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Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis—A Systematic Review of Prospective Studies
Review
Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis—A Systematic Review of Prospective Studies Abhimanyu Ghose,1 Harold Kunal Elias,2 Gunjan Guha,3 Mahender Yellu,1 Ria Kundu,4 Tahir Latif1 Abstract Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximabbased chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: CNS prophylaxis, CNS relapse, DLBCL, Lymphoma, Rituximab
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% to 58% of cases.1 The survival rate has improved significantly with the addition of rituximab, a monoclonal antibody to CD20 to standard chemotherapy regimens.2,3 With the addition of rituximab to standard chemotherapy regimens, the overall 4-year 1 Division of Hematology Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 2 Division of Internal Medicine, St Lukes Roosevelt, New York, NY 3 School of Chemical and Biotechnology, Shanmugha Arts, Science, Technology and Research Academy University, Thanjavur, India 4 Good Samaritan Hospital, Cincinnati, OH
Submitted: Nov 23, 2014; Accepted: Feb 26, 2015 Address for correspondence: Abhimanyu Ghose, MD, Division of Hematology Oncology, University of Cincinnati College of Medicine, 3125 Eden Avenue, ML 0562, Cincinnati, OH 45219 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.026
survival rate has ranged from 55% to 94% using the revised International Prognostic Index (IPI) scores4 compared with a 5-year overall survival rate of 26% to 73% using the IPI scores before the use of rituximab.5 Central nervous system (CNS) complications of DLBCL are uncommon but result in an extremely guarded prognosis. The incidence rates of CNS disease in patients with DLBCL have been highly variable, ranging from 2% to 25%.6-9 This has resulted from the large variations in the study population, differences in the risk factors, and the lack of specific guidelines for diagnostic testing and offering prophylaxis to these patients. Some studies have found a decreased incidence of CNS relapse with the use of rituximab.9,10 In contrast, multiple studies have found no reduction in the incidence of CNS relapse despite using rituximab.11,12 Not only has the incidence of CNS relapse after the introduction of rituximab compared with that during the prerituximab era been controversial, but also the role of chemoprophylaxis to prevent CNS recurrence in patients with DLBCL has been controversial in the absence of randomized clinical trials.
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Influence of Rituximab on CNS Relapse in DLBCL Studies in both the pre- and post-rituximab eras have questioned the use of CNS prophylaxis and also the mode of such prophylaxis— intrathecal (IT) or systemic, or both.9,10,13-15 We performed a systematic analysis of the data available from prospective published studies. We analyzed the influence of rituximab on the incidence and pattern of CNS relapse and whether CNS-directed prophylaxis has any role in preventing this devastating complication.
Materials and Methods Search Strategy An extensive published data search was conducted by 3 of us independently in PubMed, EMBASE, and Cochrane Central Register of Controlled Clinical Trials (CENTRAL), since their inception until March 2014, using the keywords “central nervous system,” “diffuse large B-cell lymphoma,” “relapse,” “prophylaxis,” “rituximab,” and “CHOP.” The abstract databases of major international hematology oncology conferences, including American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO), and European Hematology Association (EHA), were also searched. The references of the original and review articles were cross-checked.
Selection Criteria The following criteria were adopted for selection of the publications for the present study: (1) prospective or randomized control trials; (2) trials in which all or a significant majority of patients had newly diagnosed DLBCL; (3) no evidence of CNS involvement at baseline; (4) the use of rituximab-based chemotherapy or CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone)-based chemotherapy; and (5) studies with relevant data on the incidence and types of CNS relapse, the incidence with or without prophylaxis, and survival after CNS relapse. The exclusion criteria were (1) retrospective studies; (2) review articles; (3) case reports; (4) studies exclusively of testicular or primary mediastinal lymphoma, double-hit lymphoma, or lymphoma in patients with human immunodeficiency virus; (5) incomplete data; (6) interim analyses; (7) unpublished data; and (8) language other than English.
Data Extraction
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A total of 250 publications were identified by searching PubMed, EMBASE, and CENTRAL. An additional 40 potential records were identified by searching the major international hematology oncology conferences—ASH, ASCO, and EHA. Elimination of the duplicate studies left 185 records. The initial screening process, consisting of a review of the title and abstract excluded 150 studies, because they did not meet our inclusion or did meet the exclusion criteria. A total of 35 articles were reviewed for eligibility by reading the full texts. Of these, 7 prospective studies met our eligibility criteria and were used in the present analysis.9-11,13,16-18 The reported data collected included the study characteristics, such as age, sex, number of patients in the study, patients with stage III or IV disease, IPI intermediate-high or high ( 3 IPI or 2 ageadjusted IPI), extranodal ( 2) disease, high lactate dehydrogenase (LDH), follow-up duration, criteria for CNS prophylaxis, patients receiving CNS prophylaxis, type of prophylaxis (IT or systemic), and chemotherapy regimen used. The data collected on the
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endpoints consisted of the incidence of CNS relapse, CNS relapse with individual chemotherapy, CNS relapse with and without prophylaxis, isolated CNS relapse, median interval to CNS relapse, pattern of CNS relapse (leptomeningeal or parenchymal), and survival after CNS disease.
Study Characteristics The characteristics of each study are listed in Table 1. The studies were fairly homogeneous with respect to the inclusion and exclusion criteria.
Statistical Analysis All analyses were performed and deemed significant at the 95% confidence limit. Data are presented as the mean standard error of the mean. Significant differences (at P < .05) between the groups and couplets were determined using 1-way analysis of variance (ANOVA) and the 2-tailed unpaired t test, respectively. Variances between groups were compared using the F test. The significance (P < .05) of the Kaplan-Meier survival curves was determined using the log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests. MATLAB, version 7.0 (MathWorks, Natick, MA), Prism, version 5.00 (GraphPad, La Jolla, CA), and Excel 2007 (Microsoft, Roselle, IL) were used for the statistical and graphic evaluations.
Results A total of 4859 patients were analyzed in the 7 prospective studies. The characteristics of the study population are listed in Table 1. Of the 7 studies, 3 used rituximab-based chemotherapy, of which 2 used R-CHOP (rituximab plus CHOP) and 1 used R-CHOEP (rituximab, CHOP, plus etoposide). Two studies used CHOP-based chemotherapy. Of these, Bernstein et al13 used other nonerituximab-based regimens, apart from CHOP. Two studies used both R-CHOP and CHOP. The mean incidence of CNS relapse with rituximab-based chemotherapy (ie, R-CHOP/R-CHOEP) was 5.52% 2.21% compared with 4.43% 0.9% with CHOP-based chemotherapy. No significant difference (P < .05) was found between the 2 groups (2-tailed unpaired t test). We analyzed the pattern of CNS relapse (leptomeningeal or parenchymal) with and without the addition of rituximab. For the group who received CHOP, the mean incidence of leptomeningeal involvement was 16.17% 0.44% compared with 38.62% 1.93% for those who received rituximab in addition to standard chemotherapy. This difference was statistically significant (P < .0001) when analyzed using the 2-tailed unpaired t test. Similarly, for parenchymal disease, the mean incidence was 66.17% 0.44% for CHOP and 57.32% 3.06% for rituximab-based chemotherapy, a significant improvement (P ¼ .03) with rituximab compared with CHOP therapy. When combined, both parenchymal and leptomeningeal recurrence showed a mean incidence of 22.06% 0.41% with CHOP compared with 5.36% 1.79% with rituximab-based chemotherapy. Again, rituximab showed significant improvement (P < .0001) compared with CHOP-based chemotherapy. One-way ANOVA also showed that the use of rituximab resulted in statistically significant (P < .0001) differences in the pattern of CNS relapse compared with the that with CHOP chemotherapy (Figure 1).
Table 1 Study Characteristics
Study
Age (years)
Sex (M/F)
Patients (n)
Tilly et al,17 2003
61-69
A versus C: M, 635 (501 DLBCL) 182 versus 177; F, 141 versus 135
Feugier et al,11 2004
69
M, 92 (CHOP-R) versus 107 (CHOP)
202 versus 197
NR
Aggressive lymphoma, 899
648 versus 569
1217 (944 DLBCL)
Bernstein et al,13 2009
97; 225 receiving CHOP were >60 years
Chemotherapy
Stage 3-4
IPI IntermediateHigh/High (‡3 IPI or ‡2 Extranodal AA-IPI) (‡2)
High LDH
Follow-Up Period (mo)
267 versus 253
210 versus 207 (AA-IPI)
155 versus 156
231 versus 241
68
202 R-CHOP 161 versus versus 197 157 CHOP 225 CHOP 191/225 versus ProMACECHOP CytaBOM versus mBACOD versus MACOP-B 608 R-CHOP 687 versus 609 CHOP
121 versus 120
61 versus 51
131 versus 132
24
95/225 CHOP
81/225 CHOP
146/225 CHOP
507
212
602
24
10.5
323 ACVBP versus 312 CHOP
20 years
68
Kim et al,18 2012 Kumar et al,9 2012
59.5
NR
564
R-CHOP
276
192
193
NR
56 (prophylaxis) versus 58 (no prophylaxis)
M, 74 versus 476; F, 43 versus 396
989
R-CHOP
85 versus 454
55 versus 240
66 versus 220
57 versus 372
30
97 versus 59
156 (145 DLBCL)
R-CHOEP
150
156
41
151
36
Holte et al,16 2013
54
Patients Receiving CNS Prophylaxis
CNS Relapse (%)
None for CHOP versus ACVBP (IV MTX, etoposide, ITMTX) NA
323 (ACVBP)
A, 2.8 C, 8.3
None
R, 5.4 C, 4.6
None for CHOP
121 IT-MTX or radiation (24 Gy)
C, 4.4 P, 3 mB, 2.2 MA, 1.4
Bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands 1 Risk factor
475/1217 (IT-MTX)
R-CHOP, 3.6 C, 5.9
59 IT
2.6
High-risk site: orbit, testis, peripheral blood, vertebra, bone marrow, nasal or paranasal sinuses All patients
117/989; IT, 84/117 (Ara-c/MTX); S, 33/117 (MTX)
2
156/156 (S, Ara-c þ MTX); 1 dose of IT-MTX
4.5
Abbreviations: A ¼ ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone); AA-IPI ¼ age-adjusted International Prognostic Index; B ¼ both; C ¼ CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone); CNS ¼ central nervous system; CR ¼ complete remission; DLBCL ¼ diffuse large B-cell lymphoma; F ¼ female; IT ¼ intrathecal; L ¼ leptomeningeal; LDH ¼ lactate dehydrogenase; M ¼ male; MA ¼ MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin); mB ¼ mBACOD (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], dexamethasone, with folinic acid and granulocyte-macrophage colony-stimulating factor); MTX ¼ methotrexate; NA ¼ not applicable; NR ¼ not reported; P ¼ parenchymal; PR/PD ¼ partial remission with progressive disease; ProMACE-CytaBOM ¼ cyclophosphamide, doxorubicin, etoposide cytozar, bleomycin, vincristine, methotrexate, prednisone; R ¼ rituximab; R-CHOEP ¼ rituximab with CHOP, plus etoposide; R-CHOP ¼ rituximab plus CHOP; S ¼ systemic.
Abhimanyu Ghose et al
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Boehme et al,10 2009
Criteria for CNS Prophylaxis
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Influence of Rituximab on CNS Relapse in DLBCL Figure 1 Pattern of Central Nervous System (CNS) Relapse With and Without Rituximab-Based Chemotherapy. Rituximab Does Not Decrease the Incidence of Leptomeningeal CNS Relapse (A); Rituximab Decreases the Incidence of Parenchymal CNS Relapse (B); and Rituximab Decreases Both Types of (Leptomeningeal Plus Parenchymal) CNS Relapse (C). Data Presented as the Mean ± the Standard Error of the Mean (P < .05)
Figure 2 Central Nervous System (CNS) Prophylaxis Significantly Decreases the Percentage of CNS Relapse. Data Presented as the Mean ± the Standard Error of the Mean; Significant at P < .05 (2-Tailed Unpaired t Test)
Abbreviations: CHOP ¼ Cyclophosphamide, Doxorubicin, Vincristine (Oncovin), Prednisone; R-CHOP ¼ Rituximab Plus CHOP.
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Considering the incidence of isolated CNS relapse, we did not find any significant differences (P < .05) between R-CHOP or R-CHOEP and CHOP chemotherapy. About 74.1% of CNS relapses among patients receiving rituximab-based chemotherapy were isolated CNS relapse compared with 69.2% for those receiving CHOP chemotherapy. For the total study population, the incidence of isolated CNS relapse was 48.7% of all CNS relapses, regardless of the chemotherapy regimen used. The mean incidence of CNS relapse with the use of prophylaxis was 2.97% 0.65% and significantly lower (P ¼ .044) than that without prophylaxis (6.12% 0.21%; Figure 2). No significant variance was observed in the results (F test, P y .399). The analyses of the studies that grouped patients to receive either IT or systemic chemotherapy revealed no significant differences between the 2 groups (P ¼ .2841). The incidence of CNS relapse for patients receiving IT chemotherapy was 2.4% 0.08% and for those receiving systemic chemoprophylaxis was 3.6% 0.85%. The median interval from the diagnosis of DLBCL to CNS relapse was not significantly different (P y .65) between patients receiving R-CHOP and those receiving CHOP-based chemotherapy—6.5 0.5 months with rituximab-based chemotherapy and 7 1 months with CHOP chemotherapy. However, the difference in the median duration of survival after CNS relapse of 365 days after rituximab-based chemotherapy and 75 days after CHOP was significantly different (P < .05). The hazard ratio was 4.867 0.77 at P < .05. The log-rank (Mantel-Cox) test c2 value was 96.82 (df ¼ 1), and the Gehan-Breslow-Wilcoxon test c2 value was 106.4 (df ¼ 1); hence, both tests showed significantly different survival curves at P < .0001 (Figure 3).
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Discussion Our analysis aimed to answer several controversies in the area of CNS relapse in patients with DLBCL—the influence of rituximab on the incidence of CNS relapse, the incidence of parenchymal versus leptomeningeal disease versus both, the benefit of prophylaxis in a high-risk population with DLBCL, and overall survival after CNS relapse with or without previous rituximab therapy. Rituximab is a chimeric IgG1 monoclonal antibody to the antigen CD20 on the B cells. Given systemically, it poorly penetrates the bloodebrain barrier. Intravenous administration of rituximab results in concentrations in the cerebrospinal fluid (CSF) of, at most, 0.1% of the serum levels.19 This might explain the lack of a difference in the incidence of CNS relapse with either CHOP or R-CHOP/R-CHOEP. In our study, the incidence of CNS relapse with rituximab-based chemotherapy was 5.52% 2.21% and that before the use of rituximab with CHOP chemotherapy was 4.43% 0.9%. Published case reports have demonstrated a cytologic response and symptomatic improvement in patients with CNS lymphoma from IT rituximab at doses of 10 to 40 mg.20-22 Not only rituximab, but also the standard CHOP-based chemotherapy, poorly penetrates the bloodebrain barrier. This was reflected by the large number of patients with isolated CNS relapse in the absence of systemic disease. For the total study population, regardless of the chemotherapy regimen used, the
Abhimanyu Ghose et al Figure 3 Kaplan-Meier Plot Illustrating the Median Survival Durations After Central Nervous System Disease Between R-CHOP (Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine [Oncovin], Prednisone) and CHOP (Cyclophosphamide, Doxorubicin, Vincristine [Oncovin], Prednisone) Chemotherapy Regimens. Patients Receiving R-CHOP Had Longer Survival Times (Solid Line) Than Patients Receiving CHOP (Dashed Line; P < .0001). The Hazard Ratio (CHOP vs. R-CHOP) Was 4.867 ± 0.77 at P < .05
incidence of isolated CNS relapse was 48.7%. Apart from the study by Feugier et al,11 which reported only 3 of 20 isolated CNS events, all the studies reported an incidence of > 50% of isolated CNS relapse in the absence of systemic recurrence. No influence of rituximab on the incidence of isolated CNS relapse was found. Leptomeningeal disease was more common than parenchymal disease in the pre-rituximab era according to the Southwestern Oncology Group 8516 trial.13 However, in the post-rituximab era, parenchymal disease was more common, according to a few studies.23,24 The results of our systematic analysis demonstrated that the incidence of leptomeningeal disease is significantly greater in patients treated with rituximab—38.62% versus 16.17%. This is in accordance with the findings from the RICOVER-60 trial (a randomized control trial studying six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20þ B-cell lymphomas), which demonstrated similar findings and the poor CSF concentrations obtained with intravenous rituximab.10 Rituximab use significantly decreased the incidence of parenchymal only disease and parenchymal plus leptomeningeal disease. The median interval from the diagnosis of DLBCL to CNS relapse was 6.5 to 7 months, regardless of the use of rituximab. We found no statistically significant (P < .05) differences between the 2 groups. According to the published data, the median interval from the diagnosis of DLBCL to CNS relapse has varied from 6 months to 1 year.13,25,26 The development of CNS recurrence within such a short duration, during or immediately after initial chemotherapy, might indicate the presence of subclinical CNS disease at diagnosis. The development of better diagnostic methods to identify the
presence of CNS disease at diagnosis is important, because these patients will benefit from upfront CNS-directed therapy. It requires a thorough history and neurologic examination, neuroimaging, including magnetic resonance imaging of the brain and spine and CSF evaluation using both conventional cytology and flow cytometry. The addition of flow cytometry to conventional cytology of the CSF increases the sensitivity of identifying CNS disease to 50%.8,27,28 Assessing for monoclonality by IgH gene rearrangement is an additional diagnostic tool that might prove useful.29,30 The evidence is conflicting on the benefit of CNS prophylaxis in patients with DLBCL. This area is of intense controversy and has been discussed in detail in our previous review.31 Our results have indicated a statistically significant (P < .05) decrease in the incidence of CNS relapse. The incidence was 2.97% 0.65% in patients who had received prophylaxis compared with 6.12% 0.21% in those who had not. This demonstrates the benefit of chemoprophylaxis for patients with DLBCL. However, prophylaxis cannot be offered to every patient with DLBCL because of its inherent risks. Therefore, it is vital to recognize the highrisk patients who might benefit from prophylaxis. The risk factors found to be associated with a high risk of CNS relapse include testicular involvement of lymphoma; breast, parameningeal, and bone marrow involvement; a high IPI score, a high LDH level, higher stage, > 1 extranodal site, and B symptoms.23,32-34 Some of these factors, such as bone marrow involvement, IPI score, and B symptoms, have not been consistently shown to be associated with greater risk.15,25,35 A combination of these factors has been more consistently associated with a greater risk of CNS recurrence.32 We have previously suggested an algorithm to help physicians decide which patients might benefit from CNS prophylaxis (Figure 4).31 A recently published meta-analysis showed that the incidence of CNS relapse is less with the use of rituximab-based chemotherapy and that IT prophylaxis has no benefit in the prevention of CNS relapse.36 However, unlike our study, that meta-analysis also included retrospective studies. One of the weaknesses of our study was that we analyzed prospectively collected data from studies, whose primary endpoints might not have been the incidence of CNS relapse. This might have led to variability among the study populations and inaccurate reporting. Also, the data on CNS relapse with and without prophylaxis were limited and not available in all the studies. However, the variability of the study population emphasizes the need for CNS prophylaxis in high-risk patients, because the incidence of CNS relapse might have been inadvertently lower because of the incorporation of lower risk patients. We found no significant difference from whether the prophylaxis was given using the systemic or IT route. It must be highlighted that we did not have enough patients for this particular analysis, because only a few studies had differentiated the incidence of CNS relapse on the basis of the mode of prophylaxis. Also, the 2 studies that used systemic chemoprophylaxis had also incorporated a few doses (1 to 4) of IT methotrexate.16,17 This might have confounded the results. Large randomized clinical trials are warranted to definitely answer this important question.
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Influence of Rituximab on CNS Relapse in DLBCL Figure 4 Suggested Algorithm for Prophylactic Central Nervous System (CNS)-Directed Therapy
Abbreviations: chemo ¼ chemotherapy; DLBCL ¼ diffuse large B-cell lymphoma; IPI ¼ International Prognostic Index; IT ¼ intrathecal; LDH ¼ lactate dehydrogenase; LNs ¼ lymph nodes; RCHOP ¼ Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine (Oncovin), Prednisone. Reprinted with permission from Ghose et al. Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma. Crit Rev Oncol Hematol 2014; 91:292-303.
The median duration of survival after CNS relapse was significantly (P < .05) better in the rituximab era. The exact reason is unclear but might have resulted from advancements in management, including the supportive care of these patients, during the past decade.
Conclusion CNS relapse is an uncommon complication of DLBCL and carries a dismal prognosis. The addition of rituximab to the standard chemotherapy did not reduce the incidence of CNS recurrence, which has been around 5.5%. The median interval from diagnosis of DLBCL to CNS relapse of 6.5 to 7 months has not changed significantly with addition of rituximab. Leptomeningeal disease was more common in patients treated with rituximab-based chemotherapy than was parenchymal. CNS prophylaxis was found to reduce the incidence of CNS relapse and should be considered in high-risk populations. A large randomized control trial is warranted to differentiate the best modality for CNS prophylaxis—IT versus systemic. The survival after CNS relapse has significantly improved in the rituximab era.
Clinical Practice Points CNS relapse in DLBCL patients carries a very poor prognosis Using rituximab hasn’t changed the incidence of CNS relapse
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significantly, nor the median interval from diagnosis to CNS
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relapse. But patients seem to live longer after CNS relapse in rituximab era There is a definite role for CNS directed prophylactic chemotherapy in high risk population, even in rituximab era To answer the question of whether intrathecal or systemic chemoprophylaxis or both is necessary, we need a well designed randomized clinical trial
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011; 117:5019-32. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:11-30. 3. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20þ B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:2373-80. 4. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109:1857-61. 5. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329:987-94. 6. 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; 18:149-57.
Abhimanyu Ghose et al 7. Bierman P, Giglio P. Diagnosis and treatment of central nervous system involvement in non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am 2005; 19:597-609, v. 8. 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; 105:496-502. 9. Kumar A, Vanderplas A, LaCasce AS, et al. Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database. Cancer 2012; 118:2944-51. 10. Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. 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; 113:3896-902. 11. 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; 15:129-33. 12. Tomita N, Yokoyama M, Yamamoto W, et al. Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era. Cancer Sci 2012; 103:245-51. 13. Bernstein SH, Unger JM, Leblanc M, Friedberg J, Miller TP, Fisher RI. 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; 27:114-9. 14. Schmitz N, Zeynalova S, Glass B, et al. CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Ann Oncol 2012; 23:1267-73. 15. 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; 11:685-90. 16. Holte H, Leppa S, Bjorkholm M, et al. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol 2013; 24:1385-92. 17. Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive nonHodgkin lymphoma. Blood 2003; 102:4284-9. 18. Kim SJ PY, Lee SL, Eom HS, et al. Prospective cohort study with risk-adapted central nervous system (CNS) evaluation in diffuse large B-cell lymphoma patients treated with rituximab-CHOP: analysis of incidence and risk factors for secondary CNS involvement. Paper presented at: 54th Annual ASH Meeting; December 8-11; Atlanta, GA; 2012. Available at: https://ash.confex.com/ash/ 2012/webprogram/Paper51105.html. Accessed October 13, 2014. 19. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007; 25:1350-6.
