5  CNS disease in ALL

6 Introduction

  • In adults with ALL,the incidence of central nervous system(CNS) involvement at the time of diagnosis has ranged from 5% to 11% in the largest clinical trials of the last 25 years.[Kantarjian et al. (2000)](Rowe 2005)[Huguet et al. (2018)](Stock et al. 2019)[Lazarus (2006)](Petersdorf et al. 2001)
  • Without CNS-directed prophylaxis, the rates of CNS relapse range from 30% to 40%, justifying the routine use of CNS directed prophylaxis as a standard component in ALL management since the1980s.

7 Pathophysiology

  • The pathophysiology underlying CNS involvement in ALL is a complex process involving leukemic migration from the marrow space into the CNS (an immune-privileged space) and survival in the CNS microenvironment.

  • Recent publications have high-lighted unique mechanisms via which this occurs, including leukemic migration along the outside of emissary vessels, relying on a-integrin receptors similar to early neural progenitors.(Yao et al. 2018)

  • There is also leukemic metabolic adaptation to the CNS microenvironment to promote survival and proliferation.(Savino et al. 2020).

Three primary mechanisms of CNS invasion have been identified. A nice review on the topic (Whiteley et al. 2021)

  1. Leukaemia cells cross the blood–brain barrier to enter the CNS by promoting their own extravasation through VEGF signalling

  2. Recent work highlighted the choroid plexus as a specific site of entry for leukaemic cells into the CNS from the peripheral circulation. The choroid plexus is a secretory tissue that produces CSF within the ventricular space in the brain

  3. More recent work(Yao et al. 2018) showed that B-ALL cells bind to extracellular matrix laminin surrounding specialized emissary blood vessels in mice. These emissary vessels passage from the skull and vertebral BM through cortical bone fenestrations, emerging as leptomeningeal vasculature in the adjacent CNS, and serve as a direct scaffold for leukaemic cells to migrate from BM to leptomeninges along their surface. Leukaemia cells do not extravasate through these vessels but migrate along their abluminal (outer) surface using integrin α6 to bind to the laminin-positive basement membrane. In a small patient series, leukaemia integrin α6 expression at diagnosis was associated with subsequent CNS relapse.