RITUXIMAB, LENALIDOMIDE, AND IBRUTINIB ALONE AND COMBINED WITH CHEMOTHERAPY FOR PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B ‐CELL LYMPHOMA

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is categorized by the cell of origin (COO) classification system into germinal center (GCB) and non-GCB subtypes. Both the immunomodulatory agent lenalidomide (L) and BTK inhibitor ibrutinib (I) have shown promising activity in the non-GCB DLBCL subtype as a single agent and in combination with chemotherapy. Preclinical studies demonstrate L + I results in synthetic lethality in non-GCB DLBCL via interferon signaling (Yang et al; Cancer Cell, 2012), but no trials have evaluated the efficacy in newly diagnosed patients. We present the first "window of opportunity" trial to use targeted therapy (rituximab, R + L + I) prior to chemotherapy in newly diagnosed DLBCL patients. Method(s): In this investigator-initiated phase II trial, patients receive standard R q 21 days (d), L 25 mg po d1-10, I 560 mg po d1-21, and after two 21d RLI cycles or with progression start standard chemotherapy (initially dose adjusted EPOCH q 21d for 6 cycles, but the randomized 50303 study results prompted an amendment to allow either EPOCH or CHOP). L + I dosing may be reduced if significant toxicity criteria are met. Key eligibility criteria include histologically confirmed, treatment-naive non-GCB DLBCL, age >= 18 years, and measurable disease. COO will be determined via immunohistochemistry (IHC) for eligibility and NanoString for confirmation. Patients are restaged with PET/CT (Lugano criteria, Cheson et al, JCO 2014). The primary objectives are to determine the overall response rate (ORR) after 2 cycles of RLI and complete response (CR) rate after 6 cycles of RLI + chemotherapy. Secondary objectives include safety and survival outcomes. Exploratory objectives include evaluation of baseline and therapy induced changes in gene and protein expression, mutations, and immune cell subsets in comparison with clinical outcomes. The trial will accrue 60 patients with Bayesian futility and toxicity monitoring rules. Result(s): At data cutoff of 3/15/17, 13 patients have enrolled, 1 withdrew consent after 1 cycle, all are available for toxicity and 11 for efficacy. The median age is 65 years, 75% are female, and the median IPI is 2 with 42% having an IPI of 3-5. All patients are non-GCB via IHC testing. Toxicities are noted for no significant rash in any patients and one case of invasive asperigillosis of the brain on a patient treated with high-dose steroids. All patients have efficacy reassessment after RLI window with an ORR of 82% and CR rate of 42%. The 6 patients who have completed all therapy have all achieved a CR. Conclusion(s): The combination of RLI has shown impressive efficacy both alone and with chemotherapy in this ongoing study in newly diagnosed non-GCB DLBCL. One patient had an invasive fungal infection, prompting a protocol amendment to prohibit steroid use during the window portion, and no further events have occurred. Additional results will be presented at the meeting.