20. Schulz H, Pels H, Schmidt-Wolf I, Zeelen U, Germing U, Engert A. Intraventricular treatment of relapsed central nervous system lymphoma with the antiCD20 antibody rituximab. Haematologica 2004; 89:753-4. 21. Antonini G, Cox MC, Montefusco E, et al. Intrathecal anti-CD20 antibody: an effective and safe treatment for leptomeningeal lymphoma. J Neurooncol 2007; 81: 197-9. 22. Pels H, Schulz H, Manzke O, Hom E, Thall A, Engert A. Intraventricular and intravenous treatment of a patient with refractory primary CNS lymphoma using rituximab. J Neurooncol 2002; 59:213-6. 23. 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; 89:577-83. 24. Villa D, Connors JM, Shenkier TN, Gascoyne RD, Sehn LH, Savage KJ. 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. Ann Oncol 2010; 21:1046-52. 25. 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; 91:1178-84. 26. Tai WM, Chung J, Tang PL, et al. Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab. Ann Hematol 2011; 90:809-18. 27. French CA, Dorfman DM, Shaheen G, Cibas ES. Diagnosing lymphoproliferative disorders involving the cerebrospinal fluid: increased sensitivity using flow cytometric analysis. Diagn Cytopathol 2000; 23:369-74. 28. Roma AA, Garcia A, Avagnina A, Rescia C, Elsner B. Lymphoid and myeloid neoplasms involving cerebrospinal fluid: comparison of morphologic examination and immunophenotyping by flow cytometry. Diagn Cytopathol 2002; 27: 271-5. 29. Baehring JM, Hochberg FH, Betensky RA, Longtine J, Sklar J. Immunoglobulin gene rearrangement analysis in cerebrospinal fluid of patients with lymphoproliferative processes. J Neurol Sci 2006; 247:208-16. 30. Kros JM, Bagdi EK, Zheng P, et al. Analysis of immunoglobulin H gene rearrangement by polymerase chain reaction in primary central nervous system lymphoma. J Neurosurg 2002; 97:1390-6. 31. Ghose A, Kundu R, Latif T. Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma. Crit Rev Oncol Hematol 2014; 91:292-303. 32. Hollender A, Kvaloy S, Lote K, Nome O, Holte H. Prognostic factors in 140 adult patients with non-Hodgkin’s lymphoma with systemic central nervous system (CNS) involvement: a single centre analysis. Eur J Cancer 2000; 36:1762-8. 33. Hill QA, Owen RG. CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood Rev 2006; 20:319-32. 34. Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol 2002; 13:1099-107. 35. Yamamoto W, Tomita N, Watanabe R, et al. Central nervous system involvement in diffuse large B-cell lymphoma. Eur J Haematol 2010; 85:6-10. 36. Zhang J, Chen B, Xu X. Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis. Leuk Lymphoma 2014; 55:509-14.
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Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis—A Systematic Review of Prospective Studies Abhimanyu Ghose,1 Harold Kunal Elias,2 Gunjan Guha,3 Mahender Yellu,1 Ria Kundu,4 Tahir Latif1 Abstract Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximabbased chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: CNS prophylaxis, CNS relapse, DLBCL, Lymphoma, Rituximab
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% to 58% of cases.1 The survival rate has improved significantly with the addition of rituximab, a monoclonal antibody to CD20 to standard chemotherapy regimens.2,3 With the addition of rituximab to standard chemotherapy regimens, the overall 4-year 1 Division of Hematology Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 2 Division of Internal Medicine, St Lukes Roosevelt, New York, NY 3 School of Chemical and Biotechnology, Shanmugha Arts, Science, Technology and Research Academy University, Thanjavur, India 4 Good Samaritan Hospital, Cincinnati, OH
Submitted: Nov 23, 2014; Accepted: Feb 26, 2015 Address for correspondence: Abhimanyu Ghose, MD, Division of Hematology Oncology, University of Cincinnati College of Medicine, 3125 Eden Avenue, ML 0562, Cincinnati, OH 45219 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.026
survival rate has ranged from 55% to 94% using the revised International Prognostic Index (IPI) scores4 compared with a 5-year overall survival rate of 26% to 73% using the IPI scores before the use of rituximab.5 Central nervous system (CNS) complications of DLBCL are uncommon but result in an extremely guarded prognosis. The incidence rates of CNS disease in patients with DLBCL have been highly variable, ranging from 2% to 25%.6-9 This has resulted from the large variations in the study population, differences in the risk factors, and the lack of specific guidelines for diagnostic testing and offering prophylaxis to these patients. Some studies have found a decreased incidence of CNS relapse with the use of rituximab.9,10 In contrast, multiple studies have found no reduction in the incidence of CNS relapse despite using rituximab.11,12 Not only has the incidence of CNS relapse after the introduction of rituximab compared with that during the prerituximab era been controversial, but also the role of chemoprophylaxis to prevent CNS recurrence in patients with DLBCL has been controversial in the absence of randomized clinical trials.
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Influence of Rituximab on CNS Relapse in DLBCL Studies in both the pre- and post-rituximab eras have questioned the use of CNS prophylaxis and also the mode of such prophylaxis— intrathecal (IT) or systemic, or both.9,10,13-15 We performed a systematic analysis of the data available from prospective published studies. We analyzed the influence of rituximab on the incidence and pattern of CNS relapse and whether CNS-directed prophylaxis has any role in preventing this devastating complication.
Materials and Methods Search Strategy An extensive published data search was conducted by 3 of us independently in PubMed, EMBASE, and Cochrane Central Register of Controlled Clinical Trials (CENTRAL), since their inception until March 2014, using the keywords “central nervous system,” “diffuse large B-cell lymphoma,” “relapse,” “prophylaxis,” “rituximab,” and “CHOP.” The abstract databases of major international hematology oncology conferences, including American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO), and European Hematology Association (EHA), were also searched. The references of the original and review articles were cross-checked.
Selection Criteria The following criteria were adopted for selection of the publications for the present study: (1) prospective or randomized control trials; (2) trials in which all or a significant majority of patients had newly diagnosed DLBCL; (3) no evidence of CNS involvement at baseline; (4) the use of rituximab-based chemotherapy or CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone)-based chemotherapy; and (5) studies with relevant data on the incidence and types of CNS relapse, the incidence with or without prophylaxis, and survival after CNS relapse. The exclusion criteria were (1) retrospective studies; (2) review articles; (3) case reports; (4) studies exclusively of testicular or primary mediastinal lymphoma, double-hit lymphoma, or lymphoma in patients with human immunodeficiency virus; (5) incomplete data; (6) interim analyses; (7) unpublished data; and (8) language other than English.
