Valproate in Combination with Rituximab and CHOP As First Line Therapy in Diffuse Large B-Cell Lymphoma (VALFRID): Preliminary Results from a Phase I Trial with a Dose Expansion Cohort

Rationale: The anticonvulsant valproate is an HDAC inhibitor, which has in vitro been shown to sensitize lymphoma cell lines for CHOP chemotherapy, and to upregulate CD20 expression. Based on these findings, we initiated a dose finding trial of valproate in combination with R-CHOP in primary treatment of  diffuse large B-cell lymphoma (DLBCL), including a dose expansion cohort.

Methods: Eligibility criteria were: age 18-80 years, histologically confirmed (according to the WHO classification) diffuse large B-cell lymphoma stage II-IV, WHO performance status 0 –2.

R-CHOP was given at standard dose in 14 or 21 day cycles, 6 cycles. Valproate was given in escalating doses days 1-3, starting at 10 mg/kg every 8 hrs, by a standard 3+3 design. Prednisone was given days 1-5, R-CHOP on day 3. Response was evaluated according to the Lugano criteria.

Results: In the phase I portion, the MTD of valproate was established as 20 mg/kg every 8 hrs (total 60 mg/kg). At a dose of 80 mg/kg, 2 of 3 patients experienced tinnitus (grade 1 and 2) during the latter part of the treatment course. At a dose of 100 mg/kg, 1 of 5 patients developed hearing impairment, grade 1, after 3 cycles, which worsened to grade 2 after 4 cycles, leading to omission of valproate. By August 1, 2015, 28 patients have been included, of which 17 in the dose finding portion. The median age is 69 years (range 47-78). According to  the IPI, 43, 36 and 21% were low, low-intermediate and high intermediate/high risk, respectively. Apart from the auditory adverse effects presented above, toxicity was comparable to that of standard R-CHOP, without any impact on hematological toxicity. Presently, 17 patients are evaluable for response after 6 cycles VR-CHOP, ORR 17/17 CR 15/17 (88%).  After a median time of follow-up of 16 months, median PFS has not been reached, and estimated PFS at 18 months is 77%. One patient has died due to progressive lymphoma, 21 months after inclusion. By flow cytometry of fine needle aspirates from lymphoma lesions before and after 3 days of valproate, we could show significant upregulation of CD20 expression in 3 patients.

Conclusions: Sensitization to rituximab and CHOP by pretreatment with an HDAC inhibitor is a novel therapeutic strategy for the treatment of DLBCL. At a dose of 60 mg/kg, divided into 3 doses, the combination of valproate with R-CHOP is feasible in 1^st line treatment of DLBCL. Higher doses of valproate was associated with intolerable auditory side effects. Early data show promising efficacy, which may form the basis for a randomized phase III trial. The long-term efficacy of this regimen remains to be established by longer follow-up.