Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL)

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Abstract
In diffuse large B-cell lymphoma (DLBCL), the combination of rituximab and CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone; R-CHOP) has been shown to be more effective than CHOP for the treatment of elderly patients. Bcl-2 protein expression has been associated with poor prognosis in patients with DLBCL. To establish whether or not rituximab reduces bcl-2—associated treatment failure, we studied bcl-2 protein expression and clinical outcome in patients included in the Groupe d9Etude des Lymphomes de l9Adulte LNH-98-5 trial. Patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks. Of the 399 patients included, 292 with histologically proven DLBCL had material available for bcl-2 study. Tumors were considered positive when at least 50% of tumor cells expressed bcl-2 protein. There were 193 (66%) bcl-2+ patients and 99 (34%) bcl-2– patients. The response rates for R-CHOP and CHOP were, respectively, 78% and 60% (P = .01) in bcl-2+ patients and 76% and 73% (P = .7) in bcl-2– patients. At a median of 2 years of follow-up, R-CHOP was significantly associated with a better overall survival than CHOP in bcl-2+ patients (67% ± 9% versus 48% ± 11%, P = .004). In bcl-2– patients there was no statistically significant difference (72% ± 12% versus 67% ± 14%, P = .6). In addition, R-CHOP was associated with significantly better event-free survival than CHOP in bcl-2+ patients (58% ± 10% versus 32% ± 10%, P < .001) but not in bcl-2– patients (60% ± 13% versus 40% ± 15%, P = .13). Multivariate analysis confirmed the significant benefit for survival and event-free survival of R-CHOP in bcl-2+ patients. These results suggest that rituximab is able to prevent chemotherapy failure in patients with bcl-2 protein overexpression.