A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma

Michinori Ogura, Kiyoshi Ando, Tatsuya Suzuki, Kenichi Ishizawa, Sung Yong Oh, Kuniaki Itoh, Kazuhito Yamamoto, Wing Yan Au, Hwei-Fang Tien, Yoshihiro Matsuno, Takashi Terauchi, Keiko Yamamoto, Masahiko Mori, Yoshinobu Tanaka, Takashi Shimamoto, Kensei Tobinai, Won Seog Kim, Michinori Ogura, Kiyoshi Ando, Tatsuya Suzuki, Kenichi Ishizawa, Sung Yong Oh, Kuniaki Itoh, Kazuhito Yamamoto, Wing Yan Au, Hwei-Fang Tien, Yoshihiro Matsuno, Takashi Terauchi, Keiko Yamamoto, Masahiko Mori, Yoshinobu Tanaka, Takashi Shimamoto, Kensei Tobinai, Won Seog Kim

Abstract

Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

Keywords: HAT mutation; follicular lymphoma; indolent B-cell non-Hodgkin lymphoma; phase II trial; vorinostat.

© 2014 Merck Sharp & Dohme Corp. British Journal of Haematology published by John Wiley & Sons Ltd.

Figures

Fig 1
Fig 1
Waterfall plot showing percent change in tumour size for all assessable follicular lymphoma (FL) patients at the time of best response and results of histone acetyltransferase (HAT) mutation analysis.
Fig 2
Fig 2
Kaplan–Meier estimates of progression-free survival (PFS) or overall survival (OS). (A) PFS by disease types for all assessable patients (n = 50), patients with FL (n = 39), other (non-FL) indolent B-NHL (n = 7) and MCL (n = 4). PFS was defined as the time from allocation to the first documented disease progression or death due to any cause, whichever occurred first. (B) Correlation between Follicular Lymphoma International Prognostic Index (FLIPI) scores and outcomes for PFS of the patients with FL. PFS for the patients at low (n = 16), intermediate (n = 15), or high (n = 8) risk according to FLIPI were calculated. (C) OS by disease types for all enrolled patients (n = 56), patients with FL, other (non-FL) indolent B-NHL and MCL. FL, follicular lymphoma; B-NHL, B-cell non-Hodgkin lymphoma; MCL, mantle cell lymphoma.
Fig 3
Fig 3
CREBBP and EP300 mutations in patients with FL and other B-NHL. (A) Schematic diagram of the CREBBP protein and (B) the EP300 protein. FL, follicular lymphoma; B-NHL, B-cell non-Hodgkin lymphoma; KIX, CREB-binding domain; bromo: bromodomain; HAT, histone acetyltransferase domain.

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