A Phase I/II Study of Vorinostat (SAHA), Cladribine (2-CdA), and Rituximab Shows Significant Activity in Previously Untreated Mantle Cell Lymphoma

Abstract 441

Background: Despite significant progress in the treatment of mantle cell lymphoma (MCL), relapse remains the norm and additional therapies are needed especially for patients who are not candidates for aggressive treatment approaches. Increasingly, it has become evident that epigenetic modifications, including DNA hypomethylation and histone deacetylase inhibition, are critical to the pathogenesis and treatment of hematologic malignancies; important to cancer biology; and may be essential to the development of treatment resistance in B-cell malignancies. Further development and understanding of new and effective treatment regimens that target the epigenome are needed.

2-CdA has activity in a variety of B and T cell malignancies. In addition to its cytotoxic effects, our preliminary work shows that 2-CdA has hypomethylating properties in lymphoid malignancies. When primary MCL and CLL cells -before and 96 hours after cladribine treatment-were analyzed by HELP (HpaII tiny fragment Enrichment by Ligation mediated PCR), an array based genome-wide methylation assay, 2-CdA affected DNA hypomethylation. One of the genes hypomethylated was identified as DUSP2, a dual specificity phosphatase gene that is a p53 target gene. DUSP2 dephosphorylates phosphoserine/threonine and phosphotyrosine residues, negatively regulating mitogen-activated protein (MAP) kinases ERK1 and ERK2, which are associated with cellular proliferation and differentiation in B-NHL.

Vorinostat (SAHA) is a histone deacetylase inhibitor (HDACi), which has shown modest single agent activity in lymphoma and is FDA approved for use in cutaneous T cell lymphoma (CTCL). MCL cell lines treated with cladribine activated DUSP2 mRNA and when treated with the HDAC inhibitor SAHA synergistically increased transcription of DUSP mRNA. Furthermore, MCL treated with cladribine in vitro showed inhibition of global histone methylation. Our hypothesis is that cladribine and vorinostat synergistically activate silenced genes such as but not limited to DUSP 1 and 2 that are important for tumor cell death. The mechanism of rapid tumor cell death is under investigation, and does not appear to involve the classical apoptosis pathway. Given the need for novel therapies and the potential synergy seen with 2-CdA and SAHA, we initiated a Phase I/II trial combining SAHA, 2-CdA, and rituximab (SCR) for the treatment of B-cell non-Hodgkin's Lymphoma (NHL). The Phase I portion has been completed while Phase II is actively enrolling patients including those with newly diagnosed MCL.

Methods: Phase I enrolled 10 patients with relapsed/refractory NHL. The MTD of vorinostat for the Phase I was 400 mg (D 1–14) combined with 2-CdA 5mg/m2 IV (D 1–5), and R 375 mg/m² IV (weekly × 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Phase II eligibility includes relapsed NHL as well as previously untreated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Primary outcome is response rate (ORR). Scientific correlatives include analysis of CD20 expression, histone acetylation, gene microarray and HELP methylation analysis, ERK phosphorylation, and Q-PCR of potential target genes.

Results: 52 patients (Phase I/II) have been enrolled and 45 patients have been treated. The ORR in evaluable relapsed patients (3 DLBCL, 10 MCL, 1 FL, 1 MZL, 7 CLL) is 32% (7/22). Among these relapsed patients, complete remissions (CR) have been observed in MCL as well as follicular and marginal zone lymphomas. Of the 20 previously untreated MCL patients, 19 have completed ≥ 2 cycles and are evaluable for response. ORR is 100% (19/19) with 79% (15/19) CR. Toxicities by CTCAE 3.0 criteria have primarily included reversible myelosuppression, fatigue, dehydration, 1 gr. 4 thrombo-embolic event (probably related), and 1 grade 5 pulmonary hemorrhage in a patient with relapsed pulmonary lymphoma. One previously untreated mantle cell lymphoma patient has ongoing Gr. 3 thrombocytopenia six weeks after completing therapy. Preliminary analysis of ongoing correlative studies is available in 1 MCL patient and shows DUSP2 upregulation.

Conclusions: The SCR regimen shows activity across a number of B-cell malignancies and shows particular therapeutic promise in patients with previously untreated mantle cell lymphoma. Correlative studies are ongoing and will be presented. Future studies should continue to explore this regimen in previously untreated mantle cell lymphoma.