Rituximab May Overcome bcl-2–Associated Chemotherapy Resistance in Untreated Diffuse Large B-Cell Lymphomas

The antiapoptotic protein bcl-2 is associated with chemotherapy failure in untreated large B-cell lymphomas, and with the recently described poor-prognosis large B-cell lymphoma subtype displaying an activated B-cell genotype (Nature 403:503, 2000). In vitro, rituximab (Rituxan) down-regulates bcl-2 and sensitizes B-cell lymphomas to chemotherapy (Clin Cancer Res 7:709, 2001).

To assess if rituximab reduces bcl-2-associated failure, we have analyzed bcl-2 expression and clinical outcome from two different studies using dose-adjusted EPOCH (DA-EPOCH) alone or DA-EPOCH with rituximab (DA-EPOCH-R) (375 mg/m² of rituximab IV infusion day 1; 200 mg/m² of etoposide, 1.6 mg/m² of vincristine, and 40 mg/m² of doxorubicin IV continuous infusion × 96 hours days 1 to 5; 750 mg/m² of cyclophosphamide IV day 5 and 60 mg/m² of oral prednisone bid days 1 to 5; granulocyte colony-stimulating factor (G-CSF, Neupogen) at 5 µg/kg/d SC day 6 to neutrophil recovery. Etoposide, doxorubicin, and cyclophosphamide were escalated 20% each cycle to achieve an absolute neutrophil count nadir of less than 500/µL.

Patients received six to eight cycles every 3 weeks and no radiation. Eligibility and treatment were identical in both studies except for the use of rituximab. bcl-2 staining was available in 29/50 patients on DA-EPOCH and in 23/28 patients on DA-EPOCH-R. bcl-2 intensity was analyzed in tumor cells by immunohistochemistry and scored as 0 (none), 1 (< surrounding T cells), 2 (= T cells), and 3 (> T cells). Tumor cells were scored positive if bcl-2 was ³ 1. The International Prognostic Index (IPI) distribution of bcl-2-positive cases and patient characteristics were similar in both studies, which had a median age of 46 (range: 20-73) and 48 (range: 22-75), respectively.

IPI risk categories were not significantly associated with progression-free survival in DA-EPOCH or DA-EPOCH-R. bcl-2-positivity was significantly associated with a shorter progression-free survival in DA-EPOCH (50% and 82% at 24 months; P2 = .039) but not in DA-EPOCH-R (88% and 82% at 24 months; P2 = .62).

Although the median follow-up of 9 months for DA-EPOCH-R is short, all but two progressions on DA-EPOCH (median follow-up of 52 months) occurred within 10 months. Presently, no patients have progressed after achieving a complete response on DA-EPOCH-R.

CONCLUSION: These results suggest rituximab may overcome bcl-2-associated chemotherapy failure, but does not alter the progression-free survival of bcl-2-negative patients. Patient accrual and follow-up are ongoing with DA-EPOCH-R to confirm these findings.

Click here to read Dr. Bruce Cheson's commentary on this abstract.