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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3915-3922 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.0700 Prevalence, Clinical Pattern, and Outcome of CNS Involvement in Childhood and Adolescent Non-Hodgkin's Lymphoma Differ by Non-Hodgkin's Lymphoma Subtype: A Berlin-Frankfurt-Münster Group Report
From the Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen; Department of Hematopathology and Lymph Node Registry, and Children's University Hospital, University Hospital Schleswig-Holstein, Campus Kiel, Kiel; Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Clinic at the HELIOS Klinikum Berlin-Buch, Charité Medical School, Berlin; Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany; Department of Pediatric Hematology and Oncology, Children's University Hospital Zurich, Zurich, Switzerland; and Department of Pediatric Hematology and Oncology, St Anna Children's Hospital, Vienna, Austria Address reprint requests to Alfred Reiter, MD, NHL-BFM Study Center, Department of Pediatric Hematology and Oncology, Justus-Liebig-University, D-35385 Giessen, Germany; e-mail: alfred.reiter{at}paediat.med.uni-giessen.de
Purpose We analyzed the prevalence, clinical pattern, and prognostic impact of CNS involvement in a large cohort of children and adolescents diagnosed with non-Hodgkin's lymphoma (NHL), with special attention to differences according to NHL subtype. Patients and Methods From October 1986 to December 2002, 2,381 patients (median age, 9.37 years; range, 0.2 to 23.8 years; female-to-male ratio, 1:2.7) from Germany, Austria, and Switzerland were registered. A total of 2,086 patients were eligible for the consecutive multicenter protocols NHL–Berlin-Frankfurt-Münster [BFM] -86, NHL-BFM-90, and NHL-BFM-95, and could be evaluated for outcome. Results CNS involvement was diagnosed in 141 (5.9%) of 2,381 patients and was associated with an advanced stage of NHL. The percentage of CNS-positive patients was 8.8% for Burkitt's lymphoma/Burkitt's leukemia (BL/B-ALL), 5.4% for precursor B–lymphoblastic lymphoma (pB-LBL), 3.3% for anaplastic large-cell lymphoma, 3.2% for T-cell–LBL, 2.6% for diffuse large B-cell lymphoma, and 0% for primary mediastinal large B-cell NHL (P < .001). Most CNS-positive patients with pB-LBL, T-LBL, or BL/B-ALL had meningeal disease. The probability of event-free survival (pEFS; ± SE) at 5 years was 85% ± 1% for the 2,086 protocol patients (median follow-up, 6.5 years; range, 0.3 to 17.7 years). For the 112 CNS-positive patients, pEFS was 64% ± 5%, compared with 86% ± 1% for the 1,927 CNS-negative patients (P < .001). Although CNS disease had no impact on pEFS for advanced-stage T-LBL patients, CNS-positive patients with BL/B-ALL had a worse average outcome than CNS-negative patients with stage IV BL/B-ALL (60% ± 5% v 81% ± 3%; P < .001). In multivariate analysis, CNS disease was the strongest predictor for relapse in BL/B-ALL patients with advanced-stage disease. Conclusion Six percent of childhood/adolescent NHL patients were CNS positive. However, the prevalence, pattern, and prognostic impact of CNS involvement differed among NHL subtypes.
There have been major advances in the treatment of children and adolescents suffering from non-Hodgkin's lymphoma (NHL).1-8 Most importantly, it is now known that different subtypes of NHL require different treatment modalities.9,10 However, important issues such as the optimal treatment of patients with overt CNS involvement at diagnosis still merit clarification. Moreover, there is a paucity of research offering comprehensive analysis of the prevalence, clinical pattern, and prognostic impact of CNS involvement for different histologic subtypes of NHL. The few available studies either address a particular subtype of NHL or report single-center observations.11-13 In addition, the associations between CNS involvement and the pattern and extent of extra-CNS manifestations have been poorly evaluated. Even the definition of CNS disease differs across published reports.7,8,11-13 The purpose of this study was to provide a comprehensive analysis of the prevalence, clinical pattern, and prognostic impact of CNS involvement for different histologic subtypes of NHL in a large unselected cohort. We analyzed 2,381 children and adolescents from Germany, Austria, and Switzerland who were diagnosed with any type of NHL and registered in the Berlin-Frankfurt-Münster (BFM) multicenter studies between October 1986 and December 2002. Studies were conducted in accordance with the Declaration of Helsinki, and approval was obtained from the ethical committee of the principal investigators (H.R. and A.R.).
