Teresa O'Brien

Effect of interferon-α on CD20 antigen expression of B–cell chronic lymphocytic leukemia

Chimeric CD20 monoclonal antibody as alternative therapy in relapsed low–grade non–Hodgkin’s lymphoma (NHL) has produced responses in nearly 50% of patients. Augmenting CD20 expression on tumor cells and/or inducing its expression may increase the cell kill and effectiveness of antibody therapy. Peripheral blood lymphocytes from 19 patients with B–cell chronic lymphocytic leukemia (B–CLL) were incubated in vitro in the presence of interferon– f (IFN– f) (500 U/ml and 1000 U/ml) for 24 and 72 hours. The effect on CD20 expression was studied by flow cytometry. The differences in the percentage positivity, the mean fluorescence intensity (MFI), and the product of percentage positivity and MFI were used to assess upregulation. There was a significant upregulation of CD20 expression on B cells seen at both concentrations after 24–hour priming (p < 0.01). B–CLL cells cultured for 72 hours in the presence of IFN– f also showed upregulation of CD20 expression; however, the degree of upregulation was m...

Tumor necrosis factor modulates CD 20 expression on cells from chronic lymphocytic leukemia: A new role for TNF alpha?

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine that is constitutively produced by leukemic cells in B Chronic Lymphocytic Leukemia (B‐CLL). It has been shown to have autocrine and paracrine functions in normal B cells and in B lymphoproliferative diseases. This study was conducted to determine the effect of TNFα (in vitro) on CD20 expression on cells from patients with B‐CLL. Currently, anti‐CD20 monoclonal antibody therapy is becoming a second line treatment in the management of B cell disorders like low‐grade non‐Hodgkins lymphoma (NHL) and B‐CLL. Our results demonstrate amply that very low doses of TNFα (0.0125 ng/ml) can be used to significantly increase CD20 expression on cells from patients of B‐CLL as evidenced by increases in both percentage positivity and mean fluorescence intensity. The upregulation is evident as early as 24 hours and is maintained for up to 72 hours. We propose that the upregulation is a direct result of in vitro differentiation stimulated by TNFα. The results presented can be exploited in the designing of priming protocols prior to antibody therapy and this is discussed. Microsc. Res. Tech. 50:251–257, 2000.

Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma.

BACKGROUND We conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas. PATIENTS AND METHODS We enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m(2) on days 1-3, mitoxantrone 12 mg/m(2) on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m(2) on day 1. After 6-8 weeks, responders received (90)Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m(2) weekly × 4 doses, repeated every 6 months for 2 years). RESULTS After R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received (90)Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient. CONCLUSION R-FM with (90)Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas.

Granulocyte-macrophage colony stimulating factor-induced immune priming of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab chemoimmunotherapy in previously untreated patients with diffuse large B-cell lymphoma and mantle cell lymphoma

Abstract Granulocyte-macrophage colony stimulating factor (GM-CSF) has been shown to enhance CD20 antigen expression, augment antibody-dependent cell-mediated cytotoxicity, and stimulate immune cell proliferation. This may lead to an improved anti-tumor effect of rituximab while reducing the severity of chemotherapy-induced myelosuppression. We evaluated the safety and efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in sequential combination with GM-CSF priming and rituximab in previously untreated patients (n = 39) with diffuse-large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). CHOP was administered every 21 days on day 1, GM-CSF 250 μg/m2/day on days 9 through 15, and rituximab 375 mg/m2 on day 15 of each cycle. The overall response rate was 87%, with complete response in 64%. At a median follow-up of 84.3 months, the overall and progression-free survival rates were 54% and 49%, respectively. The most common toxicity was myelosuppression. Sequential combination of CHOP with GM-CSF priming and rituximab was feasible and effective, warranting further evaluation.

Phase 2 study of CHOP‑R‑14 followed by 90Y‑ibritumomab tiuxetan in patients with previously untreated diffuse large B‑cell lymphoma

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.