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),
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 =
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