Book Review

Polycythemia Vera and the Myeloproliferative Disorders

N Engl J Med 1995; 332:897-898March 30, 1995

Article

Polycythemia Vera and the Myeloproliferative Disorders
Edited by Louis R. Wasserman, Paul D. Berk, and Nathaniel I. Berlin. 361 pp., illustrated. Philadelphia, W.B. Saunders, 1995. $100. ISBN: 0-7216-4213-6

Overproduction of red cells resulting in erythrocytosis has been recognized by clinicians for more than 100 years, since the initial descriptions by Louis Henri Vaquez and then by William Osler. As pointed out in the preface to this book, physicians and medical scientists have been fascinated by polycythemia — not because of its public health consequences, but because of the interesting clinical and physiologic implications of this group of diseases. Studies of polycythemia have contributed directly to many advances in our understanding of hematopoiesis and the regulation of red-cell production, including the role of erythropoietin. Furthermore, confirmation of the clonal origin of myeloproliferative disorders has derived, in part, from studies of patients with polycythemia vera. Erythrocytosis may be associated with a host of medical conditions, a fact that makes the clinical approach to an elevated hematocrit or hemoglobin level of considerable importance to primary care physicians.

The Polycythemia Vera Study Group (PVSG) was formed in the 1960s to conduct clinical investigations of patients with polycythemia vera and other myeloproliferative disorders, largely in randomized clinical trials. This group has contributed greatly to our understanding of these disorders and to the care of patients. The natural history of polycythemia vera and the effects of various forms of treatment on the course and complications of this disease have been clearly defined, particularly through the large initial study (protocol PVSG 01). Data from this study as well as other trials conducted by the group have been invaluable to practicing hematologists and others who care for patients with myeloproliferative disorders.

This book was written by members of the PVSG. Although the group is no longer funded, its members continue to follow patients from the earlier studies in order to further our understanding of the natural history of the disorders and the effectiveness of various treatments. This book updates and expands on the results of these trials.

One of the important contributions of the PVSG was to establish diagnostic criteria for polycythemia vera. As N.I. Berlin stated in a 1975 article in Seminars in Hematology (12:339-51), “It is entirely possible, but cannot be proven that some individuals who do have polycythemia vera will be excluded by such criteria.” In subsequent years the diagnostic criteria of the PVSG have become widely accepted; it is important to note that patients with early, or perhaps “smoldering,” polycythemia vera may not meet these criteria at the time of initial presentation.

The initial chapters in this book review normal bone marrow physiology and the natural history of polycythemia vera and present an approach to the classification and diagnostic evaluation of patients with erythrocytosis. An excellent chapter reviews the bone marrow findings derived largely from PVSG 01 and provides prospective follow-up on the bone marrow for some of the patients in this trial. There is a concise overview of the abnormalities in hematopoiesis found in polycythemia, which have relevance both for our understanding of the pathophysiology of the disease and for diagnostic evaluation in some patients.

There is a good discussion of the use of radioisotopes in the diagnosis of polycythemia. This topic has engendered considerable controversy, particularly with regard to the standardization of results and reference ranges. In referring to blood-volume studies, the authors of this chapter state, “We therefore can not accept the opinion of those, including the Polycythemia Vera Study Group (PVSG), who consider the expression of volume per kilogram as sufficient in clinical practice.” Unfortunately, the authors do not provide any clear alternative, leaving the clinician uncertain about the role of these studies, particularly in overweight patients (who make up a large fraction of many practices). The difficulty lies in the absence of an alternative “gold standard” with which to compare the radioisotopic data.

Other chapters review cytogenetic abnormalities and the problems of coagulation and thrombosis in polycythemia. There is also an excellent discussion of rheology in normal subjects and patients with polycythemia.

An important chapter on acute leukemia in polycythemia by Landaw nicely summarizes the findings of the PVSG. The frequency of acute leukemia in patients treated by phlebotomy alone is between 1 and 2 percent, whereas in patients treated with alkylating agents or radioactive phosphorus it is 10 to 15 percent. The PVSG studies have also shown that treatment has no effect on the incidence of the “spent” phase; patients in the spent phase who receive myelosuppressive treatment are at greatest risk for acute leukemia. Unfortunately, the leukemia update in this book, which has a 1995 copyright, is based on the last update nine years ago, in January 1986.

Long-term follow-up in the study in which patients received hydroxyurea (PVSG 08) is anxiously awaited, since this drug is currently the most widely used agent for myelosuppression in myeloproliferative disorders. The relative risk of acute leukemia in patients treated with hydroxyurea remains an issue that I hope will be clarified by further follow-up of the patients enrolled in PVSG 08. The conclusions about the risk of leukemia in hydroxyurea-treated patients differ among chapters in this book.

The chapter on the treatment of polycythemia vera provides an excellent overview and summary of recommendations derived from protocols 01, 08, and 05; the last was designed to examine the role of aspirin and dipyridamole in preventing thrombotic complications in patients treated by phlebotomy alone. This study is an excellent reminder of the importance of randomized clinical trials. Many clinicians maintained that antiplatelet treatment was effective in preventing thromboembolic complications of polycythemia vera. But this study demonstrated not only that thrombotic complications were more frequent in the patients treated with aspirin and dipyridamole than in patients who received myelosuppression alone, but also that there was an increased incidence of hemorrhagic complications among the aspirin-treated patients.

There are overview chapters on secondary and relative polycythemia that provide some useful guidelines for the management of these conditions. There is a brief chapter on familial myeloproliferative disease, but surprisingly, there is no mention of the recent discovery of a mutated erythropoietin-receptor gene in one family. There are also chapters on myeloid metaplasia with myelofibrosis, essential thrombocythemia, and chronic myelocytic leukemia.

An interesting chapter deals with anagrelide, an agent that specifically lowers the platelet count in patients with myeloproliferative disorders. The final chapter of the book provides a summary of management principles derived from the studies of the PVSG and other supporting literature.

This book is an excellent overview of the pathophysiology, natural history, and treatment of polycythemia vera and related conditions. As in many multiauthored books, there is considerable variability in the writing and an unfortunate repetition of information, particularly with regard to the development of acute leukemia. Since the last overall update of the PVSG studies was in January 1987, I hope that further reports on this valuable experience will be published. The PVSG has enlightened us on the approach to patients with myeloproliferative disease. Despite a few shortcomings, this book provides an excellent summary and overview of that experience and will be of value to all physicians involved in the care of patients with myeloproliferative disorders, as well as to scientists interested in the investigation of unanswered questions.

William G. Hocking, M.D.
Marshfield Clinic, Marshfield, WI 54449