Detection of occult cerebrospinal fluid involvement during maintenance therapy identifies a group of children with acute lymphoblastic leukemia at high risk for relapse

Abstract

We aimed at assessing the clinical significance of the levels of acute lymphoblastic leukemia (ALL) cells in samples of cerebrospinal fluid (CSF) during therapy. We studied 990 CSF samples from 108 patients, at the time of diagnosis (108) and at each time of intrathecal therapy (882). The proportions of leukemic cells in CSF samples were assessed by flow cytometry (FCM). Patients with central nervous system (CNS) involvement at diagnosis (FCM1) showed predominantly a T-ALL, and higher percentages of known negative prognostic factors: high risk group, higher white blood cell counts, normal karyotype, and the BCR-ABL fusion gene. No differences in relapse free survival (RFS) and overall survival (OS) were observed between FCM1 versus FCM2 at diagnosis. Patients with CNS involvement during therapy showed significantly older age, and higher frequencies of T-cell leukemia. We found a significantly higher RFS in patients with FCM1 during therapy. The detection of subclinical CNS disease by FCM during maintenance was associated with significantly lower 3-years RFS and 3-years OS. A sensitive methodology like FCM can be applied for a close follow-up of the levels of ALL in CFS samples, and may identify a group of patients at high risk for relapse.

The ability to cross the blood–cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts

“…Additional support for high rates of subclinical seeding of the CNS at the time of diagnosis comes from clinical observations. The use of more-sensitive detection methods such as flow cytometry 7 and PCR 5,6 is able to detect occult CNS involvement in up to 40% of patients. In addition, before the era of routine CNS "prophylaxis," 50% to 75% of children relapsed in the CNS, 1 usually within a couple of months of original diagnosis, suggesting that occult CNS leukemia was present from the outset.…”

“…It is important to appreciate that CNS-1 status does not equate with absence of leukemia in the CNS; early postmortem studies on children succumbing to leukemia frequently showed leptomeningeal involvement despite negative CSF cytology. 4 Cytologic classification is insensitive [5][6][7] and clearly inadequate for risk stratification because the majority of relapses occur in CNS-1 children. 8,9 In addition, the CNS is one of the major sites of relapse in children with otherwise excellent prognosis as determined by low-risk bone marrow (BM) minimal residual disease measurements, 10 suggesting that factors influencing leukemic kill in the periphery may not apply to the CNS.…”

Central nervous system niche involvement in the leukemia

“…T-ALL is associated with high WBC count, hepatosplenomegaly and a high risk of relapse [58][59][60]. Accordingly, leukemia counts the highest prevalence of CNS affection, possibly due to the redundant expression in T-cells of receptors that are present in the CNS, such as CXCR3 and CCR (CC motif chemokine receptor) 4 (Table 3) [61,62].…”

Chemokines and relapses in childhood acute lymphoblastic leukemia: A role in migration and in resistance to antileukemic drugs

“…Leukemic relapses have been directly linked to the survival of blasts in organs such as the central nervous system (CNS) or the testes [8][9][10]. The capacity of ALL blasts for lodging behind the blood-brain barrier (BBB) would expose them to suboptimal levels of drugs, contributing to survival and relapses.…”