‘R-Squared’ Lymphoma Treatment: Possible Markers of Response Identified

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A correlative analysis of a study evaluating lenalidomide (Revlimid) plus rituximab (Rituxan) in patients with indolent non-Hodgkin lymphoma found that increases in the levels of several cytokines correlated with response to treatment.

The study by investigators from the University of California Davis Cancer Center in Sacramento was presented at the 2013 American Society of Hematology Annual Meeting by Samuel Yamshon, a medical student.1 The senior author of the study was Joseph Tuscano, MD.

“Some of the differences in cytokine levels were quite large between patients achieving a complete response and those who did not. It seems these cytokines have a strong correlation with a strong response,” Mr. Yamshon suggested.

Study Details

The phase II study included 45 patients (most with follicular lymphoma) with indolent non-Hodgkin lymphoma, including 30 previously treated (28 evaluable for response) and 15 previously untreated (13 evaluable). Patients received the so-called “R-squared” regimen of lenalidomide (20 mg/d) on days 1 to 21 of a 28-day cycle, continued until disease progression, plus rituximab (375 mg/m2) on day 15 of cycle 1 and repeated weekly for a total of four doses.

The overall response rates were 75% for previously treated patients and 100% for treatment-naive patients, including complete responses in 44% and 61%, respectively. Progressive disease was observed in 11% and 0%, respectively. At a median follow-up time of 43 and 16 months, the median duration of response was 15.4 months for the previously treated group and has not been reached in the treatment-naive cohort, respectively.

Correlative Analysis

Correlative serum cytokine samples were obtained from a subset of patients at baseline, day 15 (prior to treatment with rituximab), and days 30 and 60. These included interleukins (IL)-1, 2, 6, 8, 10, and 12; granulocyte-macrophage colony-stimulating factor (GM-CSF); interferon-gamma; tumor necrosis factor (TNF)-alpha; and CXCL 10/IP-10 levels. Cytokine levels at each time point were correlated with response to treatment.

Mr. Yamshon described the rationale for the correlative analysis. “Lenalidomide induces IL-2, interferon-gamma and TNF-alpha secretion, and it induces natural killer (NK) cells to produce GM-CSF, TNF-alpha, and various immune-recruiting chemokines,” he noted. “It also enhances CD4 and CD8 cell costimulation in vitro and NK and NK T cells in vivo.”

For several cytokines, significant changes (in absolute percentage over baseline) were observed prior to rituximab treatment in patients who achieved a complete response, compared to those with anything less than a complete response.

Significant increases were observed for interferon-gamma (652% over baseline), GM-CSF (494%), CXCL-10 (737%) and IL-2 (242%) at day 15 (P < .005).

“These are huge changes in serum cytokines that are strongly correlated with remission,” he noted. “Patients with a partial response or no response had limited or negative changes.”

Smaller Increases

The analysis also revealed increases in activating CD4 and CD8 cells in patients with complete responses, but the increases were not statistically significant. NK cell numbers also increased, but not significantly over patients without a complete response, and activating NK cells actually decreased, which was unexpected and could be the result of the timing of the assessment, he said. PD-1–positive T cells increased as well, which is consistent with previous findings that correlated this with improved outcomes in follicular lymphoma.

“The findings suggest it may be possible to predict complete response based on patients’ levels of these cytokines before starting rituximab,” he suggested. ■

Disclosure: Mr. Yamshon reported no potential conflicts of interest. Dr. Tuscano has received honoraria and research funding from Celgene.


1. Yamshon S, Qi L, Yu C, et al: Correlative analysis and clinical update of a phase II study using lenalidomide and rituximab in patients with indolent non-Hodgkin lymphoma. 2013 American Society of Hematology Annual Meeting. Abstract 249. Presented December 9, 2013.

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