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2805 Diagnosing and Staging Central Nervous System Involvement in Pediatric ALL: A Global Survey on Its Heterogeneity

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Epidemiology, Clinical Practice (Health Services and Quality), Assays, Clinical Research, Health disparities research, Pediatric, Diseases, Real-world evidence, Lymphoid Malignancies, Technology and Procedures, Study Population, Human, Pathology
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Laura Almási, MD1*, Cornelia Eckert, MD, PhD2*, Maria Thastrup, PhD3*, Vera Münch, PhD4*, Dániel Maszárovics5*, Bernadett Hon-Balla, MD5*, Lennart Lenk, PhD6*, Gábor Barna, PhD7*, Wenyu Yang, MD8*, Mignon L. Loh, MD, PhD9, Hyoung Jin Kang, MD, PhD10, Sophia Polychronopoulou, MD, PhD11*, Arja Harila, MD, PhD12*, Marko Kavcic, MD, PhD13*, Kjeld Schmiegelow, MD, PhD14, Lüder Hinrich Meyer, MD, Professor4*, Christina Halsey, MD, PhD15 and Daniel J Erdelyi, MD, PhD5*

1Pediatric Center, Semmelweis University, Budapest, Hungary
2Charité Universitätsmedizin Berlin, Department of Hematology and Oncology, Berlin, Germany
3The Laboratory of Pediatric Oncology (Bonkolab), University Hospital Rigshospitalet, Copenhagen, DNK
4Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
5Pediatric Centre, Semmelweis University, Budapest, Hungary, Budapest, Hungary
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
7Semmelweis University, Budapest, Hungary, Budapest, HUN
8Department of Pediatric Hematology and Oncology, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology& Blood Diseases Hospital, Chinese Academy of Medical Sciences& Peking Union Medical College, Tianjin, China
9Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, Fred Hutch Cancer Center, University of Washington, Seattle, WA
10Seoul National University Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
11Aghia Sophia Children’s Hospital, Athens, Athens, Greece
12Women's and Children's Health, Uppsala University, Uppsala, Sweden
13University Medical Centre, Ljubljana, SVN
14Copenhagen University, Copenhagen, DNK
15Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom

BACKGROUND

In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is associated with increased risk of relapse. Traditionally, CNS involvement has been staged using cell counting and microscopic cytomorphological assessment of centrifuged and stained samples (cytospins) of the cerebrospinal fluid (CSF). More recently CSF flow cytometry has been shown to be more sensitive than cytology and to have prognostic significance. CNS staging is a basis for treatment stratification worldwide. CSF diagnostic protocols of study groups differ in small details, however, larger variability in practice was suspected based on informal discussions within the childhood ALL community.

AIMS

To systematically evaluate real world practice of CSF diagnostics and staging in pediatric ALL patients across hospitals globally.

METHODS

A survey was developed and distributed in 2021-2022 with target hospital categories and hospital numbers per country. Questions focused on numerous details of routine practice at the given hospitals in year 2021.

RESULTS

Eighty-two centers from 47 countries across five continents responded with a median 20 new pediatric ALL patients per year per center. Significant heterogeneity was observed in testing methodologies and CNS staging.

The staging LP is contraindicated by high peripheral WBC, with threshold varying between 50 and 200 x109/L in 46% of the centers, while 54% of the centers set no threshold (LP is performed even in case of extreme leukocytosis). The timing of staging LP relative to the initiation of systemic antileukemic therapy also varies, with 57% of hospitals performing the LP strictly before therapy, while others routinely allowing some (1 and 7 days depending on hospital) systemic steroid and/or chemotherapy before.

There is heterogeneity in the selection of test modalities to analyze the CSF. Manual cell counting is applied in 73%, automated cell counting in 43%, cytospins in 84% and flow cytometry in 33% of the hospitals during routine CNS-staging. Ten percent of the centers use only one modality, 54% of them use 2 modalities. A larger proportion of centers in high income countries analyze WBCs in cytospins routinely as compared to centers in middle income countries (92% versus 65%, p = 0.006). A similar trend was observed regarding CSF flow cytometry (39% vs 17%, p = 0.07). Similarly, a heterogenous set of testing modalities and cut offs/definitions are applied for CSF red cell quantification and for defining traumatic LP (TLP).

Among hospitals which assess cytospins, the CSF volume centrifuged to prepare these specimens varies between 15 and 3000 microliters. Typical CSF volumes analyzed by flow cytometry range between 200 and 4000 microliters. There is also wide variation regarding the cut-off blast numbers to define positive findings in case of cytospins (≥1 to ≥5 cells) and flow cytometry (1 to 50 events characterized as test positivity in different centers). Interestingly, there is no correlation between the CSF volume used and the minimum number of blasts to define the tests’ positivity.

These heterogeneities are seen both within study groups and within individual countries in the same study group.

DISCUSSION

The above inconsistencies and differences in practice must have obvious clinical implications by significantly impacting CNS staging and thus CNS1/2/3/TLP frequencies and therefore treatment decisions for ALL patients worldwide. Moreover, internationally well-connected, larger pediatric oncology centers involved in research are thought to be overrepresented among survey participants. In view of this bias, global diagnostic heterogeneity can be larger and the quality of diagnostics poorer for a large proportion of patients than what our survey reflects.

These results raise concern over published findings on the prognostic value of leukemic CNS involvement, particularly the CNS2 stage, and the comparability of published studies. We propose that details on CNS staging methods and adherence to the diagnostic guidelines should be included in publications of clinical studies. There is an urgent need for standardization, ideally through the development of international consensus guidelines in this field.

Disclosures: Lenk: OSE Immunotherapeutics: Research Funding. Kang: Takeda, Handok Teva, Recordati, Novartis, MSD: Consultancy; GPCR: Other: Research funding to my institution; Takeda: Other: Travel/Accommodations/Expenses. Schmiegelow: Servier: Other: grant research; Novo Nordisk: Other: stocks. Halsey: Autolus: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy. Erdelyi: Pfizer: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Servier: Honoraria; Amgen: Honoraria.

*signifies non-member of ASH