Bruce D. Cheson, MD

he treatment of B-cell malignancies has been revolutionized by the availability of safe and effective monoclonal antibodies. The addition of rituximab to standard chemotherapy regimens prolongs the survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular non-Hodgkin lymphoma. Nevertheless, indolent and mantle cell lymphomas remain incurable, and 30% to 40% of patients with DLBCL still die from their disease. Much ongoing research has focused on optimizing monoclonal antibody use, integrating them into multiagent regimens, and developing newer antibodies. Attempts to improve on the efficacy of monoclonal antibody–based therapy have included altering the dosing schedule, optimizing patient selection, maintenance therapy, improving upon the rituximab molecule, radioimmunotherapy, as well as combinations with cytotoxic molecules and other novel agents. Preliminary data with a number of treatment regimens are promising in indolent and aggressive lymphomas. The eventual goal of targeted therapies is to individualize treatment to increase response and survival, while reducing treatment-related toxicity.

The 5-year survival of patients with locally advanced squamous cell cancers of the head and neck is still less than 30%. Treatment of these cancers involves significant functional impairment, diminished quality of life, and considerable time and expense. Local recurrence and distant metastases are still fairly common, and the development of second primary cancers has a significant impact on survival in patients with initial early-stage disease. Despite the success of combination chemoradiation in locally advanced head and neck cancers, these facts stress the need for improved treatment of this disease.

Increasing data suggest that rituximab may have activity in a variety of uncommon B-cell malignancies. Although earlier preliminary data suggested a high response rate in hairy cell leukemia (HCL) (Thomas et al: Blood 94:705a[abstract 3116], 1999), the complete response rate of 20% in patients who had previously failed cladribine (Leustatin) therapy reported by Nieva et al was considered disappointing (abstract #1535). A more promising approach to patients with refractory HCL is the BL-22 immunotoxin, in which anti-CD22 is linked to a Pseudomonas exotoxin (Kreitman et al: N Engl J Med 345:241-247, 2001). Of 16 patients treated on a phase I study who had failed at least one purine analog, 13 responded, including 11 complete remissions. At a median of 16 months, only three complete responders relapsed and these were successfully reinduced.

A number of molecularly targeted agents directed at critical pathways involved in cell survival and cell proliferation have recently entered clinical evaluation in children with cancer. These agents offer the potential for more effective anticancer therapy while diminishing acute and long-term toxic effects. Systematic evaluations of agents such as these are essential if continuing improvements in outcome are to be achieved in children with cancer. Brief summaries of the rationale for conducting studies of several agents in children are provided below. Following these summaries is a listing of phase I, phase I/II, phase II, and pilot studies of these agents in pediatric populations

Overexpression of the bcl-2 gene can be detected in approximately 80% to 90% of patients with advanced-stage follicular NHL, as well as in 20% to 30% of those with diffuse large B-cell NHL. A number of studies have attempted to correlate outcome with residual disease using PCR in patients who have achieved a clinical complete response with chemotherapy, antibody treatment, or high-dose therapy with stem-cell support. However, the studies have been inconsistent, and, therefore, the clinical value of such measurements has been limited.