Monoclonal Antibodies in Hematologic Malignancies: Targeted Approaches to Treatment

Anyone who attended the2002 American Society ofHematology (ASH) meetingin Philadelphia couldnot help but be impressedby the number of reportsof clinical trials of biologicagents. In particular,monoclonal antibody-based strategies were describedin a broad range of malignant andbenign conditions. As the reports of singleagentactivity of drugs such as rituximab (Rituxan)diminished for lymphoma trials, thenumber of chemotherapy regimens to which theantibody has been added blossomed. Whensingle-agent data were presented, they oftenrepresented longer-term follow-up with additionalpatients, confirming the safety and efficacyof these agents. Some studies describedattempts at improving the activity of antibodies,whereas others have been evaluating their rolein new malignant and benign indications.Numerous abstracts were presented in which rituximabwas incorporated into a variety of standardchemotherapy regimens, most with impressiveresults. Also of considerable potential interestwere those reports of combinations of monoclonalantibodies directed at different targets.It is quite clear, however, that some level ofcoordination and discipline is required. Randomizedtrials are needed to determine the mostactive regimens and the patient groups in whichthey are most effective. The world of clinicalresearch is hurtling toward that black hole thatimpeded progress a decade ago-study afterstudy looking at minor modifications of dosesand schedules of conventional agents, involvingtrivial differences among regimens.Thousands of patients later we learned that allthe work was for limited value.[1] Apparentdifferences among regimens were simply attributableto simple discrepancies in patient prognosticfactors.[2] The only difference in today'smyriad of trials of the multiple regimens is theubiquitous presence of rituximab. Further proliferationof regimens of standard agents shouldbe discouraged because there are so manyquestions still unanswered. Instead, the optimalscheduling of antibody-chemotherapy combinations,and the identification of the most activeof these combinations, should be resolvedthrough carefully conducted, collaborative randomizedtrials.Treatment of hematologic malignancies is rapidlymoving away from nonspecific cytotoxictherapy, and toward more targeted approaches.How these new targeted agents are prioritizedand how response to treatment is measured willsoon need to be modified. While the InternationalPrognostic Index (IPI) leveled the playingfield, determining the comparability ofpatients among studies,[2] new molecular, biologic,and immunologic factors have emergedas potentially important. For example, severalabstracts presented at ASH address suggestedin vitro studies that might be more accuratepredictors of response to rituximab-basedregimens.The International Response Criteria facilitatedcomparisons among trials; however, thoseguidelines were largely empiric and used widelyavailable, but relatively insensitive, measuresof assessment.[3] Newer regimens appearto be more effective at eradicating minimalresidual disease as assessed by polymerasechain reaction (PCR) negativity. Whether thisfinding translates into prolonged survival willalso require further study.Patients and clinicians alike should be encouragedby the data presented at ASH; however,this enthusiasm must be channeled intomoving forward to address the remaining questionsrather than duplicating what has alreadybeen done. The rational development of multitargetedstrategies has great potential to increasethe cure of patients with hematologicmalignancies.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standardregimen (CHOP) with three intensive chemotherapy regimens for advancednon-Hodgkin’s lymphoma. New Engl J Med 328:1002-1006,1993.

2.

Shipp MA, Harrington DP, Anderson JR, et al: Development of apredictive model for aggressive lymphoma: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. New Engl J Med329:987-994, 1993.

3.

Cheson BD, Horning SJ, Coiffier B, et al: Report of an InternationalWorkshop to standardize response criteria for non-Hodgkin’s lymphomas.J Clin Oncol 17:1244-1253, 1999.