Abstract LB-140: Combined epigenetic and immunotherapy produces dramatic responses in 100% of newly diagnosed mantle cell lymphoma patients.
Authors: Hasanali Zainul , Sharma Kamal , Spurgeon Stephen , Okada Craig , Stuart August , Shimko Sara , Leshchenko Violetta , Parekh Samir , Chen Yiyi , Kirschbaum Mark , Epner Elliot M. 
Published: August 2014

Background: Mantle cell lymphoma (MCL) is an incurable disease in which there is no accepted standard of care. While dose intensive approaches are effective, we and others have shown that cladribine and rituximab (RTX) combination therapy is well tolerated and can induce durable remissions. The synergistic effect observed with the combination of cladribine, a purine analogue with known but cryptic epigenetic activity as a hypomethylating agent, and a monoclonal antibody, RTX, prompted us to add a histone deacetylase inhibitor, vorinostat (SAHA), to this combination. We describe a phase II study that uses SAHA and a unique hypomethlating agent, cladribine, that potentially can inhibit both DNA and histone methylation through SAM. In combination with RTX, dramatic durable responses are observed in newly diagnosed MCL (ORR 100%, CR rate 70%) as well as in relapsed MCL and other B cell malignancies.

Objectives: The primary objective is overall response rate (ORR). Secondary objectives include progression free survival (PFS) and overall survival (OS) as well as correlative epigenetic, transcriptional and pharmacogenomic studies.

Methods: Dosing is as follows: starting dose was vorinostat 400 mg po (days 1-14) combined with cladribine 5mg/m2 IV (days 1-5), and RTX 375 mg/m2 IV (weekly x 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Responses were evaluated after 2 and 6 cycles. The majority of complete responders have received maintenance RTX. Phase II eligibility includes relapsed NHL and previously untreated MCL. Scientific correlatives included epigenetic and gene expression assays.

Results: 32 previously untreated MCL patients have been enrolled on the phase II portion of the study. 2 have not yet completed the planned 6 cycles; however, 30 patients have completed ≥ 2 cycles and are evaluable for response. The ORR is 100% (30/30) with 70% (21/30) achieving CR. Of those patients not attaining CR, 3 had blastic MCL and 2 have died, 2 have not yet completed treatment, and 1 withdrew consent after two cycles. At a median follow up of 14.7 months (.07 - 25 months) 4 patients have relapsed and 3 have died. Of the relapsing patients, two had blastic MCL. No patient achieving a CR has relapsed. The estimated PFS curve did not reach the 0.5 level. Toxicities using CTCAE 4 included neutropenia, thrombocytopenia, fatigue, anorexia, and dehydration.

We found that cladribine hypomethylates DNA in vivo (6/6 pts) and inhibits histone methylation in MCL cell lines. Upregulated genes after treatment included DUSP2 (3 pts), FOXO3 (2 pts), NOXA1 (2 pts), CEBPβ (2 pts) and p53 (3 pts). Dramatic responses and CRs were also seen in fewer patients with low grade NHLs, but not in DLBCL.

Conclusion: Combined epigenetic and immunotherapy (SCR) is nontoxic and effective in the treatment of newly diagnosed mantle cell lymphoma. This therapeutic approach potentially has broader applications in other malignancies.

Citation Format: Zainul Hasanali, Kamal Sharma, Stephen Spurgeon, Craig Okada, August Stuart, Sara Shimko, Violetta Leshchenko, Samir Parekh, Yiyi Chen, Mark Kirschbaum, Elliot M. Epner. Combined epigenetic and immunotherapy produces dramatic responses in 100% of newly diagnosed mantle cell lymphoma patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-140. doi:10.1158/1538-7445.AM2013-LB-140