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© 2003 American Society for Clinical Oncology
Toward Optimal Central Nervous System–Directed Treatment in Childhood Acute Lymphoblastic LeukemiaSt. Jude Children’s Research Hospital and the University of Tennessee Health Science Center, Memphis, TN
AS A 5-YEAR event-free survival rate as great as 80% has been achieved in some of the clinical trials in childhood acute lymphoblastic leukemia (ALL),1–3 recent efforts to improve clinical outcome have focused on more precise risk assessment, including the status of the CNS at diagnosis, to avoid over- or undertreatment. In 1993, we reported that among patients treated in St Jude Total Therapy Studies XI and XII (1984 to 1991), any number of identifiable leukemic cells in cerebrospinal fluid (CSF) at diagnosis conferred a poor prognosis.4 Therefore, we proposed a new classification of central nervous system (CNS) status at diagnosis: CNS1 denotes the absence of identifiable leukemic blast cells in CSF; CNS2, the presence of leukemic cells in a sample that contains fewer than 5 WBCs/µL; and CNS3, a nontraumatic sample that contains Although the adverse prognosis of a CNS2 status was confirmed by the Pediatric Oncology Group,5 investigators from the Children’s Cancer Group (CCG) could not establish this association in patients treated in their CCG-105 study (1983 to 1989) for intermediate-risk ALL,6 nor could van den Berg et al7 do so in their series of 19 patients with this status. Likewise, in this issue of the Journal of Clinical Oncology, investigators from the Berlin-Frankfurt-Münster (BFM) Consortium report a lack of significant difference in overall treatment outcome between patients with a CNS1 or CNS2 status treated in their BFM-95 study (1995 to 1999).8 This apparent discrepancy can be explained by differences in treatment regimens and in the patient cohorts studied. The CCG-1056 and the BFM-958 studies featured more intensive early CNS-directed therapy than did our Studies XI and XII and incorporated early consolidation and delayed intensification (or reintensification) therapies, which were not included in our studies.4 In the BFM trial, intrathecal therapy was administered with the diagnostic lumbar puncture and repeated on day 12; patients with a CNS2 status received two additional intrathecal treatments during remission induction. In contrast, in Studies XI and XII, patients first received intrathecal therapy 1 to 2 days after the diagnostic lumbar puncture. This practice could have adversely affected the distribution of drugs because of contraction or collapse of the subarachnoid space due to leakage of the CSF or to external compression by a puncture-induced epidural hematoma or hygroma or subarachnoid hematoma, preventing access to free-flowing CSF. Furthermore, in those two studies, the second intrathecal injection was delayed until day 22, and there was no provision for administration of additional intrathecal treatments in cases with blasts in the CSF, with the exception of those meeting the conventional criteria of CNS leukemia (ie, CNS3 status). This strategy reflected our lack of awareness at that time of the prognostic or therapeutic implication of small numbers of leukemic cells in CSF. It should be noted that among patients in the CCG-105 study who did not receive cranial irradiation, there was a trend toward an increased frequency of isolated CNS relapse in CNS2 cases, as compared with CNS1 cases (11.8% v 6.5%; hazard ratio, 1.85; 95% confidence interval, 0.80 to 4.30).6 Despite a similar overall event-free survival rate, the cumulative incidence of any CNS relapse (isolated plus combined) in the BFM-95 study was three times greater in CNS2 than in CNS1 patients (10% v 3.5%).8 Likewise, in the EORTC 58881 study (1989 to 1998)9 in which intrathecal therapy was given with the diagnostic lumbar puncture, repeated on day 8, and, for CNS2 cases, administered for two additional doses during remission induction, CNS2 patients had a similar event-free survival rate, but the rate of any CNS relapse was twice as high as that of CNS1 patients, prompting the investigators to further intensify intrathecal therapy for patients with CNS2 status in their current clinical trial (E. Vilmer, personal communication, October 2002). In a recent CCG study of patients of all risk groups who were enrolled in four concurrent clinical trials between 1988 and 1993, CNS2 patients in the cohort with presenting leukocyte counts greater than 50 x 109/L or age greater than 10 years had an increased risk for both hematologic and CNS