A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma

Abstract

Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 μmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 μmol/l (range 4·2-6·0 μmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.

Conflict of interest statement

All remaining authors have declared no conflicts of interest.

© 2013 Blackwell Publishing Ltd.

Figures

Figure 1. Treatment Schema

Patients received vorinostat in addtion to the RICE or ICE regimen every 21 days for up to 2 cycles. Vorinostat was given daily from days 1 to 5; ifosfamide on day 4, carboplatin on day 4; etoposide given daily from day 3 to 5; rituximab was given once on either day 3, 4 or 5 to patients with CD20+ disease. (R)ICE, (rituximab), ifosphamide, carboplatin and etoposide.

Figure 2. Progress of the two-stage dose escalation schedule

V, vorinostat; pt, patient. DLT, dose-limiting toxicity.

Figure 3

Maximal tolerated dose determined by a flat (a) versus a body surface area-based (b) or a weight-based (c) dosing schedule. DLT, dose-limiting toxicity.

Figure 4

Waterfall plot of best response after therapy (n = 27) by histology and chemoresistance. Two of the treated patients (n = 29) are not included due to lack of proper restaging study immediately after therapy. HL, Hodgkin lymphoma; DLBCL, diffuse large B cell lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma; CLL, chronic lymphocytic leukaemia; T-NHL, T-cell non-Hodgkin lymphoma.

Figure 5

Figure 5a. Vorinostat exhibited dose-dependent cytotoxicity of lymphoma cell lines. All cells were treated with vorinostat for 24 h. MTT assay was used to determine the cytotoxicity in treated cells. Representative results from three independent experiments are shown. Granta51 is a mantle cell lymphoma cell line; Peiffer, a diffuse large B cell lymphoma line; Karpas 299, an anaplastic large cell lymphoma line. Figure 5b. Dose-dependent apoptotic response of lymphoma cell lines after 24 h treatment with vorinostat. The response was measured by Annexin V assay. Figure 5c. Western blotting revealed dose-dependent accumulation of acetylated histones H3 and H4 in lymphoma cells after 24 h treatment with vorinostat. β-actin level was used as loading control.

Figure 5

Figure 5a. Vorinostat exhibited dose-dependent cytotoxicity of lymphoma cell lines. All cells were treated with vorinostat for 24 h. MTT assay was used to determine the cytotoxicity in treated cells. Representative results from three independent experiments are shown. Granta51 is a mantle cell lymphoma cell line; Peiffer, a diffuse large B cell lymphoma line; Karpas 299, an anaplastic large cell lymphoma line. Figure 5b. Dose-dependent apoptotic response of lymphoma cell lines after 24 h treatment with vorinostat. The response was measured by Annexin V assay. Figure 5c. Western blotting revealed dose-dependent accumulation of acetylated histones H3 and H4 in lymphoma cells after 24 h treatment with vorinostat. β-actin level was used as loading control.

Figure 5

Figure 5a. Vorinostat exhibited dose-dependent cytotoxicity of lymphoma cell lines. All cells were treated with vorinostat for 24 h. MTT assay was used to determine the cytotoxicity in treated cells. Representative results from three independent experiments are shown. Granta51 is a mantle cell lymphoma cell line; Peiffer, a diffuse large B cell lymphoma line; Karpas 299, an anaplastic large cell lymphoma line. Figure 5b. Dose-dependent apoptotic response of lymphoma cell lines after 24 h treatment with vorinostat. The response was measured by Annexin V assay. Figure 5c. Western blotting revealed dose-dependent accumulation of acetylated histones H3 and H4 in lymphoma cells after 24 h treatment with vorinostat. β-actin level was used as loading control.