Page 332 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Incidence and outcome of central nervous system relapse after hematopoietic stem cell transplantation in patients suffering from acute myeloid leukemia and acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Central nervous system (CNS) relapses in acute leukemia (AL) are serious disease recurrences, especially after allo- geneic hematopoietic stem cell transplantation (allo-HSCT). The incidence and overall survival (OS) after treatment and best treatment strategies remain largely unknown.
A study on 2,045 patients reports the incidence of CNS relapse after allo-HSCT for acute myeloid leukemia (AML) to be 1.81%.1 Pre-allo-HSCT CNS involvement was an inde- pendent risk factor for CNS relapse post-allo-HSCT, with a lower 3-year OS (60.3 vs. 81.5%). In AML, screening for CNS disease is unsystematic and varies: it is sometimes routine, sometimes only in patients with hyperleukocytosis or monoblasts, and irregular for the elderly. The defini- tion of CNS involvement is not clear: most only consider cytologically visible leukemic cells, others consider mi- nor infiltration in flow cytometry. A study on 48 patients (monocytic phenotype, hyperleukocytosis, FLT3-ITD+ or CNS symptoms) demonstrated a CNS involvement in 52%,2 with unknown incidence of CNS relapse post-allo-HSCT. Another study on 103 patients demonstrated 32% had CNS positivity, screened by either cytology, or flow cytometry.3 In acute lymphoblastic leukemia (ALL), CNS involvement is an established risk factor and routinely screened for; it is treated therapeutically and prophylactically. CNS relapse is the most important risk factor for relapse and mortality; CNS prophylaxis is integrated into treatment protocols.4 Around 5% of patients show cytological CNS involvement, but cytology negative CNS infiltration is frequent, demon- strated by animal and post-mortem studies.5
Central nervous system relapse after allo-HSCT is life-threat- ening; however, the exact incidence in a large leukemic cohort is not known. CNS is among the most frequent sites of extramedullary disease progression, especially in ALL.6 In AML, initial CNS involvement is present in 2-4% of patients.7-9 The incidence, OS after treatment, and best treatment strategies remain unknown. Literature is scarce and mostly reported as single case reports. One study on CNS relapse in ALL describes 457 patients after first al- lo-HSCT in first or second complete remission (CR), 15% of whom had a CNS involvement pre-allo-HSCT.10 Forty-eight
percent received post-allo-HSCT CNS prophylaxis. Overall, 18 patients (4%) developed CNS relapse, with pre-allo-HSCT CNS involvement as the only identified risk factor. Fifty percent of these patients had CNS involvement prior to allo-HSCT, regardless of post-allo-HSCT CNS prophylaxis or the conditioning regimen used. A study on allo-HSCT in 71 AML patients with CNS involvement at diagnosis, 52 of whom received intrathecal chemotherapy alone and 19 in combination with irradiation, demonstrated a worse relapse-free survival than a control group without CNS involvement and a disease-free survival and OS benefit from additional irradiation.11 A study on 1,226 AML, ALL or CML patients described the incidence of CNS relapse after allo-HSCT in a 10-year observation study as 2.3% (29 pa- tients).12 Risk factors were ALL, non-remission at allo-HSCT, prior CNS disease and prophylactic intrathecal chemother- apy post-allo-HSCT. Three-year OS after CNS relapse was 18% and 1-year OS 42%. Long-term survival was observed only in few patients, and only without systemic disease. We performed the current retrospective, multicenter anal- ysis based on the registry of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT, more than 600 transplant centers, mainly in Europe) to define the incidence and outcome of CNS relapse after HSCT in patients suffering from AML and ALL.
The study was approved by the ALWP and conducted in accordance with the Declaration of Helsinki and Good Clin- ical Practice guidelines. Data from allo-HSCT performed between 1996 and 2016 were screened and patients with the following criteria were included: ≥18 years, with AML or ALL, first allo-HSCT in first complete remission (CR), all donor types. We identified patients with and without CNS relapse. We also collected information on type of relapse, relapse site, treatment, and outcome after CNS relapse. The primary endpoint of this study was OS after CNS re- lapse. Secondary endpoints were: cumulative incidence of CNS relapse after allo-HSCT, CR after CNS relapse and incidence of acute and chronic graft-versus-host disease (GvHD) after CNS relapse.
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