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© 2001 American Society for Clinical Oncology Delay of the Diagnostic Lumbar Puncture and Intrathecal Chemotherapy in Children With Acute Lymphoblastic Leukemia Who Undergo Routine Corticosteroid Testing: Tokyo Children’s Cancer Study Group Study L89-12ByFrom the Tokyo Children’s Cancer Study Group; Department of Pediatric Hematology-Oncology, Institute of Medical Science, and Department of Pediatrics, University of Tokyo; Department of Pediatrics, Juntendo University; Department of Pediatrics, Tokyo Medical and Dental University; First Department of Pediatrics, Toho University; Department of Hematology-Oncology, Tokyo Metropolitan Kiyose Children’s Hospital; Department of Pediatrics, Jikei University; Department of Pediatrics, Nippon Medical School; Department of Pediatrics, Keio University; and Departments of Environmental Epidemiology and Hematology, National Children’s Hospital, Tokyo; Department of Pediatrics, Ibaraki Children’s Hospital, Mito; Department of Hematology-Oncology, Saitama Children’s Medical Center, Iwatsuki; Department of Pediatrics, Yokohama City University; and Department of Oncology, Kanagawa Children’s Medical Center, Yokohama; Department of Hematology-Oncology, Chiba Children’s Hospital; and Department of Pediatrics, Chiba University, Chiba; Department of Pediatrics, University of Shinshu, Matsumoto; Department of Pediatrics, Dokkyo Medical School, Tochigi; and Department of Pediatrics, Yamanashi Medical University, Kofu, Japan. Address reprint requests to Atsushi Manabe, MD, Department of Pediatric Hematology-Oncology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; email: manabe{at}ims.u-tokyo.ac.jp
PURPOSE: To determine the effects of eliminating initial lumbar punctures in 418 consecutively treated children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients were enrolled onto a trial conducted in central Japan between 1989 and 1992. Treatment consisted of standard four-drug induction therapy followed by a risk-based intensification phase, reinduction therapy, late intensification, and remission maintenance therapy (total of 104 weeks). The initial lumbar puncture, with an intrathecal injection of chemotherapy, was performed after 1 week of prednisolone sensitivity testing (day 8). End points included response to prednisolone, CNS status at the time of the day 8 lumbar puncture, subsequent adverse events in CNS and bone marrow, and event-free survival (EFS). RESULTS: The remission induction rate was 93.1% with a 6-year EFS rate (± SE) of 68.7% ± 2.4%, which is similar to historical results for patients who received their diagnostic lumbar puncture and first instillation of intrathecal chemotherapy on day 0. Overall, 84.5% of the patients had good responses to prednisolone, whereas 15.5% had poor responses. Clinical outcome was strikingly better for the good responders (6-year EFS, 74.1% ± 2.5% compared with 40.1% ± 6.4% for patients with poor responses), suggesting that omission of intrathecal chemotherapy did not alter the predictive value of drug sensitivity testing. Eighteen patients experienced CNS relapse as their first adverse event (cumulative risk, 5.1%; 95% confidence interval, 2.7% to 7.4%), coincident with reports from groups using conventional strategies of CNS clinical management. Bleeding into the CSF at the time of the day 8 lumbar puncture was apparent in 29 cases (8.1%), but leukemic blasts were identified in only two. CONCLUSION: Delay of the initial lumbar puncture and intrathecal injection of chemotherapy seems to be feasible in children with ALL. Further controlled evaluations are needed to establish the validity of this conclusion.
INVASIVE PROCEDURES directed to the CNS can cause serious hemorrhagic and nonhemorrhagic complications in children with acute lymphoblastic leukemia (ALL), including contamination of the meninges with leukemic cells.1 The Tokyo Children’s Cancer Study Group (TCCSG) does not use either lumbar puncture or intrathecal methotrexate (IT MTX) instillation at the time of diagnosis of ALL. While recognizing that careful early examination of CSF may identify blast cells predictive of relapse2 and that IT MTX injections produce significant therapeutic effects on leukemic cells in the CNS,3 we elected to delay these procedures until completion of 1 week of prephase prednisolone (PSL) sensitivity testing. As demonstrated by the Berlin-Frankfurt-Munster (BFM) group, the in vivo response to prephase corticosteroids combined with a single IT dose of MTX is a powerful independent predictor of event-free survival (EFS) and can be used effectively to stratify patients into risk groups.4 Patients with fewer than 1 x 109 blasts/L on day 8 are considered good responders with a favorable long-term prognosis, whereas those with higher counts generally have a poor outcome. The requirement for an IT MTX injection during PSL monotherapy is controversial.3,4 In the analysis presented here, we investi-gated the effects of omitting diagnostic lumber punctures and IT injections of MTX from prephase corticosteroid sensitivity testing in a large series of childhood ALL patients.
