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Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy
original article
Annals of Oncology 21: 1046–1052, 2010 doi:10.1093/annonc/mdp432 Published online 27 October 2009
Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy D. Villa1, J. M. Connors1, T. N. Shenkier1, R. D. Gascoyne2, L. H. Sehn1 & K. J. Savage1* Divisions of 1Medical Oncology and 2Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Received 24 July 2009; accepted 3 August 2009
original article
prednisone) chemotherapy improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the risk of central nervous system (CNS) relapse in the R-CHOP in a population-based cohort of patients with DLBCL. Methods: Patients with DLBCL diagnosed from 1 September 1999 to 14 January 2005 at the British Columbia Cancer Agency (BCCA) were identified. Patients were included if they were ‡16 years old with advanced stage or any stage with testicular involvement and were treated with CHOP (1999–2001) or R-CHOP (2001–2005) with curative intent. Results: Four hundred and thirty-five patients were identified; 126 (29%) were treated with CHOP and 309 (71%) with R-CHOP. With a median follow-up of 5.7 years, there were 31 CNS relapses in total with a trend to a reduced likelihood of CNS relapse in R-CHOP-treated patients (3-year risk 9.7% versus 6.4, P = 0.085). In multivariate analysis, the use of rituximab significantly reduced the risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]; this benefit was more striking in patients who achieved a complete response (HR 0.18, P = 0.005). Conclusion: The use of R-CHOP appears to reduce the overall risk of CNS relapse in patients with DLBCL particularly in patients who achieve a complete response. Key words: central nervous system, CNS relapse, diffuse large B-cell lymphoma, DLBCL, R-CHOP, rituximab
introduction Secondary central nervous system (CNS) involvement is an infrequent yet nearly always fatal event in diffuse large B-cell lymphoma (DLBCL). The reported incidence ranges from 5% to 25%, depending on the population studied, associated risk factors present, and the accuracy of the diagnostic tests used [1, 2]. Relapses can occur in the brain parenchyma, leptomeningeal compartment, or both and can take place as an isolated event or as part of widespread disease progression. With largely ineffective therapy available for secondary CNS relapse, prophylaxis is often administered at the time of primary therapy. The high propensity for CNS relapse Burkitt’s lymphoma has led to the administration of routine CNS prophylaxis in the form of intrathecal (IT) chemotherapy and high-dose methotrexate (HDMTX) with the primary therapy. With this approach, there has been a reduction in the incidence of CNS relapse and improved outcome in this type of aggressive lymphoma [3, 4]. Several studies have identified patients at higher risk of CNS relapse in DLBCL including those with advanced-stage disease, involvement of specific extranodal sites *Correspondence to: Dr K. J. Savage, Division of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada BC V5Z 4E6. Tel: +1-604-877-6000; Fax: +1-604-877-0585; E-mail: [email protected]
(e.g. bone marrow, sinus, and testes), and multiple extranodal sites of disease. However, although high-risk groups can be easily identified, the demonstration of a clear benefit of CNS prophylaxis has been elusive, and thus, the use of CNS prophylaxis remains controversial. The survival of patients with DLBCL has improved dramatically with addition of the chimeric anti-CD20 mAb rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) [5–9]. Whether the improvement in outcome is related in part to a reduction in the risk of CNS relapse is unknown. Limited data indicate no [10] or a marginal [11] benefit. We evaluated the risk and types of CNS relapse in addition to the associated risk factors in a large population-based cohort of patients with DLBCL treated with addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in comparison to CHOP.
methods patient selection All patients with DLBCL and primary mediastinal large B-cell lymphoma (PMBCL), diagnosed from 1 September 1999 to 14 January 2005, with a minimum follow-up of 18 months, were identified in the British
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Background: The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and
Annals of Oncology
Columbia Cancer Agency (BCCA) Lymphoid Cancer Database, including those from a recently published report [12]. Patients were included if they were ‡16 years of age and had advanced-stage disease [stage III/IV or stage I/II with B symptoms and/or bulky disease (‡10 cm)]. Patients with testicular DLBCL, regardless of stage, were also included in this analysis. Human immunodeficiency virus-positive individuals and those with CNS involvement at diagnosis were excluded. Evaluation of the CNS at diagnosis by either computed tomography/magnetic resonance imaging (CT/MRI) or lumber puncture with cerebrospinal fluid (CSF) analysis was carried out only if clinically indicated. All patients received at least one cycle of chemotherapy with curative intent. After 1 March 2001, all patients received R-CHOP. Patients with testicular lymphoma also received scrotal irradiation. Baseline clinical characteristics including the International Prognostic Index (IPI) score as well as the type and number of extranodal sites were recorded. In those patients who relapsed, the sites of relapse were documented. This study was approved by the University of British Columbia BCCA Research Ethics Board.
CNS prophylaxis
statistical analysis The primary study end point was the time to central nervous system relapse (TTCNS) diagnosed by CT or MRI imaging, pathology, or clinical symptomatology. TTCNS was calculated from the date of pathological diagnosis of lymphoma to the date of CNS relapse. Overall survival (OS) was calculated from the date of initial diagnosis (or from the date of CNS relapse where applicable) to the date of last follow-up or death from any cause. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of first disease progression or relapse following treatment or death from toxicity during therapy. Patients alive and without progressive disease were censored on the date of their last follow-up visit, and patients who died of causes unrelated to the lymphoma or therapy were censored at the time of death. Survival analyses and TTCNS were estimated using the Kaplan–Meier method and compared using the logrank test. Response was defined as previously described [16]. Baseline characteristics were compared between the treatment groups using the chisquare test. For univariate analysis, the log-rank test was carried out using TTCNS as the end point and P values <0.05 were considered significant. A Cox proportional hazards model including all factors with P £0.1 from the univariate analysis was performed using a stepwise forward selection method to determine the impact of the factors, including rituximab, on the risk of CNS relapse. Data were analyzed using Statistical Package for the Social Sciences (SPSS version 11.5 and 14.0 for Windows; SPSS Inc., Chicago, IL).
results baseline characteristics A total of 486 patients with DLBCL diagnosed from 1999 to 2005 were identified; however, 51 patients were excluded due to
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incomplete information, limited follow-up, or loss to followup. The final cohort included in this analysis consisted of 435 patients with DLBCL followed to April 2009: 126 (29%) were treated with CHOP with a median follow-up of 7.7 years for living patients (4.3–8.8 years); 309 (71%) were treated with R-CHOP with a median follow-up of 5.2 years (1.9–8.3 years). The majority of patients had DLBCL (89%, CHOP; 87%, R-CHOP); 11% had PMBCL and 2% had rare DLBCL subtypes [T-cell-rich B-cell lymphoma, two patients; intravascular lymphoma, three patients (two R-CHOP; one CHOP)]. Table 1 shows the baseline characteristics for both groups. The median age was 66 years for the CHOP group and 61 years for the R-CHOP group. The majority of patients had stage III or IV disease and a large proportion had more than one site of extranodal involvement. Overall, the baseline characteristics were similar between the groups, although there were a greater proportion of patients in the CHOP treatment era with an elevated lactate dehydrogenase (LDH) (71% versus 59%, P = 0.032) and B symptoms (60% versus 49%, P = 0.044). Patients in the R-CHOP group were more likely to achieve a complete remission (CR) (76% versus 63%, P £ 0.001). In contrast, patients in the CHOP group had a greater likelihood of having progressive disease or no response to their initial therapy (22% versus 9%, P < 0.001). Consistent with prior studies, the 5-year OS (67% versus 41%, P < 0.001) and PFS (61% versus 31%, P < 0.000001) were superior in the R-CHOP group.