Patients From October 1986 to December 2002, 2,381 children and adolescents from 99 institutions in Germany, Austria, and Switzerland who were diagnosed with any subtype of NHL were registered after informed consent of the patient and/or guardian. A total of 295 patients were deemed ineligible for one of the following reasons: inability to confirm diagnosis of NHL (n = 12; relapse, n = 3), immunodeficiency/HIV (n = 33; relapse, n = 10), organ transplantation (n = 28; relapse, n = 7), NHL was the second malignancy (n = 17; relapse, n = 1), inadequate therapy (n = 87; relapse, n = 23), previous chemotherapy/radiotherapy (n = 49; relapse, n = 8), patient participation in a pilot protocol (n = 27; relapse, n = 5), lack of clinic participation in the study (n = 30; relapse, n = 6), and other (n = 12; relapse, n = 3). Thus, 2,086 patients were included in the outcome analysis. Although patients with Burkitt's lymphoma (BL) and  25% bone marrow (BM) blasts (Burkitt’s leukemia [B-ALL]) were treated in the NHL-BFM trials, patients with lymphoblastic lymphoma (LBL) and 25% BM blasts were enrolled onto the ALL trials and excluded from this analysis. Seventy patients diagnosed since January 2000 with anaplastic large cell lymphoma (ALCL) were enrolled onto the international trial ALCL-99 and were not included in this analysis.
Diagnosis, Classification, and Staging Staging was accomplished by physical examination, peripheral-blood and BM aspiration smears, lumbar puncture and examination of CSF, ultrasonography, chest x-ray, cranial computed tomography and/or cranial magnetic resonance imaging, and determination of serum lactate dehydrogenase (LDH) concentration. The St Jude staging system was used.15 CNS involvement was diagnosed based on fulfillment of at least one of the following criteria: intracerebral mass(es) (ICM) on cranial computed tomography/cranial magnetic resonance imaging; cranial nerve palsy (CNP) not caused by an extradural mass (not in study NHL-BFM 86); and morphologically identifiable blasts in the CSF. In patients with LBL, more than 5 cells/µL CSF were also required. LBL patients with less than 5 cells/µL were diagnosed as CSF negative but received two additional doses of intrathecal (IT) chemotherapy during induction. Epidural NHL in the absence of fulfillment of the above criteria was not considered CNS disease. To evaluate whether initial CNS disease was associated with otherwise advanced-stage disease, each patient was restaged without consideration of CNS status to obtain what will be referred to as the adjusted stage.
Treatment CNS-positive patients with mature B-cell NHL (B-NHL) or ALCL received six courses of 5- to 7-day chemotherapy based on dexamethasone, cyclophosphamide, ifosfamide, 5 g/m2 intravenous MTX, doxorubicin, etoposide, cytarabine, and IT triple-drug therapy. In trial NHL-BFM-86, IT MTX/cytarabine/prednisolone was applied two times during each course. In studies NHL-BFM-90 and NHL-BFM-95, an Ommaya reservoir was implanted before the second course, and patients received intraventricular, triple-drug chemotherapy. Only ALCL patients with CNS disease received CRT. However, during study NHL-BFM-86, two of five CNS-positive B-NHL patients received CRT based on individual decisions. Details of the treatments have been described previously.1-4,9,16-18
Statistical Analysis The prevalence and clinical pattern of CNS involvement were analyzed in the total cohort of 2,381 patients. Outcome analyses were restricted to the 2,086 patients who were eligible for study protocols. Statistical analysis was performed using the SAS program (SAS, version 9.1; SAS Institute Inc, Cary, NC). Data were updated by October 2005.
Patient Characteristics Patient characteristics are shown in Table 1. The median age was 9.37 years (range, 0.2 to 23.8 years). BL/B-ALL was the most frequent diagnosis, followed by T-cell LBL (T-LBL), diffuse large B-cell lymphoma (DLBCL), ALCL, precursor B-cell LBL (pB-LBL), and primary mediastinal large B-cell lymphoma (PMLBL). A total of 251 patients suffered from rarer subtypes of childhood NHL or NHL that was not classified further (other).
Prevalence of CNS Disease A total of 141 patients (5.9%) were CNS positive and 2,170 patients (91.1%) were CNS negative (Table 1). Three LBL patients had less than 5 cells/µL CSF and cytomorphologic blasts. One of these patients remained in complete remission, one died as a result of BM relapse, and one developed a second cancer. In 67 patients (2.8%), CNS status at diagnosis could not be determined definitively because of treatment before evaluation of CSF (n = 38) or inappropriate CSF cytospin preparation (n = 22). In seven B-ALL patients, CNS status could not be evaluated because of blood contamination. Sixty-four of 67 patients with unspecified CNS status were treated as CNS negative, four of whom experienced relapse. One of the three patients treated as CNS positive experienced relapse. The CNS was not involved in any of the five relapses. CNS involvement was significantly more frequent in BL/B-ALL patients compared with all other NHL subgroups (P < .001); none of the 42 PMLBL patients had CNS involvement. Three of 33 patients with pre-existing immunodeficiency or HIV infection had CNS disease. Analyses of the total group and specific NHL subgroups revealed no significant differences between CNS-negative and CNS-positive patients with regard to age and sex.
