Inhibition Of Histone Deacetylases With Panobinostat As a Treatment For Relapsed Or Refractory Diffuse Large B-Cell Lymphoma: A Phase II Study By The Fondazione Italiana Linfomi

Histone deacetylases (DACs) are involved in chromatin structure regulation and function. Treatment with DACs inhibitors leads to the activation or repression of genes regulating apoptosis, proliferation, differentiation, angiogenesis, immune responses. These agents resulted to be active for the treatment of T and B-cell lymphoma and other haematological malignancies. Previous in vitro studies underlined the possible pathophysiological role of DACs in diffuse large B-cell lymphoma (DLBCL). In FIL-PanAL10 we evaluate the therapeutic activity and safety of Panobinostat, a potent pan-DACs inhibitor, in patients with relapsed or refractory (R/R) DLBCL.

FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL). Enrolled patients are ≥ 18 years old with R/R DLBCL, following ≥ 1 line of chemo-immunotherapy (R-CHOP) including high dose therapy with autologous stem cell support (ASCT) in eligible patients. Patients with > 5 prior systemic lines of treatment, CNS involvement, HIV positivity, impaired cardiac function (according to the protocol) are excluded. Patients are scheduled to receive Panobinostat po 40 mg three-times every week as part of a 4-weeks treatment cycle up to disease progression, unacceptable toxicity, or patient’s refusal. The primary endpoint of the study is to explore the antitumor activity of Panobinostat in terms of overall response (ORR) according to the Cheson criteria 1999. Secondary objectives are the evaluation of complete response (CR), time to response (TTR), progression free survival (PFS), overall survival (OS) and safety. Exploratory objectives evaluate the predictive role of pharmacogenetics, immunohistochemical and specific gene expression in relation to the response to Panobinostat; for this aim a new lymph node or other pathologic tissue biopsy is requested before starting treatment. With the null (P0) and P1 hypothesis of overall response (ORR) corresponding to <10% and ≥ 30%, 35 patients will be needed (α: 0.5; β: 0.10) and at the end of the trial treatment with Panobinostat will be considered active if ≥ 7 responses will be occurred.

Between February 2011 and May 2013, 23 patients were enrolled on this study. Patients’ median age is 73 years (range 44-83 years); 7 (30%) patients received ≥ 3 previous lines of chemotherapy. Five patients responded to Panobinostat (ORR= 22%) including 3 CR (13%) and 2 (9%) partial response (PR): 1 patient had (4%) stable disease (SD). TTR was 2.5 months (range 2-3 months ). All 6 patients with ORR or SD are still in treatment with Panobinostat after 4, 5, 12, 12, 15, 24, months; 17 patients discontinued therapy because of progression (15) or side effects (2). After a median period of observation of 11 months from the beginning of treatment, 1-year PFS and OS are 22% and 28%, respectively. Most common observed grade 3-4 adverse events were hematological and included thrombocytopenia (88%) and neutropenia (34%); grade 3-4 diarrhoea was present in 3 (13%). The therapeutic schedule was modified from the three times week to three times every other week in 15 patients; a further dose reduction from 40 mg to 30 mg resulted to be necessary in 8 patients. The analysis of exploratory biologic objectives and of their relationship with outcome is still under investigation and will be ready for December 2013.

The preliminary results of this study indicates that Panobinostat is an active salvage therapy in nearly 20% of heavily pretreated R/R DLBCL patients; the relatively short TTR observed allows a prompt shift to other rescue treatments in non responders. The analysis of biologic biomarkers will hopefully better address Panobinostat therapy to a specific biologic subgroup.

Zaja:Mundipharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy; GSK: Consultancy, Honoraria; Amgen: Consultancy. Off Label Use: Panobinostat in DLBCL.