CNS relapse in CHOP- and R-CHOP-treated patients In total, there were 31 CNS relapses (7.1%) with no significant difference in the baseline characteristics between the CHOPand R-CHOP-treated patients who developed CNS disease (Table 1). The median TTCNS was comparable between patients treated with CHOP and R-CHOP (8.1 and 6.7 months, respectively). Sixty-eight percent of the CNS relapses occurred within the first year from diagnosis in the R-CHOP compared with 50% in the CHOP group. The majority of relapses were diagnosed by CNS imaging or cytology (Table 2). Two patients in the CHOP group were diagnosed based on clinical symptoms; both developed new cranial nerve deficits after progressive disseminated disease had been documented. The majority of CNS relapses occurred in the absence of systemic recurrence particularly for R-CHOPtreated patients (79% versus 58%). There was a trend toward a greater proportion of parenchyma-only relapses in the R-CHOP group compared with the CHOP group (63% versus 25%, P = 0.075). Comparing the two treatment groups, there was a trend to a reduction in the likelihood of CNS relapse in the R-CHOP group where the projected risk of CNS relapse at 3 years was 6.4% compared with 9.7% following treatment with CHOP (P = 0.085) (Figure 1A). However, if only patients in a CR are considered, the TTCNS relapse was significantly reduced in the R-CHOP group (3-year TTCNS relapse 2.2% versus 5.8%, P = 0.009) (Figure 1B). Five patients (42%) in the CHOP group relapsed >1 year following diagnosis (range 1.6–4.6
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Before 2002, IT chemoprophylaxis consisting of alternating IT methotrexate (12 mg) and IT cytarabine (50 mg) for six doses was administered to patients with ‘high-risk’ DLBCL (bone marrow or peripheral blood involvement, epidural disease, advanced-stage testicular lymphoma, or sinus involvement) following completion of systemic chemotherapy. Based on two studies indicating that chemoprophylaxis did not lower the risk of CNS relapse [13, 14], with the possible exception of paranasal sinus involvement [15], the BCCA Lymphoma Tumour Group amended the institutional guidelines on 16 September 2002. After this date, chemoprophylaxis has been given only to patients with DLBCL with sinus involvement.
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Table 1. Baseline characteristics of R-CHOP- and CHOP-treated patients Clinical factor
R-CHOP (n = 309), n (%)
P
79 66 74 58 89 36 46 7 16 3 1 18 4 4 9 8 8 75 88 65 55 77 12
164 61 188 143 184 72 118 17 34 14 8 46 9 8 32 21 12 151 217 151 143 165 38
(53)
0.067
(61) (46) (59) (23) (38) (6) (11) (5) (3) (15) (3) (3) (10) (7) (4) (49) (71) (49) (46) (53) (12)
0.683 0.963 0.032 0.263 0.743 0.982 0.615 0.29 0.233 0.872 0.884 0.735 0.298 0.865 0.265 0.044 0.937 0.607 0.598 0.142 0.410
235 (76) 45 (15) 29 (9)
0.002
(63) (59) (46) (71) (29) (36) (6) (13) (2) (1) (14) (3) (3) (7) (6) (6) (60) (70) (52) (44) (61) (10)
79 (63) 19 (15) 28 (22)
CNS relapse cohort CHOP (n = 12), n (%)
R-CHOP (n = 19), n (%)
P
6 61 8 5 8 5 6 2 3 2 0 2 1 1 2 1 3 7 11 11 4 9 0
13 66 11 10 13 8 15 3 5 5 0 4 1 0 3 3 0 8 17 17 7 17 1
(68)
0.305
(58) (53) (68) (42) (79) (16) (26) (26)
0.625 0.552 0.745 0.880 0.093 0.948 0.935 0.531
(21) (5)
0.763 0.735 0.201 0.948 0.148 0.066 0.379 0.841 0.841 0.841 0.286 0.420
(50) (67) (42) (67) (42) (50) (17) (25) (17) (17) (8) (8) (17) (8) (25) (58) (92) (92) (33) (75)
7 (58) 1 (8) 4 (33)
(16) (16) (42) (89) (89) (37) (89) (5)
6 (32) 6 (32) 7 (37)
0.219
Numbers in bold are statistically significant. R-CHOP, addition of rituximab to CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CNS, central nervous system; PS, performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal; IT, intrathecal; IPI, International Prognostic Index; PMBCL, primary mediastinal large B-cell lymphoma; PD, progressive disease. a Bulky disease: mass ‡10 cm.
years), four of whom (80%) had concomitant systemic disease. In contrast, six patients (32%) in the R-CHOP group relapsed >1 year from diagnosis (1.25–4.8 years), only one of whom had concurrent systemic disease (17%). Only one R-CHOP-treated patient (5.3%) relapsed >2 years from diagnosis. This patient had PMBCL and developed a parenchymal CNS relapse over 4 years after completing chemotherapy.
risk factors for CNS relapse Univariate analysis of risk factors for CNS relapse was carried out (Table 3). In the entire cohort, LDH more than two times the upper limit of normal, more than one extranodal site, testicular involvement, bone marrow involvement, renal involvement, advanced-stage disease, and IPI 3–5 were all associated with an increased risk of CNS relapse. All the same prognostic factors emerged as significant if the analysis was restricted to R-CHOP-treated patients except that there was only a trend to an increased risk of CNS relapse with testicular involvement (P = 0.062) and bone marrow involvement with DLBCL was not significant (Table 3).
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Multivariate analysis using a Cox proportional hazards model was carried out to evaluate the impact of rituximab in the primary therapy on the risk of CNS relapse. All factors with a P <0.1 from the univariate analysis were included (Table 4). Testicular or renal involvement and stage IV disease remained independent predictors of CNS relapse, and the addition of rituximab was associated with a reduced risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]. In the R-CHOP-treated patients, renal involvement and stage IV disease remained significant risk factors for CNS relapse (Table 4). The risk factors for CNS relapse in the patients who achieved a CR were testicular involvement (P = 0.002) and stage IV (P = 0.003), and the addition of rituximab was protective (P = 0.005) (Table 4).
