Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment

Abstract

Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients—those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.

Use of intrathecal chemoprophylaxis in children after SCT and the risk of central nervous system relapse

“…therapy post-HSCT is limited. 4 A recent study involving 1226 adult patients with ALL, AML and CML found a slightly higher rate of CNS relapse after HSCT in the group receiving i.t. therapy.…”

Safety of liposomal cytarabine CNS prophylaxis in children, adolescent and young adult hematopoietic stem cell transplant recipients with acute leukemia and non-Hodgkin lymphoma

“…Some studies have shown significantly higher recurrence rates in patients at risk of CNS relapse, whereas others have been unable to show much of a difference. 1 These results likely reflect differences in patient populations as well as prophylactic strategies. However, there is a paucity of prospective data to truly compare the results of different prophylactic strategies.…”

Acute Lymphoblastic Leukemia

“…41,130,161 Factors associated with increased risks for CNS leukemia in children include T-cell immunophenotype, high presenting WBC counts, Ph-positive disease, t(4;11) translocation, and presence of leukemic cells in the CSF. 46 In adults with ALL, CNS leukemia at diagnosis has been associated with a significantly higher risk for CNS relapse in large trials, although no differences were observed in 5-year EFS or DFS rates compared with subgroups without CNS leukemia at presentation. 162,163 CNS leukemia at diagnosis was associated with significantly decreased 5-year OS rate in one trial (29% vs. 38%; P = .03) 162 but not in another trial (35% vs. 31%).…”

“…44,45 The observed advantage in outcomes with dexamethasone may, at least partly, be attributed to improved penetration of dexamethasone in the CNS. 46 In a recently published meta-analysis comparing outcomes with dexamethasone versus prednisone in induction regimens for childhood ALL, dexamethasone was associated with a significantly reduced risk for events (i.e., death from any cause, refractory or relapsed leukemia, or second malignancy; risk ratio [RR], 0.80; 95% CI, 0.68-0.94) and CNS relapse (RR, 0.53; 95% CI, 0.44-0.65). 47 However, no advantage was seen with a dexamethasone regarding risk for bone marrow relapse (RR, 0.90; 95% CI, 0.69-1.18) or overall mortality (RR, 0.91; 95% CI, 0.76-1.09), and dexamethasone was associated with a significantly higher risk of mortality during induction therapy (RR, 2.31; 95% CI, 1.46-3.66), neuropsychiatric adverse events (RR, 4.55; 95% CI, 2.…”