Book Review

Monoclonal Antibody Therapy of Hematologic Malignancies

N Engl J Med 2002; 346:714February 28, 2002

Article

Monoclonal Antibody Therapy of Hematologic Malignancies
(New Frontiers in Cancer Therapy.) Edited by Bruce D. Cheson. 287 pp. Abingdon, United Kingdom, Darwin Scientific, 2001. $95. ISBN: 1-903557-01-1

A variety of hematologic cancers have served as examples of how to cure the disease by a step-by-step application of new treatments as they become available, but it must be admitted that during the past 10 years there have been no real breakthroughs in the fields of conventional chemotherapy, radiotherapy, or even marrow-ablative treatment followed by transplantation of stem cells. On average, half the patients eligible for the most effective treatment are cured, but the other half, with disease that is less responsive to treatment, still has a most unfavorable prognosis. Apparently, the limits of the possible have been reached with chemoradiotherapy.

Recently, a different treatment for hematologic cancers has been reintroduced: the use of monoclonal antibodies. Paul Ehrlich introduced the idea of these “magic bullets” in 1890; however, it has taken more than 100 years for the efficacy of the approach to be established. The initial phase of clinical testing was marked by a lack of antitumor specificity of the antibodies. After Köhler and Milstein described the hybridoma technique for the production of monoclonal antibodies in 1975, a new wave of publications about the use of murine monoclonal antibodies against a variety of cancers appeared.

A major drawback, however, was the formation by the patient of antibodies against the murine proteins. It was only in the early 1990s that the large-scale production of human–mouse chimeric and humanized antibodies through genetic engineering became a reality. From that time onward, a steadily increasing number of clinically effective antibodies has been produced, culminating in 1997 in the first approval by the Food and Drug Administration of a monoclonal antibody: rituximab, used for the treatment of patients with indolent lymphoma in whom previous therapy had failed. After that, another seven monoclonal antibodies followed.

The merit of this book is that the state of the art in this rapidly progressing area of clinical research has been summarized by pioneers in the field. In a number of chapters, they recount the efficacy of the two most frequently used antibodies (rituximab and Campath) in patients with indolent or aggressive non-Hodgkin's lymphoma or chronic lymphocytic leukemia. It is clear that in patients with disease refractory to conventional chemotherapy, remissions can be induced with monoclonal antibodies.

After the initial observation that monoclonal antibodies by themselves are highly efficacious, it was logical to explore combinations of antibodies and chemotherapy. That such combination treatment can indeed lead to a survival advantage was recently reported in elderly patients with aggressive non-Hodgkin's lymphoma (who received chemotherapy plus rituximab). Promising data from additional, ongoing studies are described in various chapters of the book.

However, as with all other treatments of cancer, not all patients respond to antibody therapy. A special chapter describes the mechanisms of action of antibodies and, directly linked to these, the patterns of resistance that may develop. Resistance may be due to specific characteristics of the antibody (e.g., low affinity, poor penetration into the tumor, or immunogenicity after the use of human–mouse chimeric antibodies), the antigen (e.g., antigen specificity, low density on the target cell, biologic function, or mutation), and impaired immune effector mechanisms. The role of cytokines in stimulating immunoreactivity is extensively discussed.

The book also reports the first promising results with immunoconjugates in which monoclonal antibodies are conjugated to bacterial toxins, radioisotopes, or cytostatic drugs. Initial results show better efficacy than with monoclonal antibodies alone. However, there are more (reversible) toxic effects, especially on the hematopoietic system.

In under 300 pages, easily readable for those trained or being trained in hematology, this monograph provides the reader with an up-to-date review of a fast-moving field. In this respect, it can be highly recommended to all who want to participate in the application of this new and promising type of treatment to their patients with hematologic cancers.

Anton Hagenbeek, M.D., Ph.D.
University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands