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Valproate in combination with rituximab and CHOP as first-line therapy in diffuse large B-cell lymphoma (VALFRID)
Skane Univ Hosp, Dept Oncol, Lasarettsg 23 A, SE-22185 Lund, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Norrland Univ Hosp, Dept Oncol, Umea, Sweden.
Skane Univ Hosp, Dept Oncol, Lasarettsg 23 A, SE-22185 Lund, Sweden.
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2018 (English)In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 12, p. 1386-1392Article in journal (Refereed) Published
Abstract [en]

The aims of the present study were to establish the maximally tolerated dose (MTD) of the histone deacetylase inhibitor valproate together with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). A phase 1 dose escalation study of valproate together with R-CHOP followed by a dose expansion study using the established MTD of valproate was performed. MTD of valproate together with R-CHOP was established at 60 mg/kg per day, as higher doses resulted in auditory adverse events (AEs). In the study population, 2-year progression-free survival was 84.7% (95% confidence interval [CI], 73.2%-98%). The 2-year overall survival (OS) was 96.8% (n = 31; 95% CI, 90.8%-100%). These data were compared with 2 risk-factor matched populations of R-CHOP-treated patients from the Swedish Lymphoma Registry (cohort A, n = 330 and B, n = 165). As compared with the matched cohorts, we observed a statistically significant (P = .034 and 0.028, respectively) beneficial effect of the addition of valproate to R-CHOP on the OS in the studied population. In conclusion, addition of valproate to R-CHOP is a feasible strategy in first-line treatment of DLBCL. The proposed phase 2 dose is 60 mg/kg per day together with prednisone. Auditory AEs were unexpected and warrant close monitoring. Our findings suggest that drugs that target histone deacetylation may add benefit and are tolerable when combined with standard R-CHOP in DLBCL.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY , 2018. Vol. 2, no 12, p. 1386-1392
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Hematology
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URN: urn:nbn:se:uu:diva-360005DOI: 10.1182/bloodadvances.2018019240ISI: 000436548300004PubMedID: 29903707OAI: oai:DiVA.org:uu-360005DiVA, id: diva2:1246540
Available from: 2018-09-07 Created: 2018-09-07 Last updated: 2018-09-07Bibliographically approved

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