Central Nervous System Involvement at Diagnosis in Infants with Acute Lymphoblastic Leukemia (ALL): Incidence and Outcome

Abstract

Infants under one year with acute lymphoblastic leukaemia present with central nervous system disease three to five times more often than older children, and it identifies a group whose event-free survival is roughly half that of their central nervous system-negative peers. The newest and most effective therapy for these infants may not reach that compartment at all. Objectives: To review the published evidence on central nervous system involvement at diagnosis in infant acute lymphoblastic leukaemia: how often it occurs,
how it relates to KMT2A rearrangement and age, what it predicts for relapse and survival, and how the compartment has responded to successive treatment strategies. Material and Methods: Narrative review of international cooperative group trials, registry analyses and correlative studies indexed in PubMed and the major haematology and oncology journals. Studies were eligible if they reported the frequency or outcome of central nervous system disease in a defined infant leukaemia population, or the effect of a treatment strategy on central nervous system relapse. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: Central nervous system involvement was present in 13.8 per cent of infants at diagnosis in the largest international trial, against 2 to 5 per cent in children over one year. Among 139 infants with recorded status, 28 of 50 with central nervous system disease relapsed, giving event-free survival of 0.27 and cumulative relapse incidence of 0.65, against 21 relapses among 89 without involvement, event-free survival 0.58 and relapse incidence 0.26 (p < 0.001 for both). Of 213 relapses occurring after first remission in 442 patients, 24 per cent involved the central nervous system, comprising 11 per cent isolated and 13 per cent
combined marrow and central nervous system disease. Adding one course of a CD19-directed bispecific antibody to the same chemotherapy backbone raised two-year disease-free survival from 49.4 to 81.6 per cent, yet every relapse that occurred involved the central nervous system. Conclusion: Central nervous system disease at diagnosis is common in infants, strongly prognostic, and has proved the least tractable compartment to successive therapeutic advances. That the most effective new agent leaves relapses concentrated there is an argument for intensifying intrathecal rather than systemic therapy alongside it. Abbreviations: ALL – Acute Lymphoblastic Leukaemia, CNS – Central Nervous System, KMT2A-r – KMT2A-Rearranged, KMT2A-g – KMT2A-Germline,
EFS – Event-Free Survival, DFS – Disease-Free Survival, OS – Overall Survival, CIR – Cumulative Incidence of Relapse, CR1 – FirstComplete Remission, MRD – Minimal Residual Disease, HSCT – Haematopoietic Stem Cell Transplantation, WBC – White Blood Cell Count.