Patients Between June 1989 and August 1992, 418 previously untreated children (ages 1 to 15 years) with a diagnosis of ALL were enrolled onto the TCCSG L89-12 study. Patients with mature B-cell ALL or an age of less than 1 year were excluded. Written informed consent was obtained from the parents or guardians and then from the patients, as appropriate for age and understanding. The diagnosis of ALL was based on the morphology of bone marrow or peripheral-blood leukocytes, as judged by French-American-British criteria.5 Cell-surface antigens were detected by a standard immunofluorescence assay. Cases were subclassified as T-ALL (CD5+, CD7+ and no myeloid-associated antigens; n = 44), B-lineage ALL (CD10+, CD19+, HLA-DR+; n = 318), ALL with myeloid-associated antigens (CD13+ and/or CD33+; n = 14 with B-lineage ALL and n = 1 with T-ALL), and others (CD10-, CD19+, HLA-DR+; n = 21). Immunophenotyping was not performed in 20 cases. Karyotype analysis was performed by conventional methods with lymphoblasts grown in short-term cultures. Metaphase preparations were stained to reveal Giemsa banding patterns. Patients were then assigned to standard-risk (n = 147), intermediate-risk (n = 104), and high-risk (n = 167) groups according to age, initial leukocyte count, immunophenotype, selected genetic abnormalities, and other recognized prognostic features (Table 1). The male-to-female ratio was 1.35 (240 male and 178 female patients). Early response to PSL was not used to assess the risk status of newly diagnosed patients.
Treatment The treatment plan is outlined in Fig 1. All of the patients received oral PSL alone at 60 mg/m2/d for 1 week. Remission induction therapy uniformly consisted of vincristine, PSL, L-asparaginase, and pirarubicin. The first lumbar puncture was performed on day 8 concomitantly with IT injections of MTX, hydrocortisone and cytarabine (in age-adjusted doses) in all of the risk groups. This IT therapy was repeated on day 22 for the patients whose initial leukocyte counts exceeded 100 x 109/L.
After induction of complete remission, patients in the standard-risk group were randomized to receive either high-dose MTX with IT MTX (SR0) or 18 Gy of cranial irradiation with IT MTX (SR18). Early intensification therapy with etoposide, cytarabine, and 6-mercaptopurine was given to both groups. Intermediate-risk patients received essentially the same regimen, except that cyclophosphamide was administered in place of etoposide. All the patients in this risk group received cranial irradiation. Finally, the high-risk group was treated with two courses of high-dose MTX and IT MTX followed by CNS irradiation and early intensification with cyclophosphamide, cytarabine, and 6-mercaptopurine. After interim maintenance therapy with oral MTX and 6-mercaptopurine, patients began a reinduction phase with vincristine, dexamethasone, L-asparaginase, and pirarubicin. The standard-risk group received etoposide, 6-mercaptopurine and enocitabine, a cytarabine derivative, as late intensification. Intermediate-risk patients received late intensification therapy consisting of four phases: (1) PSL, etoposide, enocitabine, and aclarubicin, a doxorubicin derivative; (2) PSL, etoposide, cyclophosphamide, and L-asparaginase; (3) PSL, etoposide, enocitabine, and aclarubicin; and (4) PSL, etoposide, cyclophosphamide, and L-asparaginase. Finally, the high-risk group received two courses of high-dose cytarabine with mitoxantrone, followed by the same late intensification therapy given to intermediate-risk patients. Maintenance therapy with oral MTX and 6-mercaptopurine was administered over 1 year. The total duration of therapy was 104 weeks for each group. The total number of injections of IT therapy was nine in standard-risk patients, seven in intermediate-risk patients, and eight or nine in high-risk patients. Allogeneic stem-cell transplantation was performed in four patients, including one with Philadelphia chromosome–positive (Ph+) ALL. Autologous stem-cell transplantation was performed in two patients, including one with Ph+ ALL.