relapse as compared with CNS1 patients.10 Moreover, in a preliminary analysis of the CCG-1952 study (1995 to 2001) for patients with standard-risk ALL, CNS2 was also an adverse prognostic factor (J. Nachman, personal communication, October 2002). Notwithstanding these findings, intensified treatment could alter the clinical significance of the CNS2 status. To this end, in our subsequent Studies XIIIA (1991 to 1994)11 and XIIIB (1994 to 1998), reinduction treatment was given to all patients and intrathecal therapy was intensified, not only during remission induction (four weekly doses) but also during the first year of postremission therapy (every 4 weeks) for CNS2 patients. In Studies XIIIA and XIIIB, the cumulative incidence of any CNS relapse in CNS2 cases was reduced to 2.5% ± 2.5% and 4.0% ± 2.3%, respectively (unpublished data, CH Pui). An important distinction should be made between small numbers of blast cells present in the CSF during postremission therapy and at diagnosis of ALL. Indeed, in the CCG-105 study, the isolated occurrence of blast cells in CSF with a normal total cell count during postremission therapy was not associated with an adverse prognosis in patients with intermediate-risk ALL.12 Conceivably, these cells might represent reactive lymphoid cells or perhaps residual leukemic cells that eventually succumb to therapy. Whatever the explanation, the leukemic nature of the cells must be established by repeated examinations, preferably with terminal deoxynucleotidyl transferase testing or immunophenotyping, before therapeutic intervention is warranted.
The most important finding of this BFM study was an increased cumulative incidence of any CNS relapse (8%) in association with traumatic lumbar puncture ( Even though intensive intrathecal therapy can abolish the poor prognostic impact of a traumatic lumbar puncture with blasts, it can also adversely affect neuropsychologic and spinal cord function.15–17 Since the recognition of the adverse consequences of traumatic lumbar puncture, we have routinely performed this procedure under deep sedation or general anesthesia, and intrathecal chemotherapy is always administered immediately after the collection of CSF. We have also begun to identify risk factors for traumatic lumbar puncture.18 One of the modifiable risk factors is the experience of the clinician; hence, diagnostic lumbar punctures at our institution are now performed by the most experienced clinicians. Another such risk factor is a low platelet count (< 100 x 109/L). The lower rate of traumatic lumbar puncture (12.2%) in the BFM study compared with ours (21%) can be attributed largely to the more frequent use of platelet transfusions before the procedure in thrombocytopenic patients. We previously reported data indicating that lumbar puncture is generally safe in patients with thrombocytopenia,19 arguing against the use of prophylactic platelet transfusions before this procedure. In light of the adverse consequences of a traumatic diagnostic lumbar puncture, however, we have modified our strategy to include such transfusions for all thrombocytopenic patients before they receive their initial puncture. Together, these preventive measures have lowered the frequency of traumatic lumbar puncture at diagnosis with or without blasts to 4% each in our current trial. We still contend that platelet transfusions are not necessary with subsequent lumbar punctures in patients who lack circulating blasts, especially during remission induction therapy with prednisone, vincristine, and L-asparaginase, which generally induce a hypercoagulable state.20 Other investigators have taken a different approach, delaying diagnostic lumbar puncture and intrathecal chemotherapy until 1 week after prednisolone treatment, when circulating blasts are substantially reduced or eliminated in half the patients.21 However, 1 week of prednisolone treatment may also clear some of the blasts from CSF, obscuring the diagnosis of a CNS2 or CNS3 status and jeopardizing the precise application of subsequent risk-directed therapy. Indeed, on day 8 of treatment, the rate of traumatic lumbar puncture with blasts was very low in that study (0.6%), but so were the rates of CNS2 (0.6%) and CNS3 status (0.3%). Despite administration of cranial irradiation in approximately 80% of patients, the frequency of any CNS relapse was 5.1% (95% confidence interval, 2.7% to 7.4%). Most contemporary clinical trials limit the use and dose of cranial irradiation because of concern over late sequelae.2,22 In fact, two studies have omitted cranial irradiation in all patients regardless of their risk classification, resulting in rates of isolated CNS relapse of 4.2% and 3% and of any CNS relapse of 8.3% and 6%, respectively.9,23 With more precise assessment of initial risk factors, prevention of traumatic lumbar puncture, and use of optimal intrathecal and systemic chemotherapy, one would predict further reductions in the CNS relapse hazard. It would also be of interest to study whether the use of a small-gauge or blunt "pencil-point" spinal needle can improve CNS control by preventing leakage of CSF and intrathecal chemotherapy. REFERENCES