Data Extraction
2
-
A total of 250 publications were identified by searching PubMed, EMBASE, and CENTRAL. An additional 40 potential records were identified by searching the major international hematology oncology conferences—ASH, ASCO, and EHA. Elimination of the duplicate studies left 185 records. The initial screening process, consisting of a review of the title and abstract excluded 150 studies, because they did not meet our inclusion or did meet the exclusion criteria. A total of 35 articles were reviewed for eligibility by reading the full texts. Of these, 7 prospective studies met our eligibility criteria and were used in the present analysis.9-11,13,16-18 The reported data collected included the study characteristics, such as age, sex, number of patients in the study, patients with stage III or IV disease, IPI intermediate-high or high ( 3 IPI or 2 ageadjusted IPI), extranodal ( 2) disease, high lactate dehydrogenase (LDH), follow-up duration, criteria for CNS prophylaxis, patients receiving CNS prophylaxis, type of prophylaxis (IT or systemic), and chemotherapy regimen used. The data collected on the
Clinical Lymphoma, Myeloma & Leukemia Month 2015
endpoints consisted of the incidence of CNS relapse, CNS relapse with individual chemotherapy, CNS relapse with and without prophylaxis, isolated CNS relapse, median interval to CNS relapse, pattern of CNS relapse (leptomeningeal or parenchymal), and survival after CNS disease.
Study Characteristics The characteristics of each study are listed in Table 1. The studies were fairly homogeneous with respect to the inclusion and exclusion criteria.
Statistical Analysis All analyses were performed and deemed significant at the 95% confidence limit. Data are presented as the mean standard error of the mean. Significant differences (at P < .05) between the groups and couplets were determined using 1-way analysis of variance (ANOVA) and the 2-tailed unpaired t test, respectively. Variances between groups were compared using the F test. The significance (P < .05) of the Kaplan-Meier survival curves was determined using the log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests. MATLAB, version 7.0 (MathWorks, Natick, MA), Prism, version 5.00 (GraphPad, La Jolla, CA), and Excel 2007 (Microsoft, Roselle, IL) were used for the statistical and graphic evaluations.
Results A total of 4859 patients were analyzed in the 7 prospective studies. The characteristics of the study population are listed in Table 1. Of the 7 studies, 3 used rituximab-based chemotherapy, of which 2 used R-CHOP (rituximab plus CHOP) and 1 used R-CHOEP (rituximab, CHOP, plus etoposide). Two studies used CHOP-based chemotherapy. Of these, Bernstein et al13 used other nonerituximab-based regimens, apart from CHOP. Two studies used both R-CHOP and CHOP. The mean incidence of CNS relapse with rituximab-based chemotherapy (ie, R-CHOP/R-CHOEP) was 5.52% 2.21% compared with 4.43% 0.9% with CHOP-based chemotherapy. No significant difference (P < .05) was found between the 2 groups (2-tailed unpaired t test). We analyzed the pattern of CNS relapse (leptomeningeal or parenchymal) with and without the addition of rituximab. For the group who received CHOP, the mean incidence of leptomeningeal involvement was 16.17% 0.44% compared with 38.62% 1.93% for those who received rituximab in addition to standard chemotherapy. This difference was statistically significant (P < .0001) when analyzed using the 2-tailed unpaired t test. Similarly, for parenchymal disease, the mean incidence was 66.17% 0.44% for CHOP and 57.32% 3.06% for rituximab-based chemotherapy, a significant improvement (P ¼ .03) with rituximab compared with CHOP therapy. When combined, both parenchymal and leptomeningeal recurrence showed a mean incidence of 22.06% 0.41% with CHOP compared with 5.36% 1.79% with rituximab-based chemotherapy. Again, rituximab showed significant improvement (P < .0001) compared with CHOP-based chemotherapy. One-way ANOVA also showed that the use of rituximab resulted in statistically significant (P < .0001) differences in the pattern of CNS relapse compared with the that with CHOP chemotherapy (Figure 1).
Table 1 Study Characteristics
Study
Age (years)
Sex (M/F)
Patients (n)
Tilly et al,17 2003
61-69
A versus C: M, 635 (501 DLBCL) 182 versus 177; F, 141 versus 135
Feugier et al,11 2004
69
M, 92 (CHOP-R) versus 107 (CHOP)
202 versus 197
NR
Aggressive lymphoma, 899
648 versus 569
1217 (944 DLBCL)
Bernstein et al,13 2009
97; 225 receiving CHOP were >60 years
Chemotherapy
Stage 3-4
IPI IntermediateHigh/High (‡3 IPI or ‡2 Extranodal AA-IPI) (‡2)
High LDH
Follow-Up Period (mo)
267 versus 253
210 versus 207 (AA-IPI)
155 versus 156
231 versus 241
68
202 R-CHOP 161 versus versus 197 157 CHOP 225 CHOP 191/225 versus ProMACECHOP CytaBOM versus mBACOD versus MACOP-B 608 R-CHOP 687 versus 609 CHOP
121 versus 120
61 versus 51
131 versus 132
24
95/225 CHOP
81/225 CHOP
146/225 CHOP
507
212
602
24
10.5
323 ACVBP versus 312 CHOP
20 years
68
Kim et al,18 2012 Kumar et al,9 2012
59.5
NR
564
R-CHOP
276
192
193
NR
56 (prophylaxis) versus 58 (no prophylaxis)
M, 74 versus 476; F, 43 versus 396
989
R-CHOP
85 versus 454
55 versus 240
66 versus 220
57 versus 372
30
97 versus 59
156 (145 DLBCL)
R-CHOEP
150
156
41
151
36
Holte et al,16 2013
54
Patients Receiving CNS Prophylaxis
CNS Relapse (%)
None for CHOP versus ACVBP (IV MTX, etoposide, ITMTX) NA
323 (ACVBP)
A, 2.8 C, 8.3
None
R, 5.4 C, 4.6
None for CHOP
121 IT-MTX or radiation (24 Gy)
C, 4.4 P, 3 mB, 2.2 MA, 1.4
Bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands 1 Risk factor
475/1217 (IT-MTX)
R-CHOP, 3.6 C, 5.9
59 IT
2.6
High-risk site: orbit, testis, peripheral blood, vertebra, bone marrow, nasal or paranasal sinuses All patients
117/989; IT, 84/117 (Ara-c/MTX); S, 33/117 (MTX)
2
156/156 (S, Ara-c þ MTX); 1 dose of IT-MTX
4.5
Abbreviations: A ¼ ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone); AA-IPI ¼ age-adjusted International Prognostic Index; B ¼ both; C ¼ CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone); CNS ¼ central nervous system; CR ¼ complete remission; DLBCL ¼ diffuse large B-cell lymphoma; F ¼ female; IT ¼ intrathecal; L ¼ leptomeningeal; LDH ¼ lactate dehydrogenase; M ¼ male; MA ¼ MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin); mB ¼ mBACOD (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], dexamethasone, with folinic acid and granulocyte-macrophage colony-stimulating factor); MTX ¼ methotrexate; NA ¼ not applicable; NR ¼ not reported; P ¼ parenchymal; PR/PD ¼ partial remission with progressive disease; ProMACE-CytaBOM ¼ cyclophosphamide, doxorubicin, etoposide cytozar, bleomycin, vincristine, methotrexate, prednisone; R ¼ rituximab; R-CHOEP ¼ rituximab with CHOP, plus etoposide; R-CHOP ¼ rituximab plus CHOP; S ¼ systemic.
