Tag: research publications

Updated Efficacy Results of Ibrutinib Compared with Ofatumumab in Relapsed CLL (RESONATE Trial), with Analysis of Genetic and Prognostic Subgroups

Picture3By Dr. Richard Furman, MD

The role of various prognostic factors in CLL/SLL is not yet fully understood, including the implications of new genetic markers associated with high risk. Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor that is approved for the treatment of CLL patients who have received at least 1 prior therapy, and for patients with 17p deletion CLL. In results presented before the 56th annual meeting of the American Society of Hematology, updated efficacy results from the phase 3 RESONATE (PCYC-1112) study comparing ibrutinib to ofatumumab were reported.

In the phase III study 391 randomized patients received 420 mg daily of ibrutinib or ofatumumab daily, until disease progression or unacceptable toxicity for up to 24 weeks. During an interim analysis at the median follow up of 9.4 months, patients in the ofatumumab arm were provided access to the ibrutinib arm.

Comparatively, progression free survival (PFS) was significantly longer for ibrutinib compared to ofatumumab. Overall survival (OS) was significantly better for ibrutinib compared to ofatumumab, with 18-month OS rates of 85% and 78% respectively. Higher number of prior therapies (≥3) and 11q deletion were associated with significantly lower 12-month PFS rate for ofatumumab, but not for ibrutinib. The overall response rate (ORR) for ibrutinib versus ofatumumab was 90% to 25%. Compared to ofatumumab, ibrutinib improved 12-month PFS and ORR regardless of baseline genetics, complex cytogenetics, or number of prior therapies. No significant difference in 12-month PFS was observed in ibrutinib treated patients with or without del(17p) or for those who developed lymphocytosis compared to those without lymphocytosis. Median treatment duration was longer for ibrutinib versus ofatumumab and was 16 to 5 months respectively.

In this one on one comparison ibrutinib significantly outperformed ofatumumab in PFS, OS, and ORR in patients with CLL/SLL with at least one prior therapy. These results are consistent with previously published findings, and provide further evidence for the clinical utility  of ibrutinib in patients with CLL.

Demethylase Activity of AID During Germinal B-cell Maturation Could Contribute to Lymphomagenesis

shaknovich_rBy 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.

ASCO 2014: Routine Surveillance has Limited Impact in Detecting Remission of Peripheral T-cell Lymphoma

By Tiffany Tang, MD

The role of routine surveillance imaging (RSI) in first complete remission (CR1) for peripheral T-cell lymphoma (PTCL) patients is unclear. Theoretically, RSI should allow for the earlier detection of asymptomatic relapses, thus leading to the earlier initiation of second line therapy. In an abstract presented during a session of the 2014 ASCO conference, we investigated the proportion of PTCL relapses detected by RSI and those found through clinical finding, before comparing the outcomes in patients from those two groups.

341 patients were retrospectively identified through the T-cell lymphoma databases of the National Cancer Centre Singapore/Singapore General Hospital and Weill-Cornell Medical College. These patients were divided into groups based on their mode of relapse detection; through RSI or clinical findings. PTCL subtypes included PTCL-NOS, AITL, ALCL (ALK positive and negative), EATL, GDT, HSTL and ATLL, while patients with leukemias, indolent, composite and cutaneous lymphomas were excluded. Of the 341 patients, 145 patients achieved CR1 and 64 relapsed. Relapses were detected by clinical findings in 51 patients, RSI in 9 patients and only 3 patients did not have any clinical findings at the time of relapse.

This data from our findings suggests that RSI does not often impact the detection of CR1 in patients with PTCL.