1. Pui C-H, Evans WE: Acute lymphoblastic leukemia. N Engl J Med 339:605–615, 1998
2. 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
3. Silverman LB, Gelber RD, Dalton VK, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana Farber Consortium Protocol 91-01. Blood 97:1211–1218, 2001
4. 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 5. Lauer S, Shuster J, Kirschner P, et al: Prognostic significance of cerebrospinal fluid (CSF) lymphoblasts (LB) at diagnosis (dx) in children with acute lymphoblastic leukemia (ALL). Proc Am Soc Clin Oncol 13:317, 1994 (abstr 1041)
6. Gilchrist GS, Tubergen DG, Sather HN, et al: Low numbers of CSF blasts at diagnosis do not predict for the development of CNS leukemia in children with intermediate-risk acute lymphoblastic leukemia: A Children’s Cancer Group report. J Clin Oncol 12:2594–2600, 1994 7. van den Berg H, Vet R, den Ouden E, et al: Significance of lymphoblasts in cerebrospinal fluid in newly diagnosed pediatric acute lymphoblastic malignancies with bone marrow involvement: Possible benefit of dexamethasone. Med Pediatr Oncol 25:22–27, 1995[Medline]
8. Bürger B, Zimmermann M, Mann G, et al: Diagnostic cerebrospinal fluid (CSF) examination in children with acute lymphoblastic leukemia (ALL): Significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol 21:184–188, 2003 9. Vilmer E, Suciu S, Ferster A, et al: Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: A CLCG-EORTC report. Leukemia 14:2257–2266, 2000[CrossRef][Medline] 10. Nachman J, Cherlow J, Sather HN, et al: Effect of initial central nervous system (CNS) status on event-free survival (EFS) in children and adolescents with acute lymphoblastic leukemia (ALL). Med Pediatr Oncol 39:277, 2002 (abstr SL 035)[CrossRef]
11. Pui CH, 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 12. Tubergen DG, Cullen JW, Boyett JM, et al: Blasts in CSF with a normal cell count do not justify alteration of therapy for acute lymphoblastic leukemia in remission: A Children’s Cancer Group study. J Clin Oncol 12:273–278, 1994[Abstract]
13. 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 14. Gaynon PS, Trigg ME, Heerema NA, et al: Children’s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983–1995. Leukemia 14:2223–2233, 2000[CrossRef][Medline] 15. Prassopoulos P, Cavouras D, Golfinopoulos S, et al: Quantitative assessment of cerebral atrophy during and after treatment in children with acute lymphoblastic leukemia. Invest Radiol 31:749–754, 1996[CrossRef][Medline] 16. Vainionpaa L, Kovala T, Tolonen U, et al: Chemotherapy for acute lymphoblastic leukemia may cause subtle changes of the spinal cord detectable by somatosensory evoked potentials. Med Pediatr Oncol 28:41–47, 1997[CrossRef][Medline]
17. Hill DE, Ciesielski KT, Sethre-Hofstad L, et al: Visual and verbal short-term memory deficits in childhood leukemia survivors after intrathecal chemotherapy. J Pediatr Psychol 22:861–870, 1997
18. Howard SC, Gajjar AJ, Cheng C, et al: Risk factors for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia. JAMA 288:2001–2007, 2002
19. Howard SC, Gajjar A, Ribeiro RC, et al: Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia. JAMA 284:2222–2224, 2000 20. Pui CH, Jackson CW, Chesney C, et al: Sequential changes in platelet function and coagulation in leukemic children treated with L-asparaginase, prednisone, and vincristine. J Clin Oncol 1:380–385, 1983[Abstract]
21. Manabe A, Tsuchida M, Hanada R, et al: 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 L89-12. J Clin Oncol 19:3182–3187, 2001
22. Pui C-H: Cure of childhood ALL: Exacting a lower toll. Blood 99:4255, 2002 23. Manera R, Ramirez I, Mullins J, et al: Pilot studies of species-specific chemotherapy of childhood acute lymphoblastic leukemia using genotype and immunophenotype. Leukemia 14:1354–1361, 2000[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5 WBCs/µL with identifiable blasts, or the presence of a cerebral mass or cranial nerve palsy with leukemic cells in CSF.
