnikova
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorOlga Makarova
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorOleg Arakaev
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorAlexander Solodovnikov
Ural State Medical University, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorElmira Boichenko
City Children's Hospital No 1, Saint Petersburg, Russian Federation
Search for more papers by this authorKonstantin Kondratchik
Morozov Children's Hospital, Moscow, Russian Federation
Search for more papers by this authorNatalia Ponomareva
Republican Children's Hospital, Moscow, Russian Federation
Search for more papers by this authorElena Lapotentova
Belarussian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Search for more papers by this authorOlga Aleinikova
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Belarussian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Search for more papers by this authorNatalia Miakova
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorGalina Novichkova
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorAlexander Karachunskiy
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorLarisa Fechina
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorCorresponding Author
Alexander Popov
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Correspondence
Alexander Popov, National Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology, 1, S. Mashela St, Moscow, 117998, Russian Federation.
Email: [email protected]
Search for more papers by this authorGrigory Tsaur
Regional Children's Hospital, Ekaterinburg, Russian Federation
Ural State Medical University, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorZhan Permikin
Regional Children's Hospital, Ekaterinburg, Russian Federation
Ural State Medical University, Ekaterinburg, Russian Federation
Search for more papers by this authorVeronika Fominikh
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorTatiana Verzhbitskaya
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorTatiana Riger
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorAnna Demina
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorEgor Shorikov
PET-Technology Centre of Nuclear Medicine, Ekaterinburg, Russian Federation
Search for more papers by this authorAnatoly Kustanovich
The Sharett Institute of Oncology, Hadassah Medical Centre, Jerusalem, Israel
Search for more papers by this authorLiudmila Movchan
Belarussian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Search for more papers by this authorOlga Streneva
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorOlga Khlebnikova
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorOlga Makarova
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorOleg Arakaev
Regional Children's Hospital, Ekaterinburg, Russian Federation
Search for more papers by this authorAlexander Solodovnikov
Ural State Medical University, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorElmira Boichenko
City Children's Hospital No 1, Saint Petersburg, Russian Federation
Search for more papers by this authorKonstantin Kondratchik
Morozov Children's Hospital, Moscow, Russian Federation
Search for more papers by this authorNatalia Ponomareva
Republican Children's Hospital, Moscow, Russian Federation
Search for more papers by this authorElena Lapotentova
Belarussian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Search for more papers by this authorOlga Aleinikova
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Belarussian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
Search for more papers by this authorNatalia Miakova
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorGalina Novichkova
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorAlexander Karachunskiy
National Research and Clinical Centre for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Search for more papers by this authorLarisa Fechina
Regional Children's Hospital, Ekaterinburg, Russian Federation
Research Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation
Search for more papers by this authorAbstract
Aim
The aim of the study was to evaluate the incidence and prognostic impact of central nervous system (CNS) involvement in infants with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), as well as its relation with minimal residual disease (MRD) data.
Methods
A total of 139 consecutive infants with BCP-ALL from the MLL-Baby trial were studied. Cerebrospinal fluid (CSF) samples were investigated by microscopy of cytospin slides. MRD was evaluated according to the protocol schedule by flow cytometry and PCR for fusion gene transcripts (FGT).
Results
Involvement of the CNS at any level was found in 50 infants (36.0%). The incidence of CNS involvement was higher in patients with KMT2A gene rearrangements (44.0% for KMT2A-r vs. 15.4% for KMT2A-g, p = .003). The outcome of CNS-positive infants was significantly worse than that of CNS-negative infants, although this prognostic impact was limited to the KMT2A-r group (event-free survival 0.21 for CNS-positive vs. 0.48 for CNS-negative infants, p = .044). CNS-positive infants could not be treated successfully by conventional chemotherapy alone, irrespective of the rapidity of MRD response. In contrast, the combination of initial CNS negativity and FGT-MRD negativity identified a group comprising up to one-third of infants with KMT2A-r ALL who can be treated with chemotherapy and achieve very good outcomes (disease-free survival above 95%), and remaining patients should be allocated to receive other types of treatment.
Conclusion
We can conclude that this combination of initial CNS involvement and MRD data can significantly improve risk-group allocation in future clinical trials enrolling infants with ALL.
CONFLICT OF INTEREST
The authors declare that there is no relevant conflict of interest.
Supporting Information
| Filename | Description |
|---|---|
| pbc29860-sup-0001-SuppMat.docx148.2 KB | Table S1 Characteristics of patients included in the study (n = 139). Good steroid response = blast count in peripheral blood at Day 8 less than 1000 cells per microliter. M1 bone marrow status was defined as blast cells <5% at cytological examination; M2: blast cells 5%–25%; M3: blast cells ≥25% Table S2 Eligibility and risk stratification criteria in the MLL-Baby protocol Table S3 Treatment protocol of trial MLL-Baby Table S4 Relation of incidence of traumatic lumbar puncture (TLP) with presence of KMT2A rearrangements (A), initial WBC count (B), and age (C) Table S5 Outcome in CNS-positive and CNS-negative infants enrolled in MLL-Baby trial. Panel (A) depicts entire cohort, while panels (B) and (C) represent infants with and without rearrangements of KMT2A gene, respectively, when analyzed separately. CR1: first complete remission; CCR: complete continuous remission Table S6 Results of the Cox models assessing the prognostic impact on the hazard of relapse for various prognostic factors known to be relevant in infants with BCP-ALL. Multivariable Cox regression was performed using factors that showed statistical significance during the univariable analysis. Step-wise exclusion of nonsignificant (p < .1) factors was performed for multivariable Cox regression based on Wald's p-values. Panel (A) depicts the analysis for the whole cohort of patients (n = 139), whereas panel (B) shows analysis for KMT2A-r group (n = 100) Table S7 Differences in outcome according to early treatment response parameters in CNS-positive and CNS-negative KMT2A-r infants. Good steroid response: blast count in peripheral blood at Day 8 less than 1000 cells per microliter. M1 bone marrow status was defined as blast cells <5% at cytological examination; M2: blast cells 5%–25%; M3: blast cells ≥25% Figure S1 MLL-Baby protocol design with MRD time points (TP) indication Figure S2 Availability of MRD data at the most informative TPs in the MLL-Baby trial for FGT (A) and MFC (B) |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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