IT prophylaxis Eight patients (6%) in the CHOP cohort received chemoprophylaxis, and three experienced relapse in the CNS. On the other hand, 12 patients (4%) in the R-CHOP cohort received chemoprophylaxis, and none experienced a relapse.
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Age ‡60 years Median age Male sex PS > 1 LDH > 1 · ULN LDH > 2 · ULN Extranodal sites > 1 Testicular Bone marrow Kidney Sinus Bone Epidural Nasopharyngeal Lung Liver IT prophylaxis B symptoms Stages III and IV Stage IV Bulky diseasea IPI 3–5 PMBCL Response to treatment Complete response Partial response No response or PD
Entire cohort CHOP (n = 126), n (%)
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Table 2. Characteristics of patients with CNS relapse (n = 31) Clinical factor
R-CHOP (n = 19), n (%)
3 (25) 6 (50) 3 (25)
P = 0.075 12 (63) 3 (16) 4 (21)
3 (25) 7 (58) 2 (17) 7 (58) 1 (8.3)
14 (74) 5 (26) 0 P = 0.218 15 (79) 1 (5.3)
4 (33)
3 (16)
7 2 2 2 4 2
13 4 3 1 1 3
12 0
18 1
CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to CHOP; CSF, cerebrospinal fluid; WBI, whole-brain irradiation; MTX, methotrexate; IT, intrathecal; CR, complete remission.
The predominant indication in the R-CHOP cohort was sinus involvement; all others received IT prophylaxis on the basis of other extranodal sites of disease, such as testes and bone marrow, at the treating physician’s discretion. IT prophylaxis did not have a protective effect on the rate of CNS relapse in univariate analysis.
treatment of CNS relapse The median survival following CNS relapse was poor regardless of the primary therapy received (CHOP, 1.8 months; R-CHOP, 3.6 months). Most patients with parenchyma-only relapse received whole-brain radiotherapy (WBRT) at relapse (Table 2) and patients with leptomeningeal involvement received either HDMTX (n = 6) or IT chemotherapy (n = 5). Seven patients received dexamethasone or supportive care only. Three patients <60 years of age received secondary chemotherapy followed by consolidation with high-dose chemotherapy and autologous stem-cell transplantation and all relapsed and died of lymphoma following transplant. At the time of analysis, only one patient is still alive and free of disease following CNS relapse. This individual relapsed in the brain parenchyma 1 year after achieving a CR following RCHOP. HDMTX was given as the initial therapy followed by
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Figure 1. (A) TTCNS in CHOP-treated (n = 126) and R-CHOP-treated (n = 309) patients (N = 435). (B) TTCNS in CHOP- and R-CHOPtreated patients achieving a complete remission (n = 314). TTCNS, time to central nervous system relapse; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone.
WBRT 1 year later for a second relapse. A durable CR has been achieved over 2 years from the second CNS relapse.
discussion The addition of rituximab to CHOP chemotherapy has been shown in several randomized trials [6, 8, 9] as well as a population-based study [12] to improve the event-free survival and OS of patients with DLBCL. We sought to determine whether the improvement in outcome is in part related to a protective effect against CNS relapse. We observed a trend to a reduction in the actuarial TTCNS in R-CHOPtreated patients (Figure 1A), but importantly, rituximab remained protective against CNS relapse in multivariate
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Site of CNS relapse Parenchymal Leptomeninges Both Diagnosis of CNS relapse Imaging CSF Clinical Relapse in CNS versus systemic First relapse in CNS only First relapse in CNS simultaneously with other sites First relapse systemic then CNS Treatment of CNS relapse WBI High-dose MTX Dexamethasone Bone marrow transplant IT chemotherapy Supportive care only Outcomes Lymphoma-related death Alive in second CR
CHOP (n = 12), n (%)
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analysis. Further, there was a more striking reduction of CNS relapses in those patients who achieved a CR (Figure 1B). This may indicate that the beneficial effect of rituximab in this setting may be through superior eradication of systemic disease, which secondarily contributes to a reduction of late CNS relapses. This is also highlighted by the absence of concurrent systemic disease at the time of CNS relapse for the majority of R-CHOP-treated patients who relapsed >1 year from diagnosis, which was in stark contrast to the CHOP-treated patients. A large proportion of the relapses occurred early in both the groups, which may reflect the presence of occult CNS disease at
Table 3. Risk factors for CNS relapse in univariate analysis (N = 435) All patients (N = 435), P value
R-CHOP (n = 309), P value
Age ‡60 years Male sex PS > 1 LDH > 1 · ULN LDH > 2 · ULN Extranodal sites > 1 Testicular Bone marrow Kidney Sinus Bone Epidural Nasopharyngeal Lung Liver IT prophylaxis B symptoms Stages III and IV Stage IV Bulky disease IPI 0–2 versus 3–5 PMBCL Rituximab
0.321 0.861 0.550 0.311 0.0045 0.0003 0.009 0.043 <0.00001 0.404 0.476 0.127 0.938 0.211 0.395 0.676 0.813 0.0058 <0.00001 0.2130 0.0002 0.106 0.085
0.135 0.814 0.513 0.267 0.026 0.0002 0.062 0.259 <0.00001 0.481 0.492 0.499 0.454 0.413 0.080 0.364 0.565 0.043 0.0001 0.403 0.0006 0.302 N/A
Numbers in bold are statistically significant. CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to CHOP; PS, performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal; IT, intrathecal; IPI, International Prognostic Index; PMBCL, primary mediastinal large B-cell lymphoma.
Table 4. Cox proportional hazards models of risk factors for CNS relapse Clinical factor Stage IV Kidney Testicular R-CHOP
Entire cohort (n = 435) HR (95% CI)
P value
R-CHOP cohort (n = 309) HR (95% CI) P value
CR-only cohort (n = 314) HR (95% CI)
P value
9.70 3.17 3.02 0.45
<0.0001 0.022 0.035 0.034
8.0 (1.8–35.9) 3.30 (1.04–9.99) NS N/A
10.43 (2.18–50.01) NS 9.36 (2.26–38.80) 0.182 (0.056–0.593)
0.003 NS 0.002 0.005
(2.88–32.65) (1.18–8.52) (1.08–8.72) (0.21–0.94)
0.006 0.043 NS
CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to CHOP; CR, complete remission; HR, hazard ratio; CI, confidence interval; NS, not significant; N/A, not applicable.
