A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma

Abstract

Patient eligibilityPatients over the age of 18 with histologically or cytologically confirmed indolent non-Hodgkin lymphoma were eligible including: untreated, relapsed, or refractory follicular lymphomas of any grade, marginal zone B-cell lymphoma (nodal and extranodal), and mantle cell lymphoma. Patients may have had up to 4 prior regimens, not including steroids alone, rituximab alone, or local radiation. Treatment and evaluationOne cycle of therapy consisted of oral vorinostat 200 mg twice daily for 14 days followed by a 7-day break, and intravenous rituximab 375 mg/m 2 on day 1 of a 21-day cycle. Radiological assessment by computed tomography (CT) and/or positron emission tomography (PET) scan was performed at baseline and after every three cycles. Patients with measurable responses or stable disease were allowed to continue vorinostat and rituximab until progression. Patients who achieved CR received two further cycles of vorinostat and rituxmab and stopped treatment. Patients who stopped treatment in CR were allowed to resume the regimen in the event of relapse.Toxicity was assessed on days 1 and 8 of each cycle, and graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Treatment was held for patients who presented with non-hematologic toxicity of grade 3 or 4, until toxicity resolved to less than grade 2. These patients resumed treatment with vorinostat at a reduced dose of 100 mg daily. If grade 3 or greater toxicity occurred at the reduced dose, the patient was taken off treatment.Initially, CT or PET scans were performed after every three cycles of treatment to assess response. After one year of treatment, if the patient had achieved PR on two consecutive CT or PET scans, subsequent radiographic assessment was performed after every four cycles. If a patient achieved CR for more than one year, subsequent radiographic studies were performed every six months rather than every three cycles.Bone marrow biopsy for the presence of marrow involvement was performed at baseline and every three cycles if the base-line examination revealed marrow involvement. Responses were assessed according to the 2007 Cheson criteria. 12,13 Study designThe primary study objective was to evaluate the anti-tumor activity of vorinostat plus rituximab as assessed by overall response rate (ORR=CR+PR). The secondary study objectives were to evaluate the toxicity profile of vorinostat plus rituximab, time to progression, and progression-free survival. The Simon 2-stage optimal design was used to assess the overall response rate. In the first stage, 17 patients were enrolled, with the design specifying that if 4 or more patients achieved CR or PR, accrual would continue to a total of 33 patients, with 10 or more responses regarded as evidence of sufficient activity to warrant further investigation. CorrelativesThe effects of treatment on systemic blood levels of immune cytokines were evaluated by cytokine bead array analysis using Luminex X-MAP bead array technology ...

Results of a phase II study of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphoma: an interim analysis

“…The targeted agent that has been studied longest for its synergistic effect with vorinostat in MCL is rituximab. An experimental study using MCL cell lines demonstrated synergistic anti-MCL activity of vorinostat and rituximab [38], which was consistent with the results of clinical trials testing the efficacy of vorinostat with rituximab with or without a conventional regimen of cytotoxic chemotherapeutic drugs in patients with aggressive B-cell lymphomas [39][40][41]. The addition of rituximab to V-FND is a promising candidate for future clinical trials for relapsed or refractory MCL.…”

Bendamustine and rituximab in elderly patients with low‐tumour burden follicular lymphoma. Results of the LYSA phase II BRIEF study

“…Non‐chemotherapeutic approaches, such as rituximab and lenalidomide combinations (Fowler et al , ), alternative anti‐CD20 monoclonal antibodies (Negrea et al , ; Salles et al , ), BCL2 inhibitors (Roberts et al , ), HDAC inhbitors (Chen et al , ), PI3 kinase inhibitors (Gopal et al , ), immunomodulatory drugs (Fowler et al , ; Leonard et al , ), immunotherapies (Westin et al , ), or proteasome inhibitors (Evens et al , ), with or without rituximab, are promising. The role of rituximab maintenance therapy in LTBFL is unclear, with evidence from the RESORT trial indicating that maintenance treatment might be dispensable (Kahl et al , ).…”

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

“…Chiron and colleagues showed that inhibition of CDK4 with PD 0332991 (palbociclib) sensitizes ibrutinib-resistant lymphoma cells to ibrutinib in the absence of BTK mutations; however, use of PI3K inhibitors was more effective for treating cells carrying a BTK mutation (C481S) [144]. Similarly, in a recent trial with vorinostat and Rituximab, 33% of patients ( n = 3) achieved PR and ORR [145]. Additional clinical trials have been designed to evaluate the efficiency of CDK inhibitor alone and in combination for MCL (Table 3).…”