Abhimanyu Ghose et al
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Boehme et al,10 2009
Criteria for CNS Prophylaxis
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Influence of Rituximab on CNS Relapse in DLBCL Figure 1 Pattern of Central Nervous System (CNS) Relapse With and Without Rituximab-Based Chemotherapy. Rituximab Does Not Decrease the Incidence of Leptomeningeal CNS Relapse (A); Rituximab Decreases the Incidence of Parenchymal CNS Relapse (B); and Rituximab Decreases Both Types of (Leptomeningeal Plus Parenchymal) CNS Relapse (C). Data Presented as the Mean ± the Standard Error of the Mean (P < .05)
Figure 2 Central Nervous System (CNS) Prophylaxis Significantly Decreases the Percentage of CNS Relapse. Data Presented as the Mean ± the Standard Error of the Mean; Significant at P < .05 (2-Tailed Unpaired t Test)
Abbreviations: CHOP ¼ Cyclophosphamide, Doxorubicin, Vincristine (Oncovin), Prednisone; R-CHOP ¼ Rituximab Plus CHOP.
4
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Considering the incidence of isolated CNS relapse, we did not find any significant differences (P < .05) between R-CHOP or R-CHOEP and CHOP chemotherapy. About 74.1% of CNS relapses among patients receiving rituximab-based chemotherapy were isolated CNS relapse compared with 69.2% for those receiving CHOP chemotherapy. For the total study population, the incidence of isolated CNS relapse was 48.7% of all CNS relapses, regardless of the chemotherapy regimen used. The mean incidence of CNS relapse with the use of prophylaxis was 2.97% 0.65% and significantly lower (P ¼ .044) than that without prophylaxis (6.12% 0.21%; Figure 2). No significant variance was observed in the results (F test, P y .399). The analyses of the studies that grouped patients to receive either IT or systemic chemotherapy revealed no significant differences between the 2 groups (P ¼ .2841). The incidence of CNS relapse for patients receiving IT chemotherapy was 2.4% 0.08% and for those receiving systemic chemoprophylaxis was 3.6% 0.85%. The median interval from the diagnosis of DLBCL to CNS relapse was not significantly different (P y .65) between patients receiving R-CHOP and those receiving CHOP-based chemotherapy—6.5 0.5 months with rituximab-based chemotherapy and 7 1 months with CHOP chemotherapy. However, the difference in the median duration of survival after CNS relapse of 365 days after rituximab-based chemotherapy and 75 days after CHOP was significantly different (P < .05). The hazard ratio was 4.867 0.77 at P < .05. The log-rank (Mantel-Cox) test c2 value was 96.82 (df ¼ 1), and the Gehan-Breslow-Wilcoxon test c2 value was 106.4 (df ¼ 1); hence, both tests showed significantly different survival curves at P < .0001 (Figure 3).
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Discussion Our analysis aimed to answer several controversies in the area of CNS relapse in patients with DLBCL—the influence of rituximab on the incidence of CNS relapse, the incidence of parenchymal versus leptomeningeal disease versus both, the benefit of prophylaxis in a high-risk population with DLBCL, and overall survival after CNS relapse with or without previous rituximab therapy. Rituximab is a chimeric IgG1 monoclonal antibody to the antigen CD20 on the B cells. Given systemically, it poorly penetrates the bloodebrain barrier. Intravenous administration of rituximab results in concentrations in the cerebrospinal fluid (CSF) of, at most, 0.1% of the serum levels.19 This might explain the lack of a difference in the incidence of CNS relapse with either CHOP or R-CHOP/R-CHOEP. In our study, the incidence of CNS relapse with rituximab-based chemotherapy was 5.52% 2.21% and that before the use of rituximab with CHOP chemotherapy was 4.43% 0.9%. Published case reports have demonstrated a cytologic response and symptomatic improvement in patients with CNS lymphoma from IT rituximab at doses of 10 to 40 mg.20-22 Not only rituximab, but also the standard CHOP-based chemotherapy, poorly penetrates the bloodebrain barrier. This was reflected by the large number of patients with isolated CNS relapse in the absence of systemic disease. For the total study population, regardless of the chemotherapy regimen used, the
Abhimanyu Ghose et al Figure 3 Kaplan-Meier Plot Illustrating the Median Survival Durations After Central Nervous System Disease Between R-CHOP (Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine [Oncovin], Prednisone) and CHOP (Cyclophosphamide, Doxorubicin, Vincristine [Oncovin], Prednisone) Chemotherapy Regimens. Patients Receiving R-CHOP Had Longer Survival Times (Solid Line) Than Patients Receiving CHOP (Dashed Line; P < .0001). The Hazard Ratio (CHOP vs. R-CHOP) Was 4.867 ± 0.77 at P < .05
incidence of isolated CNS relapse was 48.7%. Apart from the study by Feugier et al,11 which reported only 3 of 20 isolated CNS events, all the studies reported an incidence of > 50% of isolated CNS relapse in the absence of systemic recurrence. No influence of rituximab on the incidence of isolated CNS relapse was found. Leptomeningeal disease was more common than parenchymal disease in the pre-rituximab era according to the Southwestern Oncology Group 8516 trial.13 However, in the post-rituximab era, parenchymal disease was more common, according to a few studies.23,24 The results of our systematic analysis demonstrated that the incidence of leptomeningeal disease is significantly greater in patients treated with rituximab—38.62% versus 16.17%. This is in accordance with the findings from the RICOVER-60 trial (a randomized control trial studying six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20þ B-cell lymphomas), which demonstrated similar findings and the poor CSF concentrations obtained with intravenous rituximab.10 Rituximab use significantly decreased the incidence of parenchymal only disease and parenchymal plus leptomeningeal disease. The median interval from the diagnosis of DLBCL to CNS relapse was 6.5 to 7 months, regardless of the use of rituximab. We found no statistically significant (P < .05) differences between the 2 groups. According to the published data, the median interval from the diagnosis of DLBCL to CNS relapse has varied from 6 months to 1 year.13,25,26 The development of CNS recurrence within such a short duration, during or immediately after initial chemotherapy, might indicate the presence of subclinical CNS disease at diagnosis. The development of better diagnostic methods to identify the