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Clinical factor
the time of diagnosis where rituximab may have a more limited effect. Consistent with this, the TTCNS relapse curves are largely overlapping in the first year from diagnosis (Figure 1A). This observation of a reduction in CNS relapses after 1 year has been reported in other studies [17]. These data support the mechanism of late CNS relapse in patients who may be different and more tightly linked to control of systemic disease. A limited number of studies have attempted to evaluate the overall impact of rituximab on CNS relapse in DLBCL. The GELA group evaluated the frequency of CNS relapse in elderly patients with DLBCL treated with CHOP or R-CHOP and found that the overall rates of secondary CNS occurrence were similar [10]. However, a Japanese retrospective study (n = 403) reported that rituximab did have a protective effect against CNS relapse in multivariate analysis (HR 0.485, P = 0.027) [17]. The largest study to date was carried out by the German High Grade Non-Hodgkin Study Group, which evaluated the incidence of and risk factors for CNS events in a post hoc analysis of the RICOVER-60 trial [8], in which elderly patients were randomly assigned to receive either six or eight cycles of CHOP-14 with or without rituximab (n = 1217). The overall rate of CNS relapse was 4.8%, including all aggressive B-cell histologies, of which 81.6% had DLBCL. Although the analysis was not exclusively carried out on patients with DLBCL, the addition of rituximab resulted in a reduction of the 2-year incidence of CNS disease from 6.9% in patients treated with CHOP to 4.1% in patients treated with R-CHOP (relative risk = 0.58, 95% CI 0.0; 1.0, P = 0.046) [11]. Given that the observed absolute difference in CNS events in the treatment groups in this study was only 2.3%, the benefit of rituximab is small and evaluation of a large number of patients is necessary to capture it. Overall, the risk of CNS relapse in our cohort was slightly higher (7.1%) than that reported in the literature. The reason is likely due to our inclusion of higher risk population-based patients and we confined our analysis to patients with advanced-stage disease. Further, a lumbar puncture with CSF analysis and CNS imaging were not routinely carried out at diagnosis in our study unless clinically indicated, and thus, occult CNS disease may have been present at diagnosis. Although rituximab may impart a marginal benefit, it does not eliminate the risk of CNS relapse. This may reflect poor penetration across the blood–brain barrier. Previous pharmacokinetic studies reveal that levels of rituximab in the CSF are only 0.1% of matched serum levels following an i.v. dose [18]. We observed a greater proportion of parenchymal-only relapses compared with leptomeningeal or
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acknowledgements The authors would like to thank Ryan Brinkman and Miao (Maggie) Yu for statistical support as well as Jane Donaldson and Suman Singh for database management. A preliminary analysis of the results reported in this paper was presented at the meeting of the American Society of Clinical Oncology in Chicago, IL, in June 2007.
disclosure LHS and RDG: consultant or advisory role in and research funding and honoraria from Roche; KJS: honoraria from Roche; JMC: research funding from Roche.
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leptomeningeal/parenchymal relapses in the rituximab group (63% versus 25%), which is consistent with limited penetration into this CNS compartment. This is in contrast to the results observed in the RICOVER trial, where a greater proportion of leptomeningeal relapses were seen in R-CHOP-treated patients (40.9% versus 16.7%). The reason for this discrepancy is unclear but it may reflect either chance or a possible imbalance of extranodal sites known to be associated with an increased risk of either parenchymal (e.g. testicular) or leptomeningeal relapse (e.g. sinus) and this information was not detailed in this study. There is considerable variation in the use of IT prophylaxis and reports vary as to the population studied as well as the dose, timing, indications, and type of CNS prophylaxis across institutions. We did not observe a significant effect in reducing the rate of CNS relapse, although the number of patients treated was small. Given the poor penetration of IT chemotherapy, it is unlikely to have a protect against parenchymal relapses. Since a large proportion of the relapses occur early, efforts need to concentrate on more effective therapies that can be safely combined with R-CHOP. HDMTX and cytarabine are used in the treatment of primary CNS lymphoma due to penetration across the blood–brain barrier. However, the role of these agents is less clearly established in CNS prophylaxis and requires further study in this setting. Multiple studies have attempted to identify patients at high risk for CNS relapse who would ideally benefit from prophylactic therapy [8, 11, 14, 19–26]. High LDH, advanced stage, and extranodal site involvement are the most consistently reported risk factors for CNS relapse. Within the extranodal sites, the testes, bone marrow, and paranasal sinuses appear to be most closely linked with CNS occurrence. Consistent with these reports, we identified stage IV and, interestingly, renal involvement to be associated with an increased risk of CNS R-CHOP-treated patients. In summary, the addition of rituximab to CHOP chemotherapy appears to impart a protective effect against CNS relapse. The benefit is most apparent in patients who achieve a CR, possibly through improved control of systemic disease. However, the risk is not eliminated and outcomes following CNS relapse are dismal even in the R-CHOP treatment era. Given the predominance of early relapses, efforts need to continue to focus on the incorporation of chemoprophylactic treatments with the primary therapy in high-risk populations.
original article 21. Haioun C, Besson C, Lepage E et al. Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 2000; 11(6): 685–690. 22. Tomita N, Kodama F, Sakai R et al. Predictive factors for central nervous system involvement in non-Hodgkin’s lymphoma: significance of very high serum LDH concentrations. Leuk Lymphoma 2000; 38(3–4): 335–343. 23. Jahnke K, Thiel E, Martus P et al. Retrospective study of prognostic factors in non-Hodgkin lymphoma secondarily involving the central nervous system. Ann Hematol 2006; 85(1): 45–50.
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24. Bjorkholm M, Hagberg H, Holte H et al. Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up. Ann Oncol 2007; 18(6): 1085–1089. 25. Boehme V, Zeynalova S, Kloess M et al. Incidence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol 2007; 18(1): 149–157. 26. Bernstein SH, Unger JM, Leblanc M et al. Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG 8516—the Southwest Oncology Group. J Clin Oncol 2009; 27(1): 114–119.
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Annals of Oncology 21: 1046–1052, 2010 doi:10.1093/annonc/mdp432 Published online 27 October 2009
Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy D. Villa1, J. M. Connors1, T. N. Shenkier1, R. D. Gascoyne2, L. H. Sehn1 & K. J. Savage1* Divisions of 1Medical Oncology and 2Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Received 24 July 2009; accepted 3 August 2009
original article
prednisone) chemotherapy improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the risk of central nervous system (CNS) relapse in the R-CHOP in a population-based cohort of patients with DLBCL. Methods: Patients with DLBCL diagnosed from 1 September 1999 to 14 January 2005 at the British Columbia Cancer Agency (BCCA) were identified. Patients were included if they were ‡16 years old with advanced stage or any stage with testicular involvement and were treated with CHOP (1999–2001) or R-CHOP (2001–2005) with curative intent. Results: Four hundred and thirty-five patients were identified; 126 (29%) were treated with CHOP and 309 (71%) with R-CHOP. With a median follow-up of 5.7 years, there were 31 CNS relapses in total with a trend to a reduced likelihood of CNS relapse in R-CHOP-treated patients (3-year risk 9.7% versus 6.4, P = 0.085). In multivariate analysis, the use of rituximab significantly reduced the risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]; this benefit was more striking in patients who achieved a complete response (HR 0.18, P = 0.005). Conclusion: The use of R-CHOP appears to reduce the overall risk of CNS relapse in patients with DLBCL particularly in patients who achieve a complete response. Key words: central nervous system, CNS relapse, diffuse large B-cell lymphoma, DLBCL, R-CHOP, rituximab
introduction Secondary central nervous system (CNS) involvement is an infrequent yet nearly always fatal event in diffuse large B-cell lymphoma (DLBCL). The reported incidence ranges from 5% to 25%, depending on the population studied, associated risk factors present, and the accuracy of the diagnostic tests used [1, 2]. Relapses can occur in the brain parenchyma, leptomeningeal compartment, or both and can take place as an isolated event or as part of widespread disease progression. With largely ineffective therapy available for secondary CNS relapse, prophylaxis is often administered at the time of primary therapy. The high propensity for CNS relapse Burkitt’s lymphoma has led to the administration of routine CNS prophylaxis in the form of intrathecal (IT) chemotherapy and high-dose methotrexate (HDMTX) with the primary therapy. With this approach, there has been a reduction in the incidence of CNS relapse and improved outcome in this type of aggressive lymphoma [3, 4]. Several studies have identified patients at higher risk of CNS relapse in DLBCL including those with advanced-stage disease, involvement of specific extranodal sites *Correspondence to: Dr K. J. Savage, Division of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada BC V5Z 4E6. Tel: +1-604-877-6000; Fax: +1-604-877-0585; E-mail: [email protected]
(e.g. bone marrow, sinus, and testes), and multiple extranodal sites of disease. However, although high-risk groups can be easily identified, the demonstration of a clear benefit of CNS prophylaxis has been elusive, and thus, the use of CNS prophylaxis remains controversial. The survival of patients with DLBCL has improved dramatically with addition of the chimeric anti-CD20 mAb rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) [5–9]. Whether the improvement in outcome is related in part to a reduction in the risk of CNS relapse is unknown. Limited data indicate no [10] or a marginal [11] benefit. We evaluated the risk and types of CNS relapse in addition to the associated risk factors in a large population-based cohort of patients with DLBCL treated with addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in comparison to CHOP.
methods patient selection All patients with DLBCL and primary mediastinal large B-cell lymphoma (PMBCL), diagnosed from 1 September 1999 to 14 January 2005, with a minimum follow-up of 18 months, were identified in the British
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Background: The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and
Annals of Oncology
Columbia Cancer Agency (BCCA) Lymphoid Cancer Database, including those from a recently published report [12]. Patients were included if they were ‡16 years of age and had advanced-stage disease [stage III/IV or stage I/II with B symptoms and/or bulky disease (‡10 cm)]. Patients with testicular DLBCL, regardless of stage, were also included in this analysis. Human immunodeficiency virus-positive individuals and those with CNS involvement at diagnosis were excluded. Evaluation of the CNS at diagnosis by either computed tomography/magnetic resonance imaging (CT/MRI) or lumber puncture with cerebrospinal fluid (CSF) analysis was carried out only if clinically indicated. All patients received at least one cycle of chemotherapy with curative intent. After 1 March 2001, all patients received R-CHOP. Patients with testicular lymphoma also received scrotal irradiation. Baseline clinical characteristics including the International Prognostic Index (IPI) score as well as the type and number of extranodal sites were recorded. In those patients who relapsed, the sites of relapse were documented. This study was approved by the University of British Columbia BCCA Research Ethics Board.
CNS prophylaxis
statistical analysis The primary study end point was the time to central nervous system relapse (TTCNS) diagnosed by CT or MRI imaging, pathology, or clinical symptomatology. TTCNS was calculated from the date of pathological diagnosis of lymphoma to the date of CNS relapse. Overall survival (OS) was calculated from the date of initial diagnosis (or from the date of CNS relapse where applicable) to the date of last follow-up or death from any cause. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of first disease progression or relapse following treatment or death from toxicity during therapy. Patients alive and without progressive disease were censored on the date of their last follow-up visit, and patients who died of causes unrelated to the lymphoma or therapy were censored at the time of death. Survival analyses and TTCNS were estimated using the Kaplan–Meier method and compared using the logrank test. Response was defined as previously described [16]. Baseline characteristics were compared between the treatment groups using the chisquare test. For univariate analysis, the log-rank test was carried out using TTCNS as the end point and P values <0.05 were considered significant. A Cox proportional hazards model including all factors with P £0.1 from the univariate analysis was performed using a stepwise forward selection method to determine the impact of the factors, including rituximab, on the risk of CNS relapse. Data were analyzed using Statistical Package for the Social Sciences (SPSS version 11.5 and 14.0 for Windows; SPSS Inc., Chicago, IL).
results baseline characteristics A total of 486 patients with DLBCL diagnosed from 1999 to 2005 were identified; however, 51 patients were excluded due to
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incomplete information, limited follow-up, or loss to followup. The final cohort included in this analysis consisted of 435 patients with DLBCL followed to April 2009: 126 (29%) were treated with CHOP with a median follow-up of 7.7 years for living patients (4.3–8.8 years); 309 (71%) were treated with R-CHOP with a median follow-up of 5.2 years (1.9–8.3 years). The majority of patients had DLBCL (89%, CHOP; 87%, R-CHOP); 11% had PMBCL and 2% had rare DLBCL subtypes [T-cell-rich B-cell lymphoma, two patients; intravascular lymphoma, three patients (two R-CHOP; one CHOP)]. Table 1 shows the baseline characteristics for both groups. The median age was 66 years for the CHOP group and 61 years for the R-CHOP group. The majority of patients had stage III or IV disease and a large proportion had more than one site of extranodal involvement. Overall, the baseline characteristics were similar between the groups, although there were a greater proportion of patients in the CHOP treatment era with an elevated lactate dehydrogenase (LDH) (71% versus 59%, P = 0.032) and B symptoms (60% versus 49%, P = 0.044). Patients in the R-CHOP group were more likely to achieve a complete remission (CR) (76% versus 63%, P £ 0.001). In contrast, patients in the CHOP group had a greater likelihood of having progressive disease or no response to their initial therapy (22% versus 9%, P < 0.001). Consistent with prior studies, the 5-year OS (67% versus 41%, P < 0.001) and PFS (61% versus 31%, P < 0.000001) were superior in the R-CHOP group.
