8583 Antibody dependent cellular citotoxicity (ADCC) play a significant role in rituximab's anti-tumor activity. FcγRIIIa polymorphisms have been associated with clinical responses to rituximab. The predictive value of FcγRIIIa polymorphisms is lost when rituximab is combined with chemotherapy. Alternative assays to assess the immune system had not been studied in patients treated with rituximab plus chemotherapy. To this end, we prospectively studied the pre-treatment quality and function of PMNs and NK cells from pts with refractory/relapsed B-cell lymphomas in a Phase I/II trial. Forty-two B-cell lymphoma patients pts completed treatment. Demographics: 22M:20F; Median age = 61.8 (range 35–83); Patients received R (375 mg/m2/dose) on day 1 and LD (30 mg/m2/dose) on day 3 q21 day × 6 cycles. Pre-treatment flow cytometry was performed to assess surface expression of CD11b, CD62, CD69, CD16, CD32 and CD64 in PMNs or NKcells was performed. Serum or PBMC's were isolated from each patient and used 51Cr release assays to study rituximab-associated complement mediated cytotoxicity (CMC) or ADCC. To correlate laboratory parameters with response rate, and PFS patients were divided in tertiles. Overall, R+LD was very well-tolerated. Overall response rate (ORR) = 68% (39% CR, 19% PR); median time-to-progression (TTP) = 12 m. Surface expression of CD32 in PMNs, and CD69 in NKcells correlated with better response rates. Surface expression of CD11b and CD32 in the PMN's correlated with a longer PFS (P = 0.040 and P = 0.015, respectively).There was a non-statistically significant trend towards an improved in PFS in those patients whom their PBMC's exhibited a higher degree of ex-vivo rituximab ADCC. Our data suggest that R+LD is a safe and effective regimen and that the quality of the immune system prior to a chemo-immunotherapy regimen may play a role in clinical outcomes, specifically the expression of CD11b and CD32 in PMNs or CD69 in NKcells. Our data supports further research in seeking ways to enhance the quality of the immune system to improve responses to rituximab ± chemotherapy. [Table: see text]

PURPOSE To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

In the past, the most common initial combination chemotherapy regimen used by most oncologists to treat B-cell lymphoma was the CHOP regimen. Although doxorubicin (DOX) is a major component of CHOP, it is associated with myelosuppression, alopecia, and potential cardiotoxicity. In vitro data has demonstrated synergistic activity between rituximab and certain drugs, including DOX. Because of D's unique liposomal encapsulation, delivery, and toxicity profile, it may prove to be a more effective, less toxic anthracycline to combine with R. A formal Phase I/II trial to evaluate the safety and efficacy of R+D in pts with relapsing B-cell lymphoma was undertaken. R (375 mg/m2/dose) was given on day 1 and D (30 mg/m2/dose) on day 3 on q 21 day cycles for 6 cycles. Thirteen pts have completed therapy to date: 9F, 4M; Follicular lymphoma, grade 1 (n=6), grade 2 (n=1), grade 3 (n=3), DLBCL (n=3); med age = 63 (38–78); median number of prior Rx's = 3 (range 1–8); prior anthracycline exposure (n=8). Overall, the combination of R + D was well-tolerated. Transient grade 3 cytopenias were noted in 3 pts with limited bone marrow reserve and grade 3 palmar/plantar erythrodysesthesia seen in 2 pts. All 13 pts completed the planned 6 courses of Rx. Objective responses were seen in 85% (11 of 13 pts), including 54% CR, 31% PR. Median time-to-progression has not been reached at 7+ months (range 4.5+ to 19+ months). No cardiac toxicity was seen and comparison of pre-Rx to post-Rx LVEF remained unchanged in 9, increased in 2, and decreased in 2 (yet still remaining > 50%). D + R immunochemotherapy is a well-tolerated, unique, non-cardiotoxic, and apparently effective salvage therapy for relapsed B-cell lymphoma. The study will continue until accrual of 42 pts has been reached.

Non-Hodgkin's lymphoma (NHL) is composed of a group of lymphoid malignancies that has been increasing in incidence at an annual rate of 4% to 7% over the last 20 years in both the United States and Europe. The reasons for this rise in incidence in NHL are not yet defined but most likely involve environmental exposures. Low-grade and follicular lymphomas account for approximately 40% of the incidences of NHL in the United States. While patients with intermediate- and high-grade lymphomas are potentially curable with combination chemotherapy, low-grade and follicular lymphomas are still considered to be essentially incurable with standard therapy. Although low-grade lymphomas characteristically respond well to treatment with chemotherapeutic agents, the disease typically follows a course of recurrent relapse and progressively shorter remissions, and ultimately death from lymphoma. Median survival for patients with low-grade lymphoma is 6.2 years from diagnosis and just 5 years from time of first relapse. Therefore, novel therapeutic strategies are urgently needed for these patients. One approach to the development of innovative strategies for treatment of NHL has been the generation of monoclonal antibodies to specific B-cell antigens expressed on NHL cells. Semin Oncol 29 (suppl 2):36-40. Copyright © 2002 by W.B. Saunders Company.