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Title: Quantification of Circulating t(14;18)+ Cells Predicts Response to Rituximab Therapy in Follicular Lymphoma Patients: Presented at ICML

"Quantification of Circulating t(14;18)+ Cells Predicts Response to Rituximab Therapy in Follicular Lymphoma Patients: Presented at ICML"

By Tim Allmark LUGANO, SWITZERLAND -- June 18, 2002 -- Clearance of t(14;18)-positive cells is predictive of clinical response after rituximab induction therapy in patients with follicular lymphoma. In conjunction with a multicentre clinical trial evaluating maintenance therapy with rituximab in low-grade lymphomas Swiss researchers used real-time polymerase chain reaction (PCR) to follow the t(14;18)-positive cell levels in a subset of follicular lymphoma patients with t(14;18) translocation. Dr. Jörg Hummerjohann, of the Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland, presented the findings here on June 14th at the 8th International Conference on Malignant Lymphoma (ICML). In common with results using conventional PCR, these results showed that there is a clear correlation between clinical response after induction therapy and the clearance of t(14;18)+ cells. They also showed that patients with a low number of circulating tumour cells in the blood at the outset were more prone to respond than those who had a high number of circulating tumour cells. "In our subset of patients only two pretreatment parameters were highly predictive for clinical response for rituximab induction therapy -- that was bulk and the t(14;18)-positive cell numbers. This has never been described before," said Dr. Hummerjohann. The researchers examined the value of maintenance therapy with rituximab 375 mg/m² at weeks 12, 20, 28, and 36 versus observation after stable disease or clinical response to induction therapy (four weekly doses of rituximab 375 mg/m²). This study enrolled 70 patients with follicular lymphoma. The numbers of circulating t(14:18)-positive cells (per million cells) in blood and bone marrow were monitored by real-time PCR with an ABI 7700 cycler at baseline and at weeks 8 through 12 and weeks 20 through 52. Using a tenfold dilution series of the t(14;18)-positive cell line Karpas 422 in normal mononuclear cells, a DNA-based standard curve for quantification was created with a slope of -3.29 and R² equal to 0.999. GAPDH control reagents and the t(14;18) major breakpoint region served as PCR targets. The comparative [D Ct method was used for calculations.

At baseline, 6 percent of patients were t(14;18)-negative, 34 percent carried less than 100 t(14;18)-positive cells per million mononuclear cells in blood, 42 percent carried between 100 and 10,000 cells, and 18 percent carried more than 10,000 cells.

Induction therapy effectively reduced the numbers of circulating t(14;18)-positive cells, with 59 percent of 56 t(14;18)-positive blood samples becoming t(14;18)-negative after treatment. In 85 percent of patients remaining t(14;18)-positive after treatment, t(14;18)-positive numbers fell by at least 1 log; levels fell by at least 3 logs in 23 percent.

The median baseline t(14;18)-positive blood level was 374 cells per million mononuclear cells. Among patients with t(14;18)-positive numbers below the median, 79 percent achieved complete or partial remission compared to 41 percent of those above the median. This association between t(14;18)-positive cell numbers was highly significant (p=0.002).

For blood level at baseline, bulk less than 5 (versus bulk of more than 5) and t(14;18)-positive cell numbers below or equal to the median (versus above the median) were both predictive for clinical response to induction with rituximab with odds ratios of 4.6 (p=0.0161) and 6.6 (p=0.0035), respectively.

The researchers observed a significant association between disease progression and t(14;18)-positivity during maintenance or observation. Patients remaining or becoming PC-positive during maintenance or observation had a far higher chance of progression: 11 of 16 (69 percent) versus 1 of 23 (4 percent).

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