Monoclonal Antibodies in Hematologic Malignancies: Targeted Approaches to Treatment

Anyone who attended the 2002 American Society of Hematology (ASH) meeting in Philadelphia could not help but be impressed by the number of reports of clinical trials of biologic agents. In particular, monoclonal antibody- based strategies were described in a broad range of malignant and benign conditions. As the reports of singleagent activity of drugs such as rituximab(Drug information on rituximab) (Rituxan) diminished for lymphoma trials, the number of chemotherapy regimens to which the antibody has been added blossomed. When single-agent data were presented, they often represented longer-term follow-up with additional patients, confirming the safety and efficacy of these agents. Some studies described attempts at improving the activity of antibodies, whereas others have been evaluating their role in new malignant and benign indications. Numerous abstracts were presented in which rituximab was incorporated into a variety of standard chemotherapy regimens, most with impressive results. Also of considerable potential interest were those reports of combinations of monoclonal antibodies directed at different targets. It is quite clear, however, that some level of coordination and discipline is required. Randomized trials are needed to determine the most active regimens and the patient groups in which they are most effective. The world of clinical research is hurtling toward that black hole that impeded progress a decade ago-study after study looking at minor modifications of doses and schedules of conventional agents, involving trivial differences among regimens. Thousands of patients later we learned that all the work was for limited value.[1] Apparent differences among regimens were simply attributable to simple discrepancies in patient prognostic factors.[2] The only difference in today's myriad of trials of the multiple regimens is the ubiquitous presence of rituximab. Further proliferation of regimens of standard agents should be discouraged because there are so many questions still unanswered. Instead, the optimal scheduling of antibody-chemotherapy combinations, and the identification of the most active of these combinations, should be resolved through carefully conducted, collaborative randomized trials. Treatment of hematologic malignancies is rapidly moving away from nonspecific cytotoxic therapy, and toward more targeted approaches. How these new targeted agents are prioritized and how response to treatment is measured will soon need to be modified. While the International Prognostic Index (IPI) leveled the playing field, determining the comparability of patients among studies,[2] new molecular, biologic, and immunologic factors have emerged as potentially important. For example, several abstracts presented at ASH address suggested in vitro studies that might be more accurate predictors of response to rituximab-based regimens. The International Response Criteria facilitated comparisons among trials; however, those guidelines were largely empiric and used widely available, but relatively insensitive, measures of assessment.[3] Newer regimens appear to be more effective at eradicating minimal residual disease as assessed by polymerase chain reaction (PCR) negativity. Whether this finding translates into prolonged survival will also require further study. Patients and clinicians alike should be encouraged by the data presented at ASH; however, this enthusiasm must be channeled into moving forward to address the remaining questions rather than duplicating what has already been done. The rational development of multitargeted strategies has great potential to increase the cure of patients with hematologic malignancies.