Clinical Pattern of CNS Disease
Treatment Outcome A total of 2,086 patients could be evaluated for treatment outcome. Of these patients, 112 (5.4%) were CNS positive and 1,927 (92.4%) were CNS negative. For 44 patients (2.1%), CNS-status was not determined definitely, and three LBL patients had blasts but less than 5 cells/µL in the CSF. With a median follow-up of 6.5 years (range, 0.3 to 17.7 years), pEFS (± SE) at 5 years was 85% ± 1% for the total group of 2,086 patients; for patients treated according to protocols NHL-BFM-86, NHL-BFM-90, and NHL-BFM-95, pEFS at 5 years was 80% ± 2% (n = 302), 87% ± 1% (n = 777), and 84% ± 1% (n = 1,007), respectively (P = .08). pEFS at 5 years was 64% ± 5% for the 112 CNS-positive patients and 86% ± 1% for the 1,927 CNS-negative patients (P < .001; Fig 1A). pEFS at 5 years was 82% ± 6% for the 44 patients for whom initial CNS status was not definitely determined. Considering only the patients with stage IV disease, including B-ALL, pEFS at 5 years was significantly lower for CNS-positive versus CNS-negative patients. However, the effect of CNS involvement on outcome differed across the subgroups. In BL/B-ALL patients, pEFS at 5 years was significantly lower for CNS-positive versus CNS-negative patients with stage IV/B-ALL (Fig 1B). The worse outcome for CNS-positive BL/B-ALL patients was due to a significantly higher cumulative index of relapse (29.9% ± 5.6% for CNS-positive patients v 11.5% ± 2.4% for CNS-negative stage IV patients; P < .001). In contrast, in T-LBL patients, the pEFS at 5 years for CNS-positive patients was comparable to that for CNS-negative patients with stage IV disease (Fig 1C). Because of the small numbers of patients, comparisons of pEFS at 5 years between CNS-positive and CNS-negative patients with stage IV disease for the other NHL subtypes were not meaningful.
Cox regression analysis of 614 BL/B-ALL patients with stage III/IV disease revealed that CNS involvement was a stronger predictor of treatment failure (risk ratio, 2.82; 95% CI, 1.78 to 4.47; P < .001) than was LDH 1,000 U/L (risk ratio, 1.72; 95% CI, 1.12 to 2.64; P = .013) and BM involvement (risk ratio, 1.20; 95% CI, 0.76 to 1.90; P = .43). However, in the initial pattern of CNS-disease, CSF cell count (< 5 v 5 cells/µL CSF), adjusted stage, BM involvement, and LDH had no significant impact on the cumulative index of relapse in CNS-positive BL/B-ALL patients (Table 4).
Table 5 summarizes the site of failure for CNS-positive and CNS-negative patients. Twenty-nine of 112 CNS-positive patients experienced tumor failure, only seven of these patients (three with isolated CNS relapse) survived. The CNS was the most frequent site of relapse in CNS-positive patients, especially in BL/B-ALL. Eleven of the 24 relapses in CNS-positive BL/B-ALL occurred during treatment.
Outcome of Patients With Epidural Tumors Thirty-eight patients with epidural tumors were evaluated for treatment outcome (T-LBL, n = 1; pB-LBL, n = 7; BL/B-ALL, n = 22; DLBCL, n = 2; ALCL, n = 4; and other, n = 2). The pEFS at 5 years was 85% ± 10% for 13 CNS-positive patients (two relapses with involvement of CNS) and 87% ± 7% for 25 patients diagnosed and treated as CNS negative (one death from initial complications and two relapses, one with CNS involvement; P = .78). For four patients, CNS-status could not be evaluated; none of these patients failed to respond to therapy.