presence of CNS disease at diagnosis is important, because these patients will benefit from upfront CNS-directed therapy. It requires a thorough history and neurologic examination, neuroimaging, including magnetic resonance imaging of the brain and spine and CSF evaluation using both conventional cytology and flow cytometry. The addition of flow cytometry to conventional cytology of the CSF increases the sensitivity of identifying CNS disease to 50%.8,27,28 Assessing for monoclonality by IgH gene rearrangement is an additional diagnostic tool that might prove useful.29,30 The evidence is conflicting on the benefit of CNS prophylaxis in patients with DLBCL. This area is of intense controversy and has been discussed in detail in our previous review.31 Our results have indicated a statistically significant (P < .05) decrease in the incidence of CNS relapse. The incidence was 2.97% 0.65% in patients who had received prophylaxis compared with 6.12% 0.21% in those who had not. This demonstrates the benefit of chemoprophylaxis for patients with DLBCL. However, prophylaxis cannot be offered to every patient with DLBCL because of its inherent risks. Therefore, it is vital to recognize the highrisk patients who might benefit from prophylaxis. The risk factors found to be associated with a high risk of CNS relapse include testicular involvement of lymphoma; breast, parameningeal, and bone marrow involvement; a high IPI score, a high LDH level, higher stage, > 1 extranodal site, and B symptoms.23,32-34 Some of these factors, such as bone marrow involvement, IPI score, and B symptoms, have not been consistently shown to be associated with greater risk.15,25,35 A combination of these factors has been more consistently associated with a greater risk of CNS recurrence.32 We have previously suggested an algorithm to help physicians decide which patients might benefit from CNS prophylaxis (Figure 4).31 A recently published meta-analysis showed that the incidence of CNS relapse is less with the use of rituximab-based chemotherapy and that IT prophylaxis has no benefit in the prevention of CNS relapse.36 However, unlike our study, that meta-analysis also included retrospective studies. One of the weaknesses of our study was that we analyzed prospectively collected data from studies, whose primary endpoints might not have been the incidence of CNS relapse. This might have led to variability among the study populations and inaccurate reporting. Also, the data on CNS relapse with and without prophylaxis were limited and not available in all the studies. However, the variability of the study population emphasizes the need for CNS prophylaxis in high-risk patients, because the incidence of CNS relapse might have been inadvertently lower because of the incorporation of lower risk patients. We found no significant difference from whether the prophylaxis was given using the systemic or IT route. It must be highlighted that we did not have enough patients for this particular analysis, because only a few studies had differentiated the incidence of CNS relapse on the basis of the mode of prophylaxis. Also, the 2 studies that used systemic chemoprophylaxis had also incorporated a few doses (1 to 4) of IT methotrexate.16,17 This might have confounded the results. Large randomized clinical trials are warranted to definitely answer this important question.
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Influence of Rituximab on CNS Relapse in DLBCL Figure 4 Suggested Algorithm for Prophylactic Central Nervous System (CNS)-Directed Therapy
Abbreviations: chemo ¼ chemotherapy; DLBCL ¼ diffuse large B-cell lymphoma; IPI ¼ International Prognostic Index; IT ¼ intrathecal; LDH ¼ lactate dehydrogenase; LNs ¼ lymph nodes; RCHOP ¼ Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine (Oncovin), Prednisone. Reprinted with permission from Ghose et al. Prophylactic CNS directed therapy in systemic diffuse large B cell lymphoma. Crit Rev Oncol Hematol 2014; 91:292-303.
The median duration of survival after CNS relapse was significantly (P < .05) better in the rituximab era. The exact reason is unclear but might have resulted from advancements in management, including the supportive care of these patients, during the past decade.
Conclusion CNS relapse is an uncommon complication of DLBCL and carries a dismal prognosis. The addition of rituximab to the standard chemotherapy did not reduce the incidence of CNS recurrence, which has been around 5.5%. The median interval from diagnosis of DLBCL to CNS relapse of 6.5 to 7 months has not changed significantly with addition of rituximab. Leptomeningeal disease was more common in patients treated with rituximab-based chemotherapy than was parenchymal. CNS prophylaxis was found to reduce the incidence of CNS relapse and should be considered in high-risk populations. A large randomized control trial is warranted to differentiate the best modality for CNS prophylaxis—IT versus systemic. The survival after CNS relapse has significantly improved in the rituximab era.
Clinical Practice Points CNS relapse in DLBCL patients carries a very poor prognosis Using rituximab hasn’t changed the incidence of CNS relapse
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significantly, nor the median interval from diagnosis to CNS
Clinical Lymphoma, Myeloma & Leukemia Month 2015
relapse. But patients seem to live longer after CNS relapse in rituximab era There is a definite role for CNS directed prophylactic chemotherapy in high risk population, even in rituximab era To answer the question of whether intrathecal or systemic chemoprophylaxis or both is necessary, we need a well designed randomized clinical trial
Disclosure The authors have stated that they have no conflicts of interest.
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