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K. Miyazaki et al.
Figure 1. Trial profile.
intervals (CI) were estimated using Greenwood’s formula. All analyses were performed using SAS v9.4 (Cary, NC, USA) statisti- cal package.
Results
Patients' characteristics
A total of 47 patients from 24 participating institutions were enrolled in the study between July 2012 and November 2015 (Figure 1). The central pathology review confirmed the diagnosis of all patients as CD5+ DLBCL based on the 2008 WHO criteria. The review also revealed that two patients had high-grade B-cell lymphoma, NOS based on the 2017 WHO classification. The baseline clini- cal features and disease characteristics are listed in Table 1. Thirty-six percent of the patients were over 65 years of age. Skin/subcutaneous tissue was the most frequent site of extranodal involvement (15%). One patient had pri- mary testicular DLBCL.
For one case, the quality of the RNA extracted from the FFPE tissue sample was inadequate, but the remaining 46 cases were analyzed using GEP. Thirty-nine (85%) of 46 cases were classified as ABC DLBCL, four (9%) were clas- sified as GCB DLBCL, and three (7%) were unclassified. The morphological and immunophenotypical features are summarized in Table 2. Based on Hans’ criteria, 72% of the 46 patients examined were classified as non-GCB DLBCL.
Treatment and response
Forty-five (96%) patients completed the protocol treat- ment. In the remaining two patients, treatment was dis- continued because of tumor lysis syndrome (TLS) with hyperkalemia after the first administration of rituximab and grade 3 stomatitis during the sixth cycle of DA- EPOCH-R. The dose-adjustment map of DA-EPOCH-R is shown in Online Supplementary Figure S2. The range of the dose level of DA-EPOCH-R was 1-4; median dose level of DA-EPOCH-R was two. The maximum dose level of DA- EPOCH-R was 1 in 26.1%, 2 in 32.6%, 3 in 26.1%, 4 in 15.2%, and >4 in 0%. There were no deviations or viola-
tions in determining the dose levels of DA-EPOCH-R. All patients were administered with DA-EPOCH-R/HD- MTX entirely in the hospital. Of the 47 patients evaluable for response, 43 patients achieved a CR (91%; 95%CI: 80- 98%), one patient achieved a partial response, and two patients experienced progressive disease. The ORR was 94% (95%CI: 82-99%).
Survival
With a median follow up of 3.1 years (range, 2.0-4.9), the 2-year PFS was 79% (90%CI: 67-87%; 95%CI: 64- 88%) (Figure 2A). This finding compared favorably with that of the historical control (51%). The 2-year OS was 89% (90%CI: 79-95%; 95%CI: 76-95%) (Figure 2B). One patient with CR died in a traffic accident 0.8 years after enrollment.
In a preplanned exploratory subgroup analysis, there was no significant difference in PFS (Online Supplementary Figure S3A) or OS (Online Supplementary Figure S3B) according to COO categories. The 2-year PFS and OS for CD5+ ABC DLBCL (n=39) were 77% and 87%, respective- ly. There was no significant difference in PFS according to gender and each risk factor for IPI (data not shown).
Central nervous system relapse
The 2-year CNS relapse rate was 9% (n=4; 90%CI: 4- 19%, 95%CI: 3-21%) (Figure 3A). During the follow-up period, no patient experienced CNS relapse more than 2 years from enrollment. There was no significant differ- ence in PFS among the CNS-IPI categories (P=0.58) (Figure 3B). Ten patients in the CNS IPI high-risk group were clas- sified as ABC (n=8), GCB (n=1), and unclassified DLBCL (n=1).
The clinical characteristics of four patients who experi- enced CNS relapse are summarized in Online Supplementary Table S2. Among them, one patient had pri- mary testicular DLBCL. Two patients were diagnosed as having high-grade B-cell lymphoma, NOS with MYC rearrangement based on the 2017 WHO criteria. Neither of these patients had the BCL2 translocation, and both were positive for CD10 and BCL2 by immunohistochem- istry. For the remaining one patient, the protocol treat-
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