BioOncology Watch Timely Information for Practicing Physicians
may 2002 Graft versus Host Disease (GVHD) Effect of adding Campath-1G to the conditioning regimen. Recently pretransplant treatment with Campath-1G has been reported to prevent acute GVHD. It has also been found that the CD52 antigen is expressed on dendritic cells (DCs). Thus, Phennapha Klangsinsirikul and colleagues conducted a pilot study in which Campath-1G, an anti-CD52 monoclonal antibody, was administered for 5 days (10 mg daily) during chemoradiotherapy conditioning to 10 patients who underwent allogeneic hematopoietic stem cell transplantation. After the Campath-1G treatments, DCs were undetectable in peripheral blood. In contrast, circulating DCs were detected in 6 of 7 patients receiving conditioning therapy without Campath-1G treatments. Posttransplantation analyses of the Campath-1G-treated patients showed that DCs had recovered and that the reconstituted DCs were of donor origin. These data suggest that the rapid depletion of host circulating DCs by Campath-1G may be the mechanism by which this agent prevents acute GVHD. Furthermore, the addition of Campath-1G to the conditioning regimen did not delay the reconstitution of donor DCs. (Klangsinsirikul P, et al. Blood 2002;99:2586-2591) Visilizumab treatment of steroid-refractory acute GVHD. Visilizumab is a humanized anti-CD3 monoclonal antibody directed against the invariant CD3e chain of the T-cell receptor. This agent is of interest because it selectively induces apoptosis in activated T cells. Unlike murine anti-CD3 monoclonal antibodies, visilizumab does not induce activation of resting T cells due to its human IgG2 isotype and engineered mutations within the IgG2 Fc region. Paul Carpenter and coworkers tested visilizumab in a phase I study of 17 patients with steroid-refractory GVHD. The first 6 patients received multiple doses of visilizumab and at 1 mg/m^2 prolonged lymphopenia was experienced. The next 11 patients were given a single visilizumab dose of 3 mg/m^2. In the first 6 patients, one complete response (CR) and 5 partial responses (PRs) were achieved and the median survival was 87 days. Of 9 evaluable single-dose patients, 6 had CRs and 3 had PRs. The median survival for the single-dose group was increased compared to the multiple-dose patients (359 days; p = 0.03). Visilizumab was tolerated well with only three grade 1 acute infusion-related toxicities. However, 2 of the first 7 patients developed Epstein-Barr virus (EBV) posttransplant lymphoproliferative disease (PTLD). Of the next 10 patients, 5 patients experienced rising EBV DNA titers and were treated with rituximab. EBV DNA became undetectable with rituximab therapy and no overt PTLD developed. This preliminary investigation suggests that visilizumab has activity in advanced GVHD; phase II studies are warranted. (Carpenter PA, et al. Blood 2002;99:2712-2719) Mylotarg (Gemtuzumab Ozogamicin) Hepatic toxicity. Pankaj Rajvanshi and associates at the Fred Hutchinson Cancer Research Center (Seattle, WA) recently reviewed the clinical courses of 23 patients given Mylotarg to treat AML relapsing after hematopoietic stem cell transplantation. Eleven (48%) patients experienced hepatic toxicity following Mylotarg administration. Jaundice and ascites developed in 7 patients and evidence of portal hypertension was found in 2 patients. Nine patients died: liver dysfunction and ascites resolved in 2 patients prior to their deaths due to leukemic relapse and the other 7 patients died with persistent liver dysfunction with multiorgan failure or sepsis at a median of 40 days after Mylotarg infusion. Histologic studies in 5 patients revealed sinusoidal hepatic injury with fibrosis, centrolobular congestion, and hepatocyte necrosis. These findings demonstrate that hepatic sinusoidal injury developed in patients with relapsed AML following exposure to Mylotarg. The authors suggest that the delivery of cytotoxic calicheamicin to CD33+ cells in the liver sinusoids triggers a series of events leading to sinusoidal obstruction and subsequently to hepatic necrosis. (Rajvanshi P, et al. Blood 2002;99: 2310-2314) p53 Tumor Suppression Function Effect on anti-angiogenesis therapy. The p53 tumor suppressor gene triggers cell-cycle arrest and apoptosis in response to stressful stimuli. In vitro studies demonstrated that transformed cells, in which p53 has been inactivated, have a survival advantage when cultured under hypoxic conditions. Joanne Yu et al conducted preclinical experiments to investigate whether tumor cell resistance to hypoxia due to p53 loss reduces the efficacy of anti-angiogenic therapy. Paired isogenic p53+/+ and p53-/- HCT116 colorectal carcinoma cells were injected subcutaneously into SCID mice and treatment was initiated with an antibody directed against vascular endothelial growth factor receptor-2 (DC101; ImClone Systems, Inc.) and low-dose vinblastine. This treatment inhibited the growth rate of all tumors, but after 42 days, the p53-/- tumor volume had increased by 7-fold while the p53+/+ tumor volume had only doubled. Further analyses showed a greater frequency of apoptosis in hypoxic areas of p53+/+ tumor than in hypoxic regions of p53-/- tumor. Vladimir Bykov et al identified a molecule, PRIMA-1, that restores wild-type function to mutant p53. Animal data revealed an antitumor effect with no apparent toxicity. These experiments emphasize the importance of the p53 status of tumors, especially in patients treated with anti-angiogenic agents, and that research is ongoing to develop agents that restore p53 function in p53-/- tumors. (Yu JL, et al. Science 2002;295:1526-1528 and Bykov VJN, et al. Nature Med 2002;8:282-288) Breast Cancer Combination docetaxel and trastuzumab. Esteva et al reported an overall response rate of 63% in 30 patients with HER-2-positive metastatic breast cancer using a regimen of docetaxel 35 mg/m^2 and trastuzumab 2 mg/kg administered weekly for 3 weeks every 4 weeks. This phase II study confirmed the activity and tolerability of this combination regimen. (Esteva FJ, et al. J Clin Oncol 2002;20:1800-1808)
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