New Antibody for B-Cell Lymphoma

BUFFALO, NY--Adding a chimeric anti-CD20 antibody to standardCHOP chemotherapy appears to produce a synergistic therapeuticeffect in low-grade B-cell lymphomas. Patients on the regimenhave achieved complete remissions and disappearance of the bcl-2translocation, principal investigator Myron Czuczman, of the RoswellPark Cancer Institute, said at the annual Chemotherapy Foundationsymposium.

Preliminary results of an ongoing pilot phase II trial show a100% response rate in 16 evaluable patients (11 complete responsesand 5 partial responses), with all responses ongoing at 5 to 18months. Moreover, of the four patients whose bcl-2 status wasknown prior to therapy, all became bcl-2 negative by completionof therapy.

The antibody (IDEC-C2B8, from IDEC Pharmaceuticals Corporation,San Diego) targets the CD20 antigen, which is expressed on thesurface of mature B cells and on B-cell tumors, but not on B-cellprecursors or on plasma cells.

IDEC-C2B8 binds to its target antigen and recruits host defensesto attack and kill both malignant and normal B cells. After treatment,the normal B cells regenerate from stems cells within months,without damage to the marrow.

In the ongoing trial, patients are given IDEC-C2B8 at a dose of375 mg/m2 on weeks 1 (two doses), 7, 13, 20, and 21, for a totalof six doses. CHOP (cyclophosphamide, doxorubicin, vincristine,and prednisone) is given on weeks 2, 5, 8, 11, 14, and 17, fora total of six cycles.

Forty patients have been enrolled in the study to date, and datawere reported for 27 of these patients, 16 of whom have completedall scheduled therapy.

The trial is being conducted at Roswell Park Cancer Institute,Northwestern University, the University of Alabama at Birmingham,and the Sharp Health Care and Sidney Kimmel Cancer Center in SanDiego.

Adverse events attributed to IDEC-C2B8 therapy consist primarilyof mild, flu-like symptoms, usually associated with the firstinfusion, Dr. Czuczman said. No antibody responses against IDEC-C2B8nor any unusual toxicities for the combination regimen have beenobserved.

IDEC Pharmaceuticals is currently developing IDEC-C2B8, in collaborationwith Genentech, Inc., as a single agent for the treatment of relapsedlow-grade or follicular non-Hodgkin's lymphomas. A pivotal phaseIII trial of IDEC-C2B8 for this indication, which began in April,1995, is being conducted at more than 30 clinical sites in theUnited States and Canada.

Role of bcl-2Overexpression

Molecular research has identified the bcl-2 proto-oncogene asbeing associated with the t(14;18) chromosomal translocation offollicular, low-grade lymphomas, Dr. Myron Czuczman said in hispresentation at the Chemotherapy Foundation symposium (see storyabove).

This t(14;18) translocation leads to movement of the bcl-2 genefrom 18q21 to 14q32, resulting in increased transcription andaccumulation of high levels of the bcl-2 protein.

Research has shown that bcl-2 overexpression may lead to multi-drugresistance, independent of the P170 glycoprotein, by causing resistanceto apoptosis by a number of chemotherapeutic drugs, Dr. Czuczmansaid.

For patients with low-grade lymphoma, he said, bcl-2 status post-therapymay have prognostic value and may serve as a marker to monitorminimal residual disease.