We analyzed the prevalence, clinical pattern, and prognostic impact of CNS involvement in a cohort of 2,381 children and adolescents newly diagnosed with any type of NHL during a period of 16 years and treated according to three NHL-BFM multicenter trial protocols. Treatment of CNS-positive patients was almost identical in the three protocols. Staging, including CNS evaluation, was identical for all patients. In the total cohort, 5.9% of patients had CNS involvement, which was comparable to a previous report of a smaller single-center series.13 Both the prevalence and clinical pattern of CNS disease differed significantly between the NHL subgroups. CNS involvement was most frequent in BL/B-ALL followed by pB-LBL, T-LBL, ALCL, and DLBCL; CNS involvement was absent in PMLBL patients. CSF blasts was the most frequent pattern of CNS disease in pB-LBL, T-LBL, and BL/B-ALL, whereas ICM with or without CNP was the predominant pattern in DLBCL and ALCL. Approximately 30% of CNS-positive patients had CNP. Primary CNS lymphoma was a rare observation and almost absent in LBL and BL/B-ALL patients. Nine of 10 patients with primary CNS lymphoma had an ICM, and one patient (with ALCL) had isolated meningeal disease. CNS involvement was associated with an otherwise advanced stage of disease. Only 10 of 141 CNS-positive patients had adjusted stage I/II disease, and all had a head and neck primary. Thus, this localization might be a risk factor for CNS involvement, although there was no significant association between CNS disease and head/neck manifestation in the full group of patients with all stages of disease.13 CNS involvement was associated with epidural, bone, BM, abdominal, and mediastinal sites, although the strength of the association differed according to the NHL subtype. CNS disease was not associated with sex or age at diagnosis. Interestingly, CNS involvement was not significantly more frequent in patients with immunodeficiency syndromes. Treatment outcome was inferior for CNS-positive versus CNS-negative patients, although not for all NHL subgroups. Although CNS-positive patients with BL/B-ALL had a poorer average outcome than CNS-negative patients with advanced-stage BL/B-ALL, CNS-positive and CNS-negative T-LBL patients had comparable outcomes. The inferior outcome of CNS-positive patients with BL/B-ALL was due primarily to a higher rate of tumor failure compared with CNS-negative patients with BL stage IV or B-ALL. In contrast to observations in previous studies, in our series of 81 CNS-positive patients with BL/B-ALL, aside from CNS involvement, no parameter (not the adjusted stage, BM involvement, or LDH) affected the outcome.12,13,24 The pattern of CNS disease might affect treatment outcome. Patients with CNP alone had fewer relapses compared with patients with CSF blasts and/or ICMs, although the difference was not statistically significant. However, patients with an ICM without CSF blasts did not have a better outcome than those with meningeal disease. Interestingly, only one of our 10 patients with primary CNS lymphoma experienced treatment failure. This patient had ALCL confined to the meninges and experienced relapse shortly after treatment that included CRT, with repeat diagnosis of meningeal disease. In contrast to the findings for BL/B-ALL patients, CNS involvement did not negatively affect treatment results for LBL patients in our cohort. The main difference in CNS treatment of the two subgroups was that CRT was included in the treatment of CNS-positive LBL patients but was omitted for CNS-positive B-NHL patients since study NHL-BFM-90. In the absence of a randomized trial, which might be infeasible because of the limited number of patients, it is difficult to determine whether CRT is beneficial for CNS-positive B-NHL patients, especially BL patients. Observations from other studies using CRT for CNS-positive B-NHL patients do not support a favorable impact of CRT.7,12,25 In the multinational trial, French-American-British (FAB) 96 treatment of CNS-positive B-NHL patients was based on the French Lymphoma Malignancy B (LMB) 89 protocol. However, CRT was omitted and replaced by an additional dose of 8 g/m2 MTX. The pEFS at 4 years for CNS-positive patients in these studies was 71% (FAB-96) and 77% (LMB-89), respectively.7,24,25 In our previous NHL-BFM-90 and NHL-BFM-95 studies, CNS-positive B-NHL patients received intraventricularly administered triple-drug therapy to achieve a better distribution within the CSF.26 Furthermore, MTX was fractionated during 4 days to achieve a higher concentration over time.27 The outcome for CNS-positive B-NHL patients in these studies was comparable to that in studies LMB-89 and FAB-96, in which MTX and cytarabine were administered via lumbar puncture.3,4,7,24 It is also difficult to discern whether the route and schedule of IT administration of MTX and cytarabine affect treatment efficacy. Our analysis yields several conclusions and questions regarding the future management of patients. The prevalence, pattern, prognostic impact, and optimal modality of CNS therapy differ between NHL subgroups of childhood and adolescence; thus, accurate classification is mandatory. ICM without CSF blasts and without CNP was observed in patients from all NHL subgroups, although it was observed only rarely; thus, cranial imaging seems warranted for all patients. In addition, there is need for a standardized definition of CNS disease. Although ICM and the presence of NHL cells in the CSF are generally accepted criteria for CNS disease, other criteria differ across studies.7,8,11-13 In LBL patients, the criterion used by our group and others is the presence of more than 5 CSF cells/µL and the identification of blasts.28 The primary differences in criterion relate to whether spinal cord compression is sufficient to define CNS involvement. Although in our cohort overt CNS disease was associated significantly with epidural manifestations, two of three of our patients with epidural tumors were diagnosed and treated as CNS negative. Only three of those 25 patients suffered from relapse (one patient had CNS involvement). Although CNP (unrelated to a facial tumor) is widely used to diagnose CNS disease, in our series and in others, patients with CNP alone had a trend for better outcome than those with meningeal disease and/or ICM, whereas in another report there was no impact on outcome.12,13 Patients with DLBCL and PMLBL rarely had CNS involvement and no CNS relapse was observed in our group of patients. Thus, with the exception of the few CNS-negative patients with head and neck disease, it is unclear whether CNS-negative patients diagnosed with one of these NHL subtypes need IT therapy. There is a need for improved treatment efficacy for CNS-positive BL/B-ALL patients. Systemic and IT rituximab and IT liposomal cytarabine may be new options.29,30 However, chemotherapy may still offer the possibility for improvement. In the LMB and BFM protocols, the introduction of high-dose MTX and HD cytarabine combined with intensive IT chemotherapy improved the outcome for CNS-positive patients.3,4,7,17,25,31 In the LMB protocol, the dose of MTX is 8 g/m2, whereas in the BFM protocol the dose is 5 g/m2 and the intravenous MTX infusion time is longer. However, for high-risk patients, a 24-hour intravenous infusion of MTX 5 g/m2 was significantly more effective than a 4-hour infusion.4 A higher dose of MTX and a longer infusion time (24 hours) might be a reasonable option for investigating improvement of outcome for BL/B-ALL patients with overt CNS-disease.
The author(s) indicated no potential conflicts of interest.
Conception and design: Janina Salzburg, Martin Zimmermann, Felix Niggli, Georg Mann, Helmut Gadner, Hansjoerg Riehm, Martin Schrappe, Alfred Reiter Administrative support: Martin Schrappe, Alfred Reiter Provision of study materials or patients: Janina Salzburg, Birgit Burkhardt, Olga Wachowski, Wilhelm Woessmann, Ilske Oschlies, Wolfram Klapper, Hans-Heinrich Wacker, Wolf-Dieter Ludwig, Felix Niggli, Georg Mann, Hansjoerg Riehm, Martin Schrappe, Alfred Reiter Collection and assembly of data: Janina Salzburg, Birgit Burkhardt, Martin Zimmermann, Olga Wachowski, Wilhelm Woessmann, Ilske Oschlies, Wolfram Klapper, Hans-Heinrich Wacker, Wolf-Dieter Ludwig, Felix Niggli, Georg Mann, Helmut Gadner, Hansjoerg Riehm, Alfred Reiter Data analysis and interpretation: Janina Salzburg, Birgit Burkhardt, Martin Zimmermann, Helmut Gadner, Alfred Reiter Manuscript writing: Janina Salzburg, Birgit Burkhardt, Martin Zimmermann, Alfred Reiter Final approval of manuscript: Janina Salzburg, Birgit Burkhardt, Martin Zimmermann, Olga Wachowski, Wilhelm Woessmann, Ilske Oschlies, Wolfram Klapper, Hans-Heinrich Wacker, Wolf-Dieter Ludwig, Felix Niggli, Georg Mann, Helmut Gadner, Hansjoerg Riehm, Martin Schrappe, Alfred Reiter
The following reference pathologists participated in this study: R. Parwaresch, Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel; A. Feller, Institute of Pathology, University Holspital Schleswig-Holstein, Campus Lübeck; M.L. Hansmann, Institute of Pathology, University of Frankfurt; P. Möller, Institute of Pathology, University of Ulm; H.K. Müller-Hermelink, Institute of Pathology, University of Wuerzburg; H. Stein, Institute of Pathology, Free University Berlin; I. Simonitsch, Institute of Pathology, University of Vienna, Austria.
We thank Edelgard Odenwald, Gabriele Buck (cytomorphology), Ulrike Meyer, and Bettina Paul (data management) for their expert work; we also thank the doctors, nurses, and data managers at the participating hospitals who cared for these sick children and supplied data.
Supported by the Deutsche Krebshilfe, Bonn, Germany. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher's exact test. Probability of event-free survival (pEFS) at 5 years was calculated from the date of diagnosis to the first event (death as a result of any cause, tumor progression, tumor relapse, nonresponse, or second malignancy) or to the date of last follow-up using the Kaplan and Meier method. Differences were compared using the log-rank test, and the SE was calculated according to the method of Greenwood.
