Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma.

PURPOSE: High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. PATIENTS AND METHODS: In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. RESULTS: From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. CONCLUSION: The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

Effects of desialylation of ovine submaxillary gland mucin (OSM) on humoral and cellular immune responses to Tn and sialylated Tn.

Resected carcinoma patients were immunized 3-5 times with ovine submaxillary gland mucin (OSM) containing predominantly sialylated Tn (sTn), completely desialylated ovine submaxillary gland mucin (dOSM) containing predominantly Tn, or 50% desialylated OSM containing Tn and sTn plus bacillus Calmette-Guerin (BCG) as an immunologic adjuvant. Pre- and postimmunization sera were quantified by ELISA, whole-cell ELISA, and immune stain dot blots. Fifteen of 17 patients produced IgG antibody titers from 40 to 5120 times more reactive with OSM and dOSM postimmunization. More importantly, these IgG antibodies reacted with LS-174T, a human colon carcinoma cell line. Significant DTH-like responses (1-17 cm) were observed in 15 of 17 patients; the strength of these responses was dependent on the presence or absence of sialic acid. Biopsies of these DTH-like reactions revealed infiltration with some CD8+ lymphocytes and mast cells. These results suggest that a single 9-carbon sugar can affect cellular immune responses to mucin antigens. It is thought that these large erythematous, nonindurated cellular reactions are antibody-mediated Arthus-like reactions. OSM, and especially dOSM, were also found to inhibit lymphocyte proliferation.

Rituximab for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP): report of three cases.

Three patients (one with idiopathic thrombocytopenic purpura [ITP] and two with thrombotic thrombocytopenic purpura [TTP]) were treated with rituximab (anti-CD20 chimeric antibody) at a dose of 325 mg/m2 administered weekly after they failed standard therapies. The patient with ITP who did not respond to steroids and anti-D antibody administration achieved augmentation of her platelet counts up to 180 x 10(3)/microL after four doses of rituximab. Six months later, when her counts started to decrease, she received maintenance therapy with an additional course of 4 standard doses of antibody that resulted in consolidation of her platelet counts around 100 x 10(3)/microL. One patient with TTP and concurrent idiopathic nephropathy who was previously treated with plasmapheresis, steroids, and vincristine improved only after 4 weekly administrations of the antibody. Moreover, his nephrotic-range proteinuria resolved after he received rituximab. The other patient with chronic TTP who still relapsed after splenectomy received 5 doses of rituximab with concomitant plasmapheresis. His thrombocytopenia improved slowly, and his platelet count stabilized at 300 x 10(3)/microL. All three patients showed evidence of response to anti-CD20 antibody with improvement in clinical outcome as well as augmentation of platelet counts to normal levels. We conclude that rituximab is a useful immunomodulating adjunct in the treatment of refractory ITP and TTP.

Fatal intra-alveolar hemorrhage after rituximab in a patient with non-Hodgkin lymphoma.

A 65-year-old male developed progressive dry cough and digital clubbing after starting rituximab-CHOP chemotherapy for non-Hodgkin lymphoma. A lung biopsy showed loose non-necrotic granulomas in a background of mild fibrosis and rare eosinophils, compatible with a drug-induced hypersensitivity pneumonia. Associated manifestations of this hypersensitivity reaction were a high eosinophil count, elevated serum levels of immunoglobulin E, and a skin rash consistent with pigmented purpuric dermatitis (Schamberg disease). Corticosteroids were marginally efficacious in treating this reaction. Few similar reactions have since been described, 2 of them ultimately fatal, but none was associated with pulmonary hemorrhage. A 2.5:1 ratio between the interstitial alveolar T4/T8 lymphocytes in our case is similar to the findings in methotrexate-induced pneumonitis and farmer lung disease. This report documents the serologic and immunohistologic findings associated with a pulmonary interstitial reaction to rituximab. A review of the pertinent literature is provided. The possible pathogenetic mechanisms, including the role of cytokines, cytotoxic T-lymphocytes and CD 20 positive T-cells in relation to the administration of rituximab are discussed.

Probable veno-occlusive disease after treatment with gemtuzumab ozogamicin in a patient with acute myeloid leukemia and a history of liver transplantation for familial hemochromatosis.

A 69-yr-old male with a history of familial hemochromatosis and status after liver transplantation was found to have severe thrombocytopenia (platelet count of 8000/microL). He was also anemic and was diagnosed with acute myeloid leukemia (AML) after a bone marrow biopsy. He was started on gemtuzumab ozogamicin (Mylotarg) and developed hepatic and multiorgan failure consistent with veno-occlusive disease within 2 wk. He did not have a history of hematopoietic stem cell transplantation, which is usually the case in AML patients who develop veno-occlusive disease of the liver after treatment with Mylotarg.