The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99‐15 study

Abstract

INTRODUCTIONThe long-term cure rate in childhood acute lymphoblastic leukemia (ALL) is as high as 80% [1,2], and this is largely attributable to sufficient central nervous system (CNS)-directed therapy, such as prophylactic cranial irradiation (pCRT) and intrathecal chemotherapy (IT) [3]. However, administering CNS-directed therapy always results in a dilemma between sufficient intensity and treatmentrelated toxicity. Especially, the use of pCRT should be avoided because of its substantial risk for late complications such as second malignancies, endocrinopathies, neurocognitive dysfunctions, and neurotoxic effects [4][5][6]. On the other hand, CNS relapse still occurs in 2-5% of children with ALL and remains to be a treatment obstacle [7]. Therefore, proper assessment of risk factors for CNS relapse is required.Risk factors for CNS relapse include a T-cell immunophenotype, hyperleukocytosis, specific genetic alterations such as t(9;22) and t(4;11), and the presence of CNS involvement [7]. The prognostic significance of the presence of leukemic blasts in the cerebrospinal fluid (CSF) without pleocytosis, referred to as CNS-2, has varied in clinical trials and is heavily dependent on the effectiveness of systemic and CNS-directed therapy [8][9][10][11]. By contrast, traumatic lumbar puncture with leukemic blasts (TLPþ) adversely affects the outcome of patients with ALL as well as overt CNS leukemia [2,9-11]. Though controversy over whether TLPþ is an iatrogenic event or intrinsically inevitable status still exists, clinicians should pay attention to keep the rate of TLPþ to a minimum.To overcome the problem concerning TLPþ, the Tokyo Children's Cancer Study Group (TCCSG) adopted a strategy to postpone the initial lumbar puncture (LP) and IT until 7 days after prednisolone (PSL) monotherapy in the L89-12 study in order to decrease circulating leukemic blasts substantially before the initial LP/IT [12]. This strategy yielded a significant reduction of TLPþ [12], but the net effect on the outcome was not clarified because over 80% of the patients received cranial irradiation in the L89-12 study [12,13]. We hypothesized that deferring the initial LP/ITuntil day 8 in remission induction therapy could reduce the frequency of cases with TLPþ without compromising outcome, even if the indication for pCRT is restricted. Here, we report the results of the L99-15 study adopting the day 8 LP/IT strategy and restricting the indication for pCRT.

Incidence and risk factors for central nervous system relapse in children and adolescents with acute lymphoblastic leukemia

“…Another possible contributing factor maybe the delay in performing LP in 40% of the patients. In a Japanese study in which the first LP was set to be performed on the eighth day of the chemotherapy induction phase, only 0.5% of patients were classified as CNS3 (18) . The results of both of these studies differ from most of the literature in childhood ALL, as demonstrated by Table 2.…”

“…Traumatic LP at diagnosis occurred in 38% of patients, which is in accordance with the results of different Brazilian ALL referral centers (19,20) . As to international referral centers, a lower incidence of traumatic LP is observed with rates varying from 3.4% to 21% at diagnosis (5,7,8,18) . Of the studied factors, low "age" was the only risk factor shown to have an association with traumatic LP as anesthesia did not reduce the incidence of traumatic LP.…”

Secondary cancers among children with acute lymphoblastic leukaemia treated by the Tokyo Children's Cancer Study Group protocols: a retrospective cohort study

“…Details of the treatment regimens and main therapeutic results have been previously published. (Tsunematsu et al , ; Toyoda et al , ; Manabe et al , ; Igarashi et al , ; Hasegawa et al , ) Although the patients in our cohort were treated according to therapeutic protocols, we do not have detailed information regarding actual doses of additional therapeutic exposures given to the relapsed patients, which potentially could have influenced the development of secondary cancers. As a sensitivity analysis, we conducted the same analysis on 1716 patients (referred to as the per protocol group), limited to the patients who had completed all planned treatment leading to first CR (Fig ).…”

Prognostic factors and treatment of pediatric acute lymphoblastic leukemia

“…TLP may result in circulating leukemic blasts seeding the CNS and may also confound the diagnosis of initial CNS involvement. One study showed that delaying the initial intrathecal therapy for up to 1 week decreased the rate of TLP without adversely affecting long-term outcome35). Hence, a delay of the initial intrathecal chemotherapy for a maximum of 1 week may be considered in patients who are at high risk of experiencing TLP, such as patients with extreme hyperleukocytosis or obese adolescents with a significant number of peripheral blasts.…”