PMID- 29903707
OWN - NLM
STAT- MEDLINE
DCOM- 20190416
LR  - 20190416
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 2
IP  - 12
DP  - 2018 Jun 26
TI  - Valproate in combination with rituximab and CHOP as first-line therapy in diffuse 
      large B-cell lymphoma (VALFRID).
PG  - 1386-1392
LID - 10.1182/bloodadvances.2018019240 [doi]
AB  - 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. The phase 1 trial was registered at www.clinicaltrials.gov as 
      #NCT01622439.
CI  - (c) 2018 by The American Society of Hematology.
FAU - Drott, Kristina
AU  - Drott K
AD  - Department of Oncology, Skane University Hospital, Lund, Sweden.
FAU - Hagberg, Hans
AU  - Hagberg H
AD  - Department of Oncology, Akademiska, Uppsala University Hospital, Uppsala, Sweden; 
      and.
FAU - Papworth, Karin
AU  - Papworth K
AD  - Department of Oncology, Norrland University Hospital, Umea, Sweden.
FAU - Relander, Thomas
AU  - Relander T
AD  - Department of Oncology, Skane University Hospital, Lund, Sweden.
FAU - Jerkeman, Mats
AU  - Jerkeman M
AD  - Department of Oncology, Skane University Hospital, Lund, Sweden.
LA  - eng
SI  - ClinicalTrials.gov/NCT01622439
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 4F4X42SYQ6 (Rituximab)
RN  - 5J49Q6B70F (Vincristine)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 80168379AG (Doxorubicin)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - VB0R961HZT (Prednisone)
RN  - CHOP protocol
SB  - IM
MH  - Aged
MH  - *Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Cyclophosphamide/therapeutic use
MH  - Doxorubicin/therapeutic use
MH  - Female
MH  - Histone Deacetylase Inhibitors/therapeutic use
MH  - Humans
MH  - Lymphoma, Large B-Cell, Diffuse/*drug therapy
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Prednisone/therapeutic use
MH  - Rituximab/therapeutic use
MH  - Valproic Acid/administration & dosage/adverse effects/*therapeutic use
MH  - Vincristine/therapeutic use
PMC - PMC6020808
COIS- Conflict-of-interest disclosure: K.D. is a shareholder and board member of 
      Respiratorius AB., K.D., and M.J. have received honoraria from Roche. The 
      remaining authors declare no competing financial interests.
EDAT- 2018/06/16 06:00
MHDA- 2019/04/17 06:00
PMCR- 2018/06/14
CRDT- 2018/06/16 06:00
PHST- 2018/03/29 00:00 [received]
PHST- 2018/05/02 00:00 [accepted]
PHST- 2018/06/16 06:00 [entrez]
PHST- 2018/06/16 06:00 [pubmed]
PHST- 2019/04/17 06:00 [medline]
PHST- 2018/06/14 00:00 [pmc-release]
AID - bloodadvances.2018019240 [pii]
AID - 2018/019240 [pii]
AID - 10.1182/bloodadvances.2018019240 [doi]
PST - ppublish
SO  - Blood Adv. 2018 Jun 26;2(12):1386-1392. doi: 10.1182/bloodadvances.2018019240.