By Jia Ruan, MD, PhD
Yesterdays results presented at ASH 2014 provides the first demonstrated feasibility and efficacy of a chemotherapy-free, biologic approach using lenalidomide and rituximab as an initial therapy for mantle cell lymphoma (MCL). These findings present an important chemotherapy-free alternative initial treatment for MCL, as current conventional upfront chemoimmunotherapies are generally not curative.
During this multi-center phase II study patients were administered lenalidomide at 20 mg in days 1-21 of a 28-day cycle for a total of 12 cycles, with doses escalated to 25 mg when tolerated. Rituximab was administered weekly x 4 during first cycle and then once every other cycle for a total of 9 doses. The induction phase was followed by a maintenance phase, which at the 13th cycle, lenalidomide was administered at 15 mg on days 1-21 of a 28 day cycle, while rituximab maintenance was employed once every other cycle until disease progression.
Of the 38 patients with previously untreated MCL the median age was 65 years (range 42-86), with a male to female ratio of 2.5:1. Treatment was generally well tolerated with mild to moderate side effects. The overall response rate in patients was 84.2%, complete response rate was over 50%, with median time to objective response being 2.8 months. The median progression-free survival has not been reached, and the 2 year progression free survival rate is estimated to be 83.9%.
This study demonstrated that a high proportion of MCL patients can achieve durable remissions while maintaining a high quality of life. The data gathered from this trial justifies further evaluations of the lenalidomide and rituximab regimen both alone and in combination with other treatment approaches to MCL.
By Dr. Richard Furman, MD
Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years. Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase (BTK), currently approved as treatment for CLL patients relapsed after one prior therapy or patients with del 17p at any line of therapy. Ibrutinib’s initial approval was based upon phase II data published in June 2013. The expanded approval is based upon results from the RESONATE trial comparing ibrutinib to ofatumumab.
At the 56th annual meeting of the American Society of Hematology (ASH), investigators presented the results of the phase II RESONATE -17 (PCYC-1117-CA) study investigating ibrutinib in relapsed CLL patients with deletion of 17p.
The study was designed to evaluate the efficacy and safety of single-agent ibrutinib as treatment of patients with relapsed or refractory CLL with del 17p or small lymphocytic leukemia (SLL). 144 patients (137 CLL patients, 7 SLL patients) were enrolled and received ibrutinib 420 mg once daily until progression. The primary endpoint was overall response rate (ORR), with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib.
At a median follow up of 13 months, the median PFS and DOR had not been reached. At 12 months, 79.3% of patients were alive and progression-free, and 88.3% of responders were progression-free, with only 20 patients (13.9%) reporting progressive disease. At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib.
Efficacy results were consistent with earlier results, and the PFS compares favorably to that of treatment-naïve del 17p CLL patients receiving FCR or alemtuzumab. These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL.
By Rita Shaknovich, MD, PhD
Diffuse large B-cell lymphomas (DLBCL) are aggressive tumors that arise from germinal center B-cells (GCB). Post GCB are noted for their heterogeneity and variable clinical outcomes. In previous genome wide studies we found profound alterations in the cytosine methylation patterning of DLBCL and that the expression of activation-induced deaminase (AID) was associated with the loss of methylation in DLBCL patients. AID functions as demethylase during embryonic development, which led us to ask whether AID has demethylase activity during the transit of B-cells through the germinal center, and if over expression contributes to lymphomagenesis through the disruption of DNA methylation.
This question was addressed in an abstract during the 56th annual meeting of the American Society of Hematology (ASH). We studied the epigenetic function of AID in GCB and germinal center-derived lymphomas. Our preliminary results indicate that high AID expression is correlated with a more aggressive phenotype of the disease. We are currently analyzing the epigenetic targets of AID in both normal GCB and tumors, in order to find genes that could be epigenetically deregulated and contribute to the formation of lymphomas. These results demonstrate – for the first time – that AID functions as a demethylase in GCB in vivo. This suggests that the epigenetic role of AID could contribute to lymphomagenesis.