Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and potential for therapy

Abstract

Central nervous system acute lymphoblastic leukaemia (CNS-ALL) is a major clinical problem. CNS-directed 'prophylactic' chemo-or radiotherapy is associated with significant early and long-term toxicity. Moreover, greater than a third of the relapses occur in the CNS. To design specific, more effective and less toxic therapy and for personalized precise adjustment of prophylactic therapy there is a need for better understanding of the biology of this disease. Specifically, the precise neurotropic mechanisms of ALL are currently unclear, as is the pathogenesis of CNS relapse. Here we review and contrast the recent findings with earlier studies of pathogenesis of CNS leukaemia. We also describe the challenges in research of this devastating complication of ALL.

Targeted therapy of CNS leukemia?

“…These results contrast with murine gene ablation studies for the common pathway coagulation factors (F10, F5, and prothrombin), which demonstrate a mixture of embryonic lethality and fatal perinatal bleeding. [2][3][4][5] F10 deficiency in humans is a rare autosomal recessive bleeding disorder in which the majority of reported genetic defects are either homozygous or compound heterozygous …”

“…C NS leukemia is a major clinical problem in patients with ALL. 2 It is estimated that the majority of children with ALL have leukemic infiltration of the meninges at the time of diagnosis. Prophylactic CNS-directed chemotherapy (or radiotherapy) has reduced the rate of CNS relapse from 70% to less than 5%.…”

“…Furthermore, CNS relapses are hypothesized to rise from dormant residual leukemic cells in the subarachnoid space. 2 However, if VEGF has a major role in enhancing the survival of ALL cells in the subarachnoid space, then VEGF antagonists could be the first targeted and less toxic therapy for CNS leukemia and for the prevention of CNS relapses. Because bevacizumab is an approved drug and has been used for the treatment of brain tumors, 8 a clinical trial in refractory CNS relapse of ALL may be warranted.…”

“Mouse‐MRD” in central nervous system acute lymphoblastic leukaemia: assessing bone marrow minimal residual disease using a xenograft model – from bedside to the bench and back again

“…Isolated central nervous system (CNS) relapse is frequent in relapsed childhood B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) (Frishman‐Levy & Izraeli, ), and is usually stratified as low or intermediate risk disease. Isolated CNS relapse is thought to be fuelled by cell clones in the bone marrow (BM).…”

“…"Mouse-MRD" in central nervous system acute lymphoblastic leukaemia: assessing bone marrow minimal residual disease using a xenograft modelfrom bedside to the bench and back again Isolated central nervous system (CNS) relapse is frequent in relapsed childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) (Frishman-Levy & Izraeli, 2017), and is usually stratified as low or intermediate risk disease. Isolated CNS relapse is thought to be fuelled by cell clones in the bone marrow (BM).…”