Definitions
Statistical Analysis
Clinical Outcome The remission induction rate was 93.1%. Among the 29 patients (14 boys and 15 girls) who did not enter complete remission during this phase of treatment, 19 had high-risk features. Twelve patients died of nonleukemic causes before they could receive an entire course of induction therapy, eight of infectious complications and four as a result of bleeding in major organs. In the remaining 17 patients, 14 entered complete remission with subsequent treatments. The mean EFS rate (± SE) at 6 years for all patients was 68.7% ± 2.4%. Relapse at any site ended complete remission in 102 cases (24.4%). Bone marrow was the most common site of relapse, followed by the CNS and testis (Table 2). Acute myelogenous leukemia was diagnosed at relapse in two patients and myelodysplastic syndrome in one.
Early Response to 7 days of PSL Monotherapy Three hundred ninety-three patients could be assessed for their response to initial PSL therapy. By the peripheral-blood leukemic blast cell count on day 8, 332 were considered good responders. Forty-nine percent of these patients lacked detectable blood blasts altogether. The EFS rate was strikingly higher in the good responders compared with the poor responders (Fig 2; 74.1% ± 2.5% v 40.1% ± 6.4%; P = .001). Response to PSL monotherapy showed prognostic significance in both the standard- and high-risk groups but not in patients classified as intermediate risk (Table 3). In a stepwise regression analysis (not shown), only age, leukocyte count, and response to PSL had independent prognostic significance in the overall patient population. Notably, the corticosteroid sensitivity of blast cells identified a subgroup of patients (  1 x 109 circulating blasts/L) whose failure hazard was more than twice that of the competing subgroup (risk ratio, 2.35; 95% confidence interval, 1.51 to 3.65). Neither age (1 to 9 years v 10 years) nor leukocyte count x 109/L (< 10 v 10 to 49 v 50 x 109/L) afforded this degree of prognostic discrimination.
Relation Between CNS Status on Day 8 and CNS Relapse The precise CNS status on day 8 was known for 359 patients (Table 4). Results on whether the CSF contained blasts or erythrocytes were available for 59 patients (cytocentrifuged samples were not analyzed in detail). CNS leukemia at diagnosis was inferred in four patients, three of whom had been noted on day 0 to have cranial nerve palsy and one of whom had a CNS-3 status at the initial CSF sampling (day 8). Three patients (two with CNS-2 and one with CNS-3) had detectable leukemic blasts in the CSF without bleeding. Although bleeding into the CSF was noted in 29 patients (8.1%), leukemic blasts were identified in only two. Of the 32 patients who had either erythrocytes or blasts in CSF, 17 lacked leukemic blasts in the peripheral blood on day 8.
Altogether, 18 patients experienced CNS relapse as their first adverse event: isolated CNS relapse, 14; CNS relapse combined with bone marrow relapse, three; and CNS relapse combined with testicular relapse, one (Table 2). Figure 3 shows the cumulative incidence of isolated CNS relapse and CNS relapse combined with other sites among 403 patients who entered complete remission at the initial stage of the treatment. Only two of the 18 patients with CNS relapse were judged to have had CNS leukemia at diagnosis: one had a CNS-3 status on the day 8 examination of CSF, whereas the other had cranial nerve palsy at diagnosis. Another patient had a CNS-2 status on day 8 and was not diagnosed as having CNS leukemia at presentation. The treatment arms for the 18 patients who had CNS relapse were as follows: four patients received standard-risk treatment without cranial irradiation; three received standard-risk treatment with cranial irradiation; two received intermediate-risk treatment; nine received high-risk treatment. A total of 14 patients received cranial irradiation. Prominent characteristics of the subgroup of patients who developed CNS relapse were high initial leukocyte counts (n = 5), male sex (n = 16), T-cell ALL (n = 7), and Ph+ ALL (n = 3). The remaining patients lacked known risk factors for CNS relapse, including older age, higher-risk classification at diagnosis, poor response to PSL monotherapy, and a positive CSF finding on day 8.