CNS relapse in CHOP- and R-CHOP-treated patients In total, there were 31 CNS relapses (7.1%) with no significant difference in the baseline characteristics between the CHOPand R-CHOP-treated patients who developed CNS disease (Table 1). The median TTCNS was comparable between patients treated with CHOP and R-CHOP (8.1 and 6.7 months, respectively). Sixty-eight percent of the CNS relapses occurred within the first year from diagnosis in the R-CHOP compared with 50% in the CHOP group. The majority of relapses were diagnosed by CNS imaging or cytology (Table 2). Two patients in the CHOP group were diagnosed based on clinical symptoms; both developed new cranial nerve deficits after progressive disseminated disease had been documented. The majority of CNS relapses occurred in the absence of systemic recurrence particularly for R-CHOPtreated patients (79% versus 58%). There was a trend toward a greater proportion of parenchyma-only relapses in the R-CHOP group compared with the CHOP group (63% versus 25%, P = 0.075). Comparing the two treatment groups, there was a trend to a reduction in the likelihood of CNS relapse in the R-CHOP group where the projected risk of CNS relapse at 3 years was 6.4% compared with 9.7% following treatment with CHOP (P = 0.085) (Figure 1A). However, if only patients in a CR are considered, the TTCNS relapse was significantly reduced in the R-CHOP group (3-year TTCNS relapse 2.2% versus 5.8%, P = 0.009) (Figure 1B). Five patients (42%) in the CHOP group relapsed >1 year following diagnosis (range 1.6–4.6
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Before 2002, IT chemoprophylaxis consisting of alternating IT methotrexate (12 mg) and IT cytarabine (50 mg) for six doses was administered to patients with ‘high-risk’ DLBCL (bone marrow or peripheral blood involvement, epidural disease, advanced-stage testicular lymphoma, or sinus involvement) following completion of systemic chemotherapy. Based on two studies indicating that chemoprophylaxis did not lower the risk of CNS relapse [13, 14], with the possible exception of paranasal sinus involvement [15], the BCCA Lymphoma Tumour Group amended the institutional guidelines on 16 September 2002. After this date, chemoprophylaxis has been given only to patients with DLBCL with sinus involvement.
original article
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Annals of Oncology
Table 1. Baseline characteristics of R-CHOP- and CHOP-treated patients Clinical factor
R-CHOP (n = 309), n (%)
P
79 66 74 58 89 36 46 7 16 3 1 18 4 4 9 8 8 75 88 65 55 77 12
164 61 188 143 184 72 118 17 34 14 8 46 9 8 32 21 12 151 217 151 143 165 38
(53)
0.067
(61) (46) (59) (23) (38) (6) (11) (5) (3) (15) (3) (3) (10) (7) (4) (49) (71) (49) (46) (53) (12)
0.683 0.963 0.032 0.263 0.743 0.982 0.615 0.29 0.233 0.872 0.884 0.735 0.298 0.865 0.265 0.044 0.937 0.607 0.598 0.142 0.410
235 (76) 45 (15) 29 (9)
0.002
(63) (59) (46) (71) (29) (36) (6) (13) (2) (1) (14) (3) (3) (7) (6) (6) (60) (70) (52) (44) (61) (10)
79 (63) 19 (15) 28 (22)
CNS relapse cohort CHOP (n = 12), n (%)
R-CHOP (n = 19), n (%)
P
6 61 8 5 8 5 6 2 3 2 0 2 1 1 2 1 3 7 11 11 4 9 0
13 66 11 10 13 8 15 3 5 5 0 4 1 0 3 3 0 8 17 17 7 17 1
(68)
0.305
(58) (53) (68) (42) (79) (16) (26) (26)
0.625 0.552 0.745 0.880 0.093 0.948 0.935 0.531
(21) (5)
0.763 0.735 0.201 0.948 0.148 0.066 0.379 0.841 0.841 0.841 0.286 0.420
(50) (67) (42) (67) (42) (50) (17) (25) (17) (17) (8) (8) (17) (8) (25) (58) (92) (92) (33) (75)
7 (58) 1 (8) 4 (33)
(16) (16) (42) (89) (89) (37) (89) (5)
6 (32) 6 (32) 7 (37)
0.219
Numbers in bold are statistically significant. R-CHOP, addition of rituximab to CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CNS, central nervous system; PS, performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal; IT, intrathecal; IPI, International Prognostic Index; PMBCL, primary mediastinal large B-cell lymphoma; PD, progressive disease. a Bulky disease: mass ‡10 cm.
years), four of whom (80%) had concomitant systemic disease. In contrast, six patients (32%) in the R-CHOP group relapsed >1 year from diagnosis (1.25–4.8 years), only one of whom had concurrent systemic disease (17%). Only one R-CHOP-treated patient (5.3%) relapsed >2 years from diagnosis. This patient had PMBCL and developed a parenchymal CNS relapse over 4 years after completing chemotherapy.
risk factors for CNS relapse Univariate analysis of risk factors for CNS relapse was carried out (Table 3). In the entire cohort, LDH more than two times the upper limit of normal, more than one extranodal site, testicular involvement, bone marrow involvement, renal involvement, advanced-stage disease, and IPI 3–5 were all associated with an increased risk of CNS relapse. All the same prognostic factors emerged as significant if the analysis was restricted to R-CHOP-treated patients except that there was only a trend to an increased risk of CNS relapse with testicular involvement (P = 0.062) and bone marrow involvement with DLBCL was not significant (Table 3).
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Multivariate analysis using a Cox proportional hazards model was carried out to evaluate the impact of rituximab in the primary therapy on the risk of CNS relapse. All factors with a P <0.1 from the univariate analysis were included (Table 4). Testicular or renal involvement and stage IV disease remained independent predictors of CNS relapse, and the addition of rituximab was associated with a reduced risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]. In the R-CHOP-treated patients, renal involvement and stage IV disease remained significant risk factors for CNS relapse (Table 4). The risk factors for CNS relapse in the patients who achieved a CR were testicular involvement (P = 0.002) and stage IV (P = 0.003), and the addition of rituximab was protective (P = 0.005) (Table 4).
IT prophylaxis Eight patients (6%) in the CHOP cohort received chemoprophylaxis, and three experienced relapse in the CNS. On the other hand, 12 patients (4%) in the R-CHOP cohort received chemoprophylaxis, and none experienced a relapse.
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Age ‡60 years Median age Male sex PS > 1 LDH > 1 · ULN LDH > 2 · ULN Extranodal sites > 1 Testicular Bone marrow Kidney Sinus Bone Epidural Nasopharyngeal Lung Liver IT prophylaxis B symptoms Stages III and IV Stage IV Bulky diseasea IPI 3–5 PMBCL Response to treatment Complete response Partial response No response or PD
Entire cohort CHOP (n = 126), n (%)
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Annals of Oncology
Table 2. Characteristics of patients with CNS relapse (n = 31) Clinical factor
R-CHOP (n = 19), n (%)
3 (25) 6 (50) 3 (25)
P = 0.075 12 (63) 3 (16) 4 (21)
3 (25) 7 (58) 2 (17) 7 (58) 1 (8.3)
14 (74) 5 (26) 0 P = 0.218 15 (79) 1 (5.3)
4 (33)
3 (16)
7 2 2 2 4 2
13 4 3 1 1 3
12 0
18 1
CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to CHOP; CSF, cerebrospinal fluid; WBI, whole-brain irradiation; MTX, methotrexate; IT, intrathecal; CR, complete remission.
