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DA-EPOCH-R/HD-MTX for CD5+ DLBCL
low/low-intermediate IPI risk (53%) were enrolled in the present study. In the subgroup analysis of PFS, there was no significant difference between those with and those without risk factors for gender, PS, and IPI group, although the sample size was small. Considering these results, fur- ther studies are needed to establish DA-EPOCH-R/HD- MTX as a standard therapy for newly diagnosed stage II- IV CD5+ DLBCL. Nevertheless, we consider that this reg- imen might be regarded as a treatment option, because CD5 expression can be easily examined in clinical prac- tice.
The incidence of CNS relapse for all patients with DLBCL treated with R-CHOP has been reported to be 1.9- 6.4%,30-32 whereas the incidence of CNS relapse for CD5+ DLBCL in the R-era were reported as 13% in our retro- spective study,8 8% in a study in Western countries,9 and 33% in ten patients treated with DA-EPOCH-R in a retro- spective study.29 Although our present trial does not have a sufficient statistical power to assess the reduction in CNS relapse, the incidence of CNS relapse in the present study (9%; 95%CI: 3-21%) seems to be lower than that for DA-EPOCH-R alone. To further reduce the incidence of CNS relapse, development of systemic chemotherapy in combination with one or more newer agents that cross
Table 3. Hematologic and non-hematologic toxicities. Grade 1-2
the blood-brain barrier, including ibrutinib,33,34 lenalido- mide35 and tumor necrosis factor-a coupled with NGR,36 is warranted. Combining a high CNS-IPI score and ABC/classified COO were reported to identify a patient subgroup at high risk for developing CNS relapse.37 Of note, in the present trial, 90% of patients in the CNS-IPI high-risk group were ABC/unclassified DLBCL. However, in four patients with CNS relapse, one patient had pri- mary testicular lymphoma, which should be treated with a specific treatment strategy including local radiotherapy.38 Moreover, 2 of the 4 patients with CNS relapse had high- grade B-cell lymphoma, NOS with MYC translocation, which is known to result in a relatively high incidence of CNS relapse.39 These results suggest that CD5+ DLBCL diagnosed according to the 2008 WHO criteria was a het- erogeneous lymphoma and that DA-EPOCH-R/HD-MTX might be beneficial for patients with CD5+ DLBCL in the WHO 2017 era.
As expected, the incidence of grade 3 peripheral motor neuropathy, peripheral sensory neuropathy and cardiac events was low (4%, 4%, and 0%, respectively) and was comparable to that in previous studies including DA- EPOCH-R.17,18 Two-thirds (66%) of the patients in this study experienced FN, and the incidence was higher than
Grade 3
1 (2%) 0
22 (47%) 26 (55%) 31 (66%)*
2 (4%) 5 (11%) 13 (28%) 1 (2%) 7 (15%) 0
8 (17%) 1 (2%) 0
3 (6%) 2(4%) 1(2%) 1 (2%) Infection - 4(9%)‡
Grade 4
46 (98%) 46 (98%) 12 (26%) 10 (21%) 0
0
0
0
0
0
1 (2%)† 0
1 (2%) 0
0
0
0
0
0
0
1 (2%)
Grade 5
0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Hematologic adverse event Neutropenia
Leukopenia Thrombocytopenia Anemia
Febrile neutropenia
Non-hematologic adverse event
0
1 (2%) 13 (28%) 11 (23%) -
Blood bilirubin increased AST increased
ALT increased Hyperglycemia Hyponatremia Hyperkalemia Hypokalemia Hypocalcaemia
9 (19%) 36 (77%) 30 (64%) 40 (85%) 36 (77%) 20 (43%) 38 (81%) 44 (94%) -
Cardiac disorders
Constipation
Ileus 1(2%) Nausea 33(70%) Vomiting 9 (19%)
31 (66%)
Allergic reaction
Tumor lysis syndrome
Peripheral motor neuropathy
Peripheral sensory neuropathy
Pneumonitis
Others - 10(21%)§ 0
11 (23%) 0
11 (23%) 29 (62%) 2 (4%)
0
3 (6%)
2(4%) 0 2(4%) 0 1 (2%) 0
AST:aspartate aminotransferase;ALT:alanine aminotransferase.*Observed in 23% of all cycles of DA-EPOCH-R (Online Supplementary Table S3).†One patient experienced tumor lysis syndrome with hyperkalemia after the first administration of rituximab.‡Catheter related infection (n=1),cellulitis (n=1),infective endocarditis (n=1),and urinary tract infec- tion (n=1).§Oral mucositis (n=3),hypertension (n=2),pulmonary embolism (n=2),deep vein thrombosis (n=1),Palmar-Planter erythrodysesthesia syndrome (n=1),and anorexia (n=1).
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