Page 131 - 2020_09-Haematologica-web

DA-EPOCH-R/HD-MTX for CD5+ DLBCL
Introduction
Methods
Diffuse large B-cell lymphoma (DLBCL) includes a het- erogeneous group of lymphomas with various clinico- pathological and genetic features.1,2 The current standard first-line therapy of DLBCL is rituximab, cyclophos- phamide, doxorubicin, vincristine, and prednisone (R-CHOP). Gene expression profiling (GEP) has identified activated B-cell-like (ABC), germinal center B-cell-like (GCB), and unclassified DLBCL.3 ABC DLBCL exhibits worse prognosis than GCB DLBCL after R-CHOP.4
CD5-positive (CD5+) DLBCL is an immunohistochemi- cal subgroup of DLBCL, not otherwise specified (NOS) in the 2008 World Health Organization (WHO) classification and accounts for 5-10% of DLBCL.1 It is associated with various clinical characteristics, such as elderly onset, advanced stage at diagnosis, elevated lactate dehydroge- nase (LDH) level, and frequent involvement of extranodal sites.5-10 Ninety percent of CD5+ DLBCL cases are positive for BCL2,6,9 which has been reported as a risk factor for short survival in DLBCL. The patients with CD5+ DLBCL show significantly worse survival than those with CD5– negative (CD5–) DLBCL after R-CHOP,7,9-14 and is also char- acterized by a high incidence of central nervous system (CNS) relapse (8-13%), mainly brain parenchymal relapse.8,10 CNS relapse strongly affects the prognosis of CD5+ DLBL.8 Up to 80% of CD5+ DLBCL are classified as ABC DLBCL by GEP,9,15,16 and CD5 expression is signifi- cantly associated with the poor prognosis of patients with ABC DLBCL.9,15
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA- EPOCH-R) is an infusional regimen that incorporates a dynamic dose adjustment and has shown excellent effica- cy in BCL2+ DLBCL.17,18 High-dose methotrexate (HD- MTX) is commonly used in the treatment of primary DLBCL of the CNS.19 To explore a more effective first-line chemotherapy for CD5+ DLBCL, we have been investigat- ing DA-EPOCH-R combined with high-dose methotrex- ate (HD-MTX) therapy (DA-EPOCH-R/HD-MTX) since 2009.20 In 2009, when we were planning this study, eight cycles of R-CHOP was used as the standard treatment for the patients with advanced DLBCL.21 In previous phase II trials using DA-EPOCH-R, patients received two cycles beyond complete response (CR) or stable changes after six cycles of DA-EPOCH-R.17,18 Considering the aggressive- ness of CD5+ DLBCL, we selected eight cycles of DA- EPOCH-R based on the maximum number of cycles in original studies of DA-EPOCH-R.17,18,22 Because most CNS relapse events in patients with CD5+ DLBCL during R-CHOP have been documented within 6 months after diagnosis,8 we added two cycles of HD-MTX between the fourth and the fifth cycles of DA-EPOCH-R. In our retro- spective analysis of five patients with untreated stage IV CD5+ DLBCL who received DA-EPOCH-R/HD-MTX, the overall response rate (ORR) was 100%, and all toxicities were manageable.20 Of note, all of the patients belonged to the high-risk group of the International Prognostic Index (IPI),23 and three patients had CNS involvement at diagno- sis. To further evaluate the efficacy of DA-EPOCH-R/HD- MTX for newly diagnosed CD5+ DLBCL, we have been conducting a prospective, multicenter, single-arm, open- label, phase II trial in 31 hospitals in Japan since 2015 (reg- istered at: UMIN000008507). Here, we report the primary analysis results of that trial.
Study design and participants
In this multicenter phase II trial, eligible patients were 20-75 years of age and had newly diagnosed CD5+ CD20+ DLBCL with Ann Arbor stage II-IV disease (see Online Supplementary Methods). The diagnosis of CD5+ DLBCL was made according to the 2008 WHO criteria1 as DLBCL, NOS with CD5 and CD20 expression in tumor cells based on immunohistochemistry and/or flow cytom- etry. A complete list of inclusion and exclusion criteria is shown in Online Supplementary Table S1. The study was approved by the protocol review committee of the study as well as the institutional review board of each institution in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients before enrollment.
Treatment
The protocol treatment comprised four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DA-EPOCH-R. DA-EPOCH-R was administered according to original reports.17,18,22 The treatment details are described in the Online Supplementary Methods. The fourth and fifth cycles of DA- EPOCH-R were administered at the same dose level. MTX was administered intravenously at a dose of 3.5 g/m2 on a 14-day cycle with leucovorin rescue. The patients did not receive intrathecal chemotherapy. Acyclovir and trimethoprim-sulfamethoxazole were administered prophylactically. Radiation therapy was not permitted during the protocol treatment.
Diffuse large B-cell lymphoma subtyping
Following patient enrollment, formalin-fixed paraffin-embed- ded (FFPE) sections were histologically reviewed according to both the 2008 WHO criteria and the 2017 WHO criteria by the central pathology review board because the WHO classification was up- dated during the study period.1,2 DLBCL cell-of-origin (COO) sub- types were determined based on an immunohistochemical method developed by Hans et al.24 and gene-expression-based Lymph2Cx assay.25 The details of immunohistochemistry and the methods of Lymph2Cx assay are given in the Online Supplementary Methods.
End points
The primary end point was 2-year progression-free survival (PFS) (see the Online Supplementary Methods). Secondary end points were CR rate, ORR, 2-year overall survival (OS), 2-year CNS relapse rate, and toxicity. As a preplanned exploratory analysis, we assessed survival in each subgroup of COO, IPI, and CNS-IPI cat- egories.26 Treatment responses were assessed at each participating institute using positron emission tomography-computed tomogra- phy within 6-8 weeks after the beginning of the eighth cycle of DA-EPOCH-R according to the revised International Working Group Criteria.27 Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0.
Statistical analysis
Because this was the first clinical trial for untreated CD5+ DLBCL, we obtained historical controls of 2-year PFS (51%) from the data set of our previous retrospective study of CD5+ DLBCL.8 (See the Online Supplementary Methods and Online Supplementary Figure S1 for details) We anticipated that 41 evaluable patients were needed to achieve 80% power to detect a 20% difference in 2-year PFS from the historical control (51%) with a one-sided type I error of 0.05. The planned sample size was 45 patients with the expectation that 10% would be ineligible. Survival estimates were calculated using the Kaplan-Meier method, and 95% confidence
haematologica | 2020; 105(9)
2309