The predominant indication in the R-CHOP cohort was sinus involvement; all others received IT prophylaxis on the basis of other extranodal sites of disease, such as testes and bone marrow, at the treating physician’s discretion. IT prophylaxis did not have a protective effect on the rate of CNS relapse in univariate analysis.
treatment of CNS relapse The median survival following CNS relapse was poor regardless of the primary therapy received (CHOP, 1.8 months; R-CHOP, 3.6 months). Most patients with parenchyma-only relapse received whole-brain radiotherapy (WBRT) at relapse (Table 2) and patients with leptomeningeal involvement received either HDMTX (n = 6) or IT chemotherapy (n = 5). Seven patients received dexamethasone or supportive care only. Three patients <60 years of age received secondary chemotherapy followed by consolidation with high-dose chemotherapy and autologous stem-cell transplantation and all relapsed and died of lymphoma following transplant. At the time of analysis, only one patient is still alive and free of disease following CNS relapse. This individual relapsed in the brain parenchyma 1 year after achieving a CR following RCHOP. HDMTX was given as the initial therapy followed by
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Figure 1. (A) TTCNS in CHOP-treated (n = 126) and R-CHOP-treated (n = 309) patients (N = 435). (B) TTCNS in CHOP- and R-CHOPtreated patients achieving a complete remission (n = 314). TTCNS, time to central nervous system relapse; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone.
WBRT 1 year later for a second relapse. A durable CR has been achieved over 2 years from the second CNS relapse.
discussion The addition of rituximab to CHOP chemotherapy has been shown in several randomized trials [6, 8, 9] as well as a population-based study [12] to improve the event-free survival and OS of patients with DLBCL. We sought to determine whether the improvement in outcome is in part related to a protective effect against CNS relapse. We observed a trend to a reduction in the actuarial TTCNS in R-CHOPtreated patients (Figure 1A), but importantly, rituximab remained protective against CNS relapse in multivariate
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Site of CNS relapse Parenchymal Leptomeninges Both Diagnosis of CNS relapse Imaging CSF Clinical Relapse in CNS versus systemic First relapse in CNS only First relapse in CNS simultaneously with other sites First relapse systemic then CNS Treatment of CNS relapse WBI High-dose MTX Dexamethasone Bone marrow transplant IT chemotherapy Supportive care only Outcomes Lymphoma-related death Alive in second CR
CHOP (n = 12), n (%)
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Annals of Oncology
analysis. Further, there was a more striking reduction of CNS relapses in those patients who achieved a CR (Figure 1B). This may indicate that the beneficial effect of rituximab in this setting may be through superior eradication of systemic disease, which secondarily contributes to a reduction of late CNS relapses. This is also highlighted by the absence of concurrent systemic disease at the time of CNS relapse for the majority of R-CHOP-treated patients who relapsed >1 year from diagnosis, which was in stark contrast to the CHOP-treated patients. A large proportion of the relapses occurred early in both the groups, which may reflect the presence of occult CNS disease at
Table 3. Risk factors for CNS relapse in univariate analysis (N = 435) All patients (N = 435), P value
R-CHOP (n = 309), P value
Age ‡60 years Male sex PS > 1 LDH > 1 · ULN LDH > 2 · ULN Extranodal sites > 1 Testicular Bone marrow Kidney Sinus Bone Epidural Nasopharyngeal Lung Liver IT prophylaxis B symptoms Stages III and IV Stage IV Bulky disease IPI 0–2 versus 3–5 PMBCL Rituximab
0.321 0.861 0.550 0.311 0.0045 0.0003 0.009 0.043 <0.00001 0.404 0.476 0.127 0.938 0.211 0.395 0.676 0.813 0.0058 <0.00001 0.2130 0.0002 0.106 0.085
0.135 0.814 0.513 0.267 0.026 0.0002 0.062 0.259 <0.00001 0.481 0.492 0.499 0.454 0.413 0.080 0.364 0.565 0.043 0.0001 0.403 0.0006 0.302 N/A
Numbers in bold are statistically significant. CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to CHOP; PS, performance status; LDH, lactate dehydrogenase; ULN, upper limit of normal; IT, intrathecal; IPI, International Prognostic Index; PMBCL, primary mediastinal large B-cell lymphoma.
Table 4. Cox proportional hazards models of risk factors for CNS relapse Clinical factor Stage IV Kidney Testicular R-CHOP
Entire cohort (n = 435) HR (95% CI)
P value
R-CHOP cohort (n = 309) HR (95% CI) P value
CR-only cohort (n = 314) HR (95% CI)
P value
9.70 3.17 3.02 0.45
<0.0001 0.022 0.035 0.034
8.0 (1.8–35.9) 3.30 (1.04–9.99) NS N/A
10.43 (2.18–50.01) NS 9.36 (2.26–38.80) 0.182 (0.056–0.593)
0.003 NS 0.002 0.005
(2.88–32.65) (1.18–8.52) (1.08–8.72) (0.21–0.94)
0.006 0.043 NS
CNS, central nervous system; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP, addition of rituximab to CHOP; CR, complete remission; HR, hazard ratio; CI, confidence interval; NS, not significant; N/A, not applicable.
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Clinical factor
the time of diagnosis where rituximab may have a more limited effect. Consistent with this, the TTCNS relapse curves are largely overlapping in the first year from diagnosis (Figure 1A). This observation of a reduction in CNS relapses after 1 year has been reported in other studies [17]. These data support the mechanism of late CNS relapse in patients who may be different and more tightly linked to control of systemic disease. A limited number of studies have attempted to evaluate the overall impact of rituximab on CNS relapse in DLBCL. The GELA group evaluated the frequency of CNS relapse in elderly patients with DLBCL treated with CHOP or R-CHOP and found that the overall rates of secondary CNS occurrence were similar [10]. However, a Japanese retrospective study (n = 403) reported that rituximab did have a protective effect against CNS relapse in multivariate analysis (HR 0.485, P = 0.027) [17]. The largest study to date was carried out by the German High Grade Non-Hodgkin Study Group, which evaluated the incidence of and risk factors for CNS events in a post hoc analysis of the RICOVER-60 trial [8], in which elderly patients were randomly assigned to receive either six or eight cycles of CHOP-14 with or without rituximab (n = 1217). The overall rate of CNS relapse was 4.8%, including all aggressive B-cell histologies, of which 81.6% had DLBCL. Although the analysis was not exclusively carried out on patients with DLBCL, the addition of rituximab resulted in a reduction of the 2-year incidence of CNS disease from 6.9% in patients treated with CHOP to 4.1% in patients treated with R-CHOP (relative risk = 0.58, 95% CI 0.0; 1.0, P = 0.046) [11]. Given that the observed absolute difference in CNS events in the treatment groups in this study was only 2.3%, the benefit of rituximab is small and evaluation of a large number of patients is necessary to capture it. Overall, the risk of CNS relapse in our cohort was slightly higher (7.1%) than that reported in the literature. The reason is likely due to our inclusion of higher risk population-based patients and we confined our analysis to patients with advanced-stage disease. Further, a lumbar puncture with CSF analysis and CNS imaging were not routinely carried out at diagnosis in our study unless clinically indicated, and thus, occult CNS disease may have been present at diagnosis. Although rituximab may impart a marginal benefit, it does not eliminate the risk of CNS relapse. This may reflect poor penetration across the blood–brain barrier. Previous pharmacokinetic studies reveal that levels of rituximab in the CSF are only 0.1% of matched serum levels following an i.v. dose [18]. We observed a greater proportion of parenchymal-only relapses compared with leptomeningeal or
original article
Annals of Oncology
acknowledgements The authors would like to thank Ryan Brinkman and Miao (Maggie) Yu for statistical support as well as Jane Donaldson and Suman Singh for database management. A preliminary analysis of the results reported in this paper was presented at the meeting of the American Society of Clinical Oncology in Chicago, IL, in June 2007.
