Myelodysplasia and the leukemias
The armistice after World War II marked the beginning of an era that was to last to the end of the present century. It was an era in which many changes in medicine and nursing combined to alter the entire philosophy of managing malignant disease. More specifically, the fluid-phase tumors, which comprise myelodysplasia and the leukemias, were singled out for special attention. First there was the ease with which blood and bone marrow could be sampled, making serial investigations simple and practical. Second, cytotoxic drugs became available ranging from nitrogen mustard through cytosine rabinoside, the anthracycline antibiotics, and the epi-podophyllotoxins. Although cytomorphology of the hematopoietic tissue had been exquisitely defined with the use of Romanowsky stains coupled with electron microscopy, the diagnosis of leukemia was before 1945, a death sentence for want of effective therapy. This changed dramatically with the introduction of the folate antagonists, and progress was unremitting as the range of new products expanded. Suddenly responses could be obtained with single agents, and fairly rapidly combinations were developed for cumulative antitumor effect. Many agents had undesirable toxicity among different organs. Although slightly different for myeloblastic or lymphoblastic variants, this approach produced apparent disease eradication. The concept of complete remission, both clinical and hematologic, was born. Some of our early enthusiasm has had to be tempered with the somber appreciation that not all patients can improve and many others experience relapses. Where then do we stand? Leukemic cells themselves seldom kill. It is the relentless and uncontrolled expansion of a neoplastic clone that leads to bone marrow failure, albeit at different rates in the various subtypes. In the acute forms, the common presentation remain symptomatic anemia, neutropenic sepsis, and thrombocytopenic bleeding. Differentiation from marrow aplasia may not be possible at first on clinical grounds, although bone tenderness, gingival hypertrophy, and skin infiltration are among the general useful different signs. Findings in the circulation and the marrow are of cardinal importance in diagnosis; they provide the basis for classification. Improved accuracy has followed the introduction of cytochemical stains, and a widening range of monoclonal antibodies, and greater recourse to karyotyping, have enhanced diagnostic acumen. Treatment decisions rest on many variables or prognostic factors that include age, performance status, comorbidity, and disease category, with an ever-increasing regard for the part played by cellular and molecular genetics. Despite skillful utilization of this wealth of information for optimal management, outcome often leaves much to be desired. Myelodysplasia encompasses a number of different syndromes in which the refractory anemias are indolent, whereas those with excess blasts progress toward overt leukemia. Considerable judgment is necessary in selecting patients for whom use growth factors that include erythropoietin, granulocyte or granulocyte monocyte-colony stimulating factors, and thrombopoietin can be justified. The often unfavorable result has been a stimulus to current investigations that examine the value of intensive chemotherapy or the more innovative bone marrow transplantation and its peripheral blood equivalent. Autografting is a newer alternative that does not have proved potential. Acute leukemia, whether myeloblastic or lymphoblastic, has been managed with mixed success. Remission rates have steadily increased and, notably among children, moved toward 100% in certain groupings. The downside of nonspecific drug regimens is that some patients simply may not respond, whereas others experience remissions and then relapses. Some progress has followed postremission intensification with dosage escalation into ranges that require myeloprotection with growth factors or hematopoietic stem and progenitor cells derived from blood or marrow by means of cell separator technology. Apart from short- and long-term complications and high cost, survival rates, which have undoubtedly improved, are in many categories less than 50% beyond 5 years. Chronic leukemia is crisply separable into granulocytic or lymphocytic, and management of these conditions has brought, respectively, reward and frustration. In the former, the early promise of interferon has not been fully realized, and although allografting has for the first time produced long and stable disease-free survival periods, the relapse rate is substantial, particularly after T-cell depletion. Nevertheless, the ability to return patients to cytogenetic remission by means of adoptive immunotherapy with mononuclear cells of donor origin, has reawakened interest in the role of this therapy as a more specific tumor-directed intervention. In lymphocytic leukemia, the purine analogues are useful, but cure is rare. Accordingly, feasibility studies have tested the concept that more aggressive efforts to eliminate the disease, followed by grafting, deserve attention. Preliminary data suggest that in some instances lymphocytic leukemia is no longer detectable, even with stringent molecular diagnostic techniques. It seems unlikely that contemporary practices will ever be acceptable, because of their lack of specificity and side effects. All serious students of the hematologic malignant diseases, whether basic or clinical scientists, should rekindle an interest in the physiologic aspects of hematopoiesis at the cellular level. The practicing hematologist and oncologist is going to see more emphasis on genetics in diagnosis and as a factor in the prediction of results of treatment. Hematologist-oncologists will have the potential to intervene with greater directness in individual cases. For example, maturation-induction with retinoic acid has an established place in therapy for acute progranulocytic leukemia. Antisense oligonucleotides are being explored in a number of different hematologic and other malignant diseases. A variety of biologic reagents are being synthesized to upregulate apoptotic pathways, and immunologic mechanisms are being developed for their antileukemic activity. The 21st century is confidently expected to witness much closer interdependence between basic scientists and clinicians. Nowhere is this be more evident than in the multidisciplinary management of myelodysplasia and the leukemias.