Secondary CNS Relapse in DLBCL in the Rituximab Era - an Analysis of Prospective Studies
Authors: Ghose Abhimanyu , Elias Harold Kunal , Guha Gunjan , Yellu Mahender , Kundu Ria , Latif Tahir 
Published: October 2019

Abstract
INTRODUCTION
CNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy.
METHOD
Extensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords CNS, diffuse large B-cell lymphoma, relapse, prophylaxis, rituximab, CHOP were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P<0.05) between groups and couplets were determined by one-way ANOVA and by two-tailed unpaired t-test respectively. Significance of the Kaplan-Meier survival curves was determined using Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests.
RESULTS
The study population characteristics are shown in Table. The mean incidence of CNS relapse with rituximab-chemotherapy (R-CHOP/R-CHOEP) was found to be 5.52% (3.21%-7.73%), while that with CHOP-based chemotherapy alone was 4.43% (3.53% -5.33%). No significant difference was observed by two-tailed unpaired t test (P = 0.94). The median time from diagnosis to CNS relapse was 6.5-7 months. The mean incidence of leptomeningeal, parenchymal and both relapses in the rituximab-chemotherapy group were 38.62(±1.93)%, 57.32(±3.06)%, 5.36(±1.79)% compared to 16.17(±0.44)%, 66.17(±0.44)%, 22.06(±0.41)% with chemotherapy alone. One-way ANOVA also showed that use of rituximab resulted in statistically significant (P<0.0001) differences between the patterns of CNS relapse. About 74.1% of CNS relapses among patients receiving rituximab-chemotherapy were isolated CNS relapse, compared to 69.2% for those receiving CHOP chemotherapy. The mean incidence of CNS relapse with the use of any prophylactic CNS directed therapy was observed to be a significantly (P = 0.044) lower [2.97% (2.32%-3.62%)] compared to that without [6.12% (5.91%-6.335]. Median survival following CNS relapse of 365 days following rituximab based chemotherapy and 75 days after CHOP were significantly different (HR for CHOP use 4.867±0.77 at P<0.05).
CONCLUSION
Rituximab hasn't significantly decreased overall incidence, but causes less parenchymal CNS relapse. CNS prophylaxis has a definite role in high risk population. There is significantly better survival after CNS relapse in the rituximab era.
Abstract 1644. TABLE STUDY Age (yr) Sex (M:F) No. Stage 3/4 IPI int-high/ high (>=3 IPI or >=2 aa IPI) Extranodal (>=2) high LDH Follow up (m) Criteria for CNS prophylaxis Patients receiving CNS prophylaxis (IT=intrathecal, S=systemic) Chemo Tilly 2003 61-69 ACVBP vs CHOP : M 182 vs 177 F 141 vs 135 635 (501 DLBCL) 267 vs 253 210 vs 207 (aa IPI) 155 VS 156 231 VS 241 68 None for CHOP VS ACVBP (IV methotrexate, etop + IT mtx) 323 (ACVBP) 323 ACVBP vs 312 CHOP Feugier 2004 69 M 92 (CHOP-R) vs 107 (CHOP) 202 vs 197 161 vs 157 121 vs 120 61 vs 51 131 vs 132 24 NA no prophylaxis 202 R-CHOP Vs 197 CHOP Bernstein 2009 97/ 225 for CHOP were >60 yrs NR 899 aggressive lymphoma 191/ 225 CHOP 95/ 225 CHOP 81/225 CHOP 146/ 225 CHOP 20 years none for CHOP 121 IT MTX or radiation (24 Gy) 225 CHOP vs ProMACE-CytaBOM vs mBACOD vs MACOP-B Boehme 2009 68 648 vs 569 1217 (944 DLBCL) 687 507 212 602 24 bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands. 475/1217 (IT-MTX) 608 RCHOP Vs 609 CHOP Kim 2012 59.5 NR 564 276 192 193 NR 10.5 ≥1 risk factor 59 IT RCHOP Kumar 2012 56 (prophylaxis) VS 58 (no prophylaxis) male: 74 vs 476 female: 43 vs 396 989 85 vs 454 55 vs 240 66 vs 220 57 vs 372 30 High risk site involvement : orbit, testis, peripheral blood, vertebra, bone marrow, nasal/paranasal sinuses 117/989 IT- 84/117 (AraC/MTX) S--33/117 (MTX) R-CHOP Holte 2013 54 97 vs 59 156 (145 DLBCL) 150 156 41 151 36 everyone 156/156 (S- Ara-c+ MTX) 1 dose of IT-MTX RCHOEP
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Disclosures
No relevant conflicts of interest to declare.