disclosure LHS and RDG: consultant or advisory role in and research funding and honoraria from Roche; KJS: honoraria from Roche; JMC: research funding from Roche.
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references 1. Bierman P, Giglio P. Diagnosis and treatment of central nervous system involvement in non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am 2005; 19(4): 597–609v. 2. Hegde U, Filie A, Little RF et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood 2005; 105(2): 496–502. 3. Hill QA, Owen RG. CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood Rev 2006; 20(6): 319–332. 4. Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. Blood 2004; 104(10): 3009–3020. 5. Habermann TM, Weller EA, Morrison VA et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24(19): 3121–3127. 6. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346(4): 235–242. 7. Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23(18): 4117–4126. 8. Pfreundschuh M, Schubert J, Ziepert M et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ Bcell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9(2): 105–116. 9. Pfreundschuh M, Trumper L, Osterborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with goodprognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7(5): 379–391. 10. Feugier P, Virion JM, Tilly H et al. Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol 2004; 15(1): 129–133. 11. Boehme V, Schmitz N, Zeynalova S et al. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German high-grade non-Hodgkin lymphoma study group (DSHNHL). Blood 2009; 113(17): 3896–13092. 12. Sehn LH, Donaldson J, Chhanabhai M et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 2005; 23(22): 5027–5033. 13. Chua SL, Seymour JF, Streater J et al. Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediategrade non-Hodgkin’s lymphoma. Leuk Lymphoma 2002; 43(9): 1783–1788. 14. Hollender A, Kvaloy S, Nome O et al. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol 2002; 13(7): 1099–1107. 15. Laskin JJ, Savage KJ, Voss N et al. Primary paranasal sinus lymphoma: natural history and improved outcome with central nervous system chemoprophylaxis. Leuk Lymphoma 2005; 46(12): 1721–1727. 16. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 1999; 17(4): 1244–1253. 17. Shimazu Y, Notohara K, Ueda Y. Diffuse large B-cell lymphoma with central nervous system relapse: prognosis and risk factors according to retrospective analysis from a single-center experience. Int J Hematol 2009; 89: 577–583. 18. Rubenstein JL, Combs D, Rosenberg J et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 2003; 101(2): 466–468. 19. Bos GM, van Putten WL, van der Holt B et al. For which patients with aggressive non-Hodgkin’s lymphoma is prophylaxis for central nervous system disease mandatory? Dutch HOVON Group. Ann Oncol 1998; 9(2): 191–194. 20. van Besien K, Ha CS, Murphy S et al. Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 1998; 91(4): 1178–1184.
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leptomeningeal/parenchymal relapses in the rituximab group (63% versus 25%), which is consistent with limited penetration into this CNS compartment. This is in contrast to the results observed in the RICOVER trial, where a greater proportion of leptomeningeal relapses were seen in R-CHOP-treated patients (40.9% versus 16.7%). The reason for this discrepancy is unclear but it may reflect either chance or a possible imbalance of extranodal sites known to be associated with an increased risk of either parenchymal (e.g. testicular) or leptomeningeal relapse (e.g. sinus) and this information was not detailed in this study. There is considerable variation in the use of IT prophylaxis and reports vary as to the population studied as well as the dose, timing, indications, and type of CNS prophylaxis across institutions. We did not observe a significant effect in reducing the rate of CNS relapse, although the number of patients treated was small. Given the poor penetration of IT chemotherapy, it is unlikely to have a protect against parenchymal relapses. Since a large proportion of the relapses occur early, efforts need to concentrate on more effective therapies that can be safely combined with R-CHOP. HDMTX and cytarabine are used in the treatment of primary CNS lymphoma due to penetration across the blood–brain barrier. However, the role of these agents is less clearly established in CNS prophylaxis and requires further study in this setting. Multiple studies have attempted to identify patients at high risk for CNS relapse who would ideally benefit from prophylactic therapy [8, 11, 14, 19–26]. High LDH, advanced stage, and extranodal site involvement are the most consistently reported risk factors for CNS relapse. Within the extranodal sites, the testes, bone marrow, and paranasal sinuses appear to be most closely linked with CNS occurrence. Consistent with these reports, we identified stage IV and, interestingly, renal involvement to be associated with an increased risk of CNS R-CHOP-treated patients. In summary, the addition of rituximab to CHOP chemotherapy appears to impart a protective effect against CNS relapse. The benefit is most apparent in patients who achieve a CR, possibly through improved control of systemic disease. However, the risk is not eliminated and outcomes following CNS relapse are dismal even in the R-CHOP treatment era. Given the predominance of early relapses, efforts need to continue to focus on the incorporation of chemoprophylactic treatments with the primary therapy in high-risk populations.
original article 21. Haioun C, Besson C, Lepage E et al. Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d’Etudes des Lymphomes de l’Adulte. Ann Oncol 2000; 11(6): 685–690. 22. Tomita N, Kodama F, Sakai R et al. Predictive factors for central nervous system involvement in non-Hodgkin’s lymphoma: significance of very high serum LDH concentrations. Leuk Lymphoma 2000; 38(3–4): 335–343. 23. Jahnke K, Thiel E, Martus P et al. Retrospective study of prognostic factors in non-Hodgkin lymphoma secondarily involving the central nervous system. Ann Hematol 2006; 85(1): 45–50.
Annals of Oncology
24. Bjorkholm M, Hagberg H, Holte H et al. Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up. Ann Oncol 2007; 18(6): 1085–1089. 25. Boehme V, Zeynalova S, Kloess M et al. Incidence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Ann Oncol 2007; 18(1): 149–157. 26. Bernstein SH, Unger JM, Leblanc M et al. Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: a 20-year follow-up analysis of SWOG 8516—the Southwest Oncology Group. J Clin Oncol 2009; 27(1): 114–119.
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