A Phase II Study of Valproic Acid and Lenalidomide Combination Therapy in Patients with Myelodysplastic Syndrome (MDS) and a Favorable Risk Proﬁle: Final Results of the Valena Trial
Authors: Kuendgen Andrea , Lübbert Michael , Schlenk Richard F. , Platzbecker Uwe , Haase Detlef , Haferlach Torsten , Schnittger Susanne , Giagounidis Aristoteles , Brings Carolin , Germing Ulrich , Haas Rainer , Gattermann Norbert 
Published: October 2019

Abstract
Introduction:
Lenalidomide (LEN) has shown impressive single agent activity in MDS with del(5q). In patients with non-del(5q) MDS the response rate is much lower (around 26%) and response duration is shorter. Valproic acid (VPA), an anticonvulsive drug and histone deacetylase inhibitor, has shown promising activity, improving cell counts in lower risk MDS. In our previous study, the overall response rate in that subset of patients was 29%. Here we report final results of a phase II trial of VPA and LEN combination therapy in patients with IPSS low or intermediate-I MDS without del(5q).The primary objective of the trial was to evaluate efficacy and safety of the combination of LEN and VPA, which are both effective in lower-risk MDS.
Patients/Methods:
A total of 26 patients were evaluated for eligibility. 23 patients were enrolled in the trial. VPA was given continuously according to serum level (target range: 50-110 µg/l), LEN was given at 10 mg/d for 21 days per 28 day cycle. Only 12 patients finished the originally planned 16 week treatment period, mainly due to hematological toxicity. Median age was 66 (48-81) years. 16 patients had RCMD, 3 RCMD-RS, 1 RA, and 3 RAEB I. The IPSS score was low in 11 and int-I in 12 patients. IPSS-R score was low in 8, intermediate in 15, and high in 1 patient. Most patients (n=19) had a normal karyotype. Only 4 patients showed an aberrant karyotype, including isolated +8 in two, and t(1;2)(p36;p21) and del(11q)(q21q24) in one patient each. Analysis of molecular markers (DNMT3A, EZH2, CBL, RUNX1, TET2, JAK2, FLT3, MLL-PTD, KRAS, NRAS, ASXL1, IDH1, IDH2, TP53, SF3B1, SRSF2) has been performed in 10 out of 23 patients as yet.
Results:
Response according to International Working Group (IWG 2006) criteria was observed in 9 of 23 patients, including 3 complete remission (CR) dysplastic, 1 marrow CR with hematologic improvement- erythroid (HI-E), and 5 stable disease (SD) with HI-E. 13 patients had stable disease and 1 showed progressive disease. Patients with hematologic improvement achieved transfusion independence. Median response duration was 8 (6-20) months.
The most relevant side effect was hematological toxicity. 12 patients exhibited grade 3/4 neutropenia (8 grade 1/2) and 12 patients grade 3/4 thrombocytopenia (4 grade 1/2). After 6 patients had been included, the LEN starting dose was reduced from 10 to 5 mg. Of 12 patients who completed the full treatment period of at least 16 weeks, 8 (67%) responded. In the first 2 patients we observed an interesting response pattern. Both developed grade 3/4 neutropenia and thrombocytopenia together with unspecific symptoms of infection. Both had to stop study treatment. One developed a tri-lineage response for 13 months without restarting treatment. The other continued on VPA alone and responded for 6 months. Such a pattern of acute toxicity and response was no longer observed after the LEN starting dose had been reduced.
Out of 8 patients with a platelet count <150.000/µl at baseline, 1 (13%) responded. None of 6 patients with neutrophil count <1.800/µl responded. No correlation of MDS subtype, IPSS, IPSS-R, blast count, and cytogenetic abnormalities and response to VPA plus LEN could be shown in univariable analyses. As yet, none of the molecular markers showed significant correlation with treatment outcome (final results will be presented at the meeting).
Conclusion:
We found a response rate of 39% (9/23) according to IWG criteria. There were no unusual or unexpected non-hematologic toxicities. However, bone-marrow toxicity was more severe than expected and required a reduction of the LEN starting dose. In our view, hematological toxicity limits the tolerability of LEN/VPA combination therapy in patients with lower-risk MDS.

Disclosures
Kuendgen: Celgene: Research Funding, Travel expenses Other. Off Label Use: Lenalidomide and valproic acid are not approved for lower risk MDS treatment without del5q. Lübbert:Ratiopharm: study drug supply VPA, study drug supply VPA Other; Celgene: Travel support, Travel support Other. Schlenk:Celgene: Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Haferlach:MLL: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment. Germing:Celgene: Honoraria, Research Funding. Gattermann:Celgene: Research Funding; Novartis: Honoraria.