Mylotarg? (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation

Abstract

BACKGROUND Mylotarg™ (Wyeth‐Ayerst Laboratories, St. Davids, PA) is the brand name for a calicheamicin‐conjugated humanized anti‐CD33 monoclonal antibody (gemtuzumab ozogamicin, CMA‐676) and has been approved recently for the treatment of a subset of elderly patients who have relapsed acute myeloid leukemia (AML). Mylotarg is associated with an incidence of approximately 20% Grade 3 or 4 hyperbilirubinemia and liver transaminitis in this patient population. Hepatic venoocclusive disease (VOD) has been reported in patients who have undergone stem cell transplantation (SCT) after Mylotarg therapy. Outside of the SCT setting, VOD has been associated very rarely with cytotoxic therapy. METHODS The authors assessed the incidence of VOD in 119 patients who were receiving Mylotarg‐containing non‐SCT regimens. VOD was diagnosed through the use of standard Seattle and Baltimore criteria. RESULTS A cohort of 119 (61 previously untreated, 58 with relapsed disease) patients with AML (92 patients), advanced myelodysplastic syndrome (25 patients), or chronic myeloid leukemia in blast phase (2 patients), received Mylotarg‐based regimens. Fourteen (12%) developed VOD. The diagnosis of VOD was supported by histology in 2 patients and radiologic studies in a further 10 patients. Five (36%) of 14 patients with VOD had received no prior antileukemic cytotoxic therapy, including 2 patients who received single‐agent Mylotarg therapy. CONCLUSIONS Mylotarg was shown to be associated with the development of potentially fatal VOD in patients with leukemia who had not received SCT. VOD occured when Mylotarg was used either as a single agent or when it was given with other cytotoxic agents. VOD occured in Mylotarg‐treated patients who had received no prior cytotoxic therapy. The current study concluded that risk factors for VOD should be assessed when considering Mylotarg therapy, and that attempts to avoid and treat VOD are warranted in patients who receive Mylotarg therapy. Cancer 2001;92:406–13. © 2001 American Cancer Society.

Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy

“…Severe thrombocytopenia and neutropenia developed in most of the patients. Hepatic veno-occlusive disease was found in 12% of the patients who received GO [34].…”

New agents in acute myeloid leukemia and other myeloid disorders

“…111 Venoocclusive disease (VOD) was reported in 14 of 119 patients (12%) who were treated with GO alone or in combinations. 112 The incidence of VOD with GO in the setting of transplantation may be higher. Rajvanshi et al reported liver toxicity in 11 of 23 patients (48%) who received GO for recurrent AML after undergoing stem cell transplantation.…”

Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high‐risk myelodysplastic syndromes

“…Patients who developed VOD had the typical clinical picture seen with gemtuzumab -associated VOD. 5,6,16 This syndrome included the abrupt onset of significant weight gain, associated with ascites, abdominal distension, and right upper quadrant pain. No evident alternate explanations for this clinical picture, including acute hepatitis, progressive systemic or abdominal sepsis, pancreatitis, or bowel obstruction, were present at the time of diagnosis of VOD.…”

“…2 Drugs that warrant investigation in combination with gemtuzumab include ara-C, anthracyclines, fludarabine, and topotecan. 5 The mechanisms of cytotoxicity of gemtuzumab and anthracyclines are somewhat similar. Therefore, aside from combining these agents, we are also investigating combinations of gemtuzumab with topotecan and fludarabine.…”

“…Therefore, aside from combining these agents, we are also investigating combinations of gemtuzumab with topotecan and fludarabine. 5,6 The combination of fludarabine and ara-C (FA) is effective in patients with either untreated or refractory AML. [7][8][9] Linenberger et al 10 reported that the resistance to gemtuzumab is correlated with the expression and function of the multidrug resistance (MDR) protein, P-glycoprotein (PGP), in leukemic blasts and can be reversed in vitro by the PGP inhibitor, cyclosporine (CSA).…”