In principle, a delay of invasive procedures affecting the CNS might prevent relapse in this site or in the bone marrow. A study from St Jude Children’s Research Hospital showed that 114 (20.9%) of 546 patients had a traumatic lumbar puncture at diagnosis.1 The EFS rate for patients whose traumatic puncture led to blasts in the CSF was significantly worse than that for the subgroup with a traumatic puncture and no RBCs or lymphoblasts in the CSF. In our study, 29 (8.1%) of 359 patients had bleeding after the initial lumbar puncture, but blast cell contamination was rare. This outcome is best explained as a secondary effect of PSL monotherapy, which eliminated detectable blasts in the peripheral blood of nearly half of our patients. One might argue that omitting the lumbar puncture at diagnosis would eliminate opportunities to identify patients at high risk for CNS relapse who would benefit from intensive CNS-directed therapy.2 However, when the CNS status (CNS-2, CNS-3, or contaminated [traumatic]) is determined on day 0, treatment intensification may still be indicated for as many as 39% of patients.6 In our study, CNS leukemia was diagnosed in four patients on day 8 (one had CNS-3 and the other three had cranial nerve palsy at diagnosis). In our previous protocol studies, which started in 1981 (L81-10) and in 1984 (L84-11), lumbar puncture or intrathecal injection of chemotherapy on day 1 was performed only in the very high-risk group patients in L84-11. Accordingly, we cannot directly compare the results form our experience. The feasibility of eliminating initial lumbar punctures for patients not scheduled to receive prephase corticosteroid therapy is uncertain and will require testing in a controlled clinical study. The clinical impact of PSL monotherapy was less than the impact of response to the BFM prephase, using both IT MTX and variable doses of PSL.4 The European Organization for Research and Treatment of Cancer demonstrated a therapeutic systemic effect of low doses of IT MTX in childhood ALL, such that the proportion of corticosteroid good responders was higher when MTX injections were given on the first day of corticosteroid monotherapy or as soon as possible thereafter (88.5% v 79.4% for patients receiving their injections on day 8).3 This suggests that a truer estimate of blast cell sensitivity to corticosteroids can be obtained by eliminating IT MTX from the prephase regimen. Thus failure of the early blast cell response to PSL to exert significant prognostic strength in our intermediate-risk group indicates that routine corticosteroid sensitivity testing in this relatively large subset of patients may not add useful information to that available from conventional risk assessment. The cumulative risk of CNS relapse was 5.1%, and it was comparable with the relapse rate of 4.6% reported by the BFM group for patients given an IT injection of MTX at diagnosis or shortly after.4 This suggests that a delay of IT therapy does not compromise the control of CNS disease in children with ALL who receive corticosteroid monotherapy. We would qualify this conclusion with the caveat that approximately 80% of our patients received cranial irradiation as part of their preventive CNS treatment, compared with a much smaller percentage in other studies.7-9 It should also be stressed that most (65%) of the patients who relapsed in the CNS had high-risk features for this complication, including an initial leukocyte count more than 50 x 109/L, T-cell immunophenotype, and/or the Ph chromosome. Use of the early blast cell response to corticosteroids as a means to stratify patients into risk groups has gained wide acceptance among institutions that have adopted BFM-type protocols.3,4,9,10 In the context of this strategy, omission of a lumbar puncture or injection of IT therapy at diagnosis seems to be a feasible option. The impact of delaying the initial lumbar puncture and IT chemotherapy until after the corticosteroid prephase (or until after the first week of induction therapy if no prephase treatment is used) warrants further testing in a large controlled clinical study.
Supported in part by a grant from Children’s Cancer Association of Japan, Tokyo, Japan. We thank all the members of the TCCSG for their cooperation in this study. We also thank J. Gilbert for editorial assistance and critical comments.
1. Gajjar A, Harrison PL, Sandlund JT, et al: Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia. Blood 96: 3381-3384, 2000
2.
Mahmoud HH, Rivera GK, Hancock ML, et al: Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med 329: 314-319, 1993
3.
Thyss A, Suciu S, Bertrand Y, et al: Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 15: 1824-1830, 1997
4.
Reiter A, Schrappe M, Ludwig W-D, et al: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: Results and conclusions of the multicenter trial ALL-BFM 86. Blood 84: 3122-3133, 1994 5. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukaemias: French-American-British (FAB) cooperative group. Br J Haematol 33: 451-458, 1976[Medline]
6.
Pui C-H, Mahmoud HH, Rivera GK, et al: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92: 411-415, 1998
7.
Pullen J, Boyett J, Shuster J, et al: Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: A Pediatric Oncology Group Study. J Clin Oncol 11: 839-849, 1993 8. Nachman J, Sather HN, Cherlow JM, et al: Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: A report from the Children’s Cancer Group. J Clin Oncol 16: 920-930, 1998[Abstract]
9.
Kamps WA, Bokkerink LPM, Hahlen K, et al: Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: Results of Dutch Childhood Leukemia Study Group protocol ALL-7 (1998-1991). Blood 94: 1226-1236, 1999
10.
Schrappe M, Reiter A, Ludwig WD, et al: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: Results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95: 3310-3322, 2000 Submitted January 16, 2001; accepted April 3, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
