Document NekJjZzO3xx7jzo4rVZx6YdoV

VOL 19, NO 1 FEBRUARY 1992 Semi0nars 0 in {-1 I 11 8 I i-,* ....-.' "I *. ?., i EDITOR-IN-CHIEF JohnW. Yarbro, MD, PhD ASSOCIATE EDITORS Richard S. Bornstein, M D Michael J. Mastrangelo, M D Myelodysplastic Syndromes Donald C. Doll, MD, and Alan F. List, MD, Guest Editors . Cheson Masahi VOL 19, NO 1 Semimzrs in Oncology Myelodysplastic Syndromes FEBRUARY 1992 Table of Contents MyelodysplasticSyndromes: Introduction..................................... Donald C. Doll andAlan F. List Classification and Morphologic Features of the Myelodysplastic Syndromes....Jean E. Goasguen andJohnM. Bennett Biology and Pathogenesis of the Myelodysplastic Syndromes..........Alan F. List and Allan Jacobs Chromosome Abnormalities in Myelodysplastic Syndromes................................... Peter C. Nowell In Vitro Marrow Culture Studies in the Myelodysplastic Syndromes................PeterL. Greenberg 1 4 14 25 34 Leukemias and Myelodysplastic Syndromes Secondary to Drug, Radiation, and Environmental Exposure.......................................................................... Ellis G. Levine and Clara D. Bloomfield 47 Chemotherapy and Bone Marrow Transplantation for Myelodysplastic Syndromes Bruce D. Cheson 85 Differentiation-Inducing Agents in the Treatment of Myelodysplastic Syndromes Masahiro Kizaki and H. Phillip Koefier 95 Treatment of Myelodysplastic Syndromes With Hemopoietic Growth Factors Peter L. Greenberg 106 Vol 19, No 1 Seminars in Oncology February 1992 Myelodysplastic Syndromes: Introduction Donald C. Doll and Alan F. List IN NEARLY 20 years of publication of Seminars in Oncology, this is the first issue devoted to the biology and management of the myelodysplastic syndromes (MDS). Although the terminology and classification of MDS is relatively new, the concept of such disorders is at least five decades old. In 1938, Rhoades and Barker' described 100 patients who had refractory anemia, 60 of whom had primary refractory anemia while the other 40 cases were secondary to an underlying illness. Eleven years later, Hamilton-Paterson' used the term "pre-leukemic anemia" to describe three cases of refractory anemia antedating acute myelogenous leukemia. Block and colleagues3 later coined the term "preleukemia" in their 1953report describing 12 patients with refractory cytopenia(s), with evolution to acute leukemia. Although this nosologic reference persists even to date, case studies revealed that both the hematologic presentation and natural history of the preleukemic states vary. Bjorkman` chronicled four cases of refractory anemia associated with ringed sideroblasts in the bone marrow in which leukemic conversion appeared to be uncommon. In 1963, Rheingold et a15described an apparent variant of acute leukemia characterized by a prolonged and often benign clinical course with a variable but comparatively lower percentage of marrow-blasts, which the authors termed "smoldering acute leukemia." Not until the 1970s, however, was a unique preleukemic syndrome recognized distinguished by myeloproliferative features of excess monocytes and granulocyte production, designated chronic myelomonocytic leukemia."' Dreyfus'' seminal observation that patients with refractory anemia accompanied by an excess number of myeloblasts ( > 5 % ) in the bone marrow experience a more aggressive clinical course provided a prognostically useful means to dis- cern differences in clinical behavior. A number of additional terms have been applied to de- scribe the preleukemic states and are summa- rized in Table 1. In 1976, the French-American-British (FAB) cooperative group initially defined refractory anemia with excess blasts and chronic my- elomonocytic leukemia as preleukemic states.'' Six years later, the FAB group further refined this classification and adopted the term "myelo- dysplastic syndromes," which includes the five current subtypes: refractory anemia (EU),re- fractory anemia with ringed sideroblasts (RARS), chronic myelomonocytic leukemia (CMML), refractory anemia with excess blasts (RAEB) and refractory anemia with excess blasts in transformation (RAEB-t).I9Although the need and validity of this new scheme has been it has enjoyed widespread application because of its reproducibility and clinical relevance. With the possible exception of CMML, the MDS are invariably associated with cytopenias. Controversypersists over the inclusionof CMML among the MDS because of its proliferative phase akin to chronic myelogenous leukemia (see article by Goasguen and Bennett). Indeed, many cases previously characterized as Ph- negative chronic myelogenous leukemia are in _______~ From the Department of Medicine. Section of Hematology1 Oncology, University of Missouri, Veterans Affairs Medical Center, Columbia, MO; and Arizona Cancer Center, Tucson, AZ. Address reprint requests to Dr Donald Doll, Department of Medicine, Section of HematologylOncology, Universiy of Missouri, Veterans Affairs Medical Center, Columbia, MO 65212. Copyright 0 1992 by W.B. Saunders Company 0093- 77541921I901 -0001~05.00l o Semmarsm Oncology, Vol 19. No 1 (February), 1992: pp 1-3 1 i 1 I I ! 2 DOLL AND LIST Table 1. Chronology and Terminology of the Myelodysplastic Syndrome Term Year Author Refractory anemia Preleukemic anemia Preleukemia Refractory anemia with ringed sideroblasts Refractory normoblastic anemia Smoldering acute leukemia Chronic erythemic myelosis Preleukemic syndrome Subacute myelomonocytic leukemia Chronic myelomonocytic leukemia Hypoplastic acute myelogenous leukemia Refractory anemia with excess myeloblasts Hematopoietic dysplasia Subacute myeloid leukemia Dysmyelopoietic syndrome Myelodysplastic syndromes 1938 1949 1953 1956 Rhoads and Barker' Hamilton-Paterson' Block et a13 Bjorkman4 1959 Dacie et allo 1963 Rheingold et a15 1969 Dameshek" 1973 Saarni and Linman16 1974 Sexauer et all3 1974 Miescher and Farquef 1975 Beard et all' 1976 Dreyfuss 1978 Linman and Bagby15 1979 Cohen et all* 1980 Streuli et al" 1982 Bennett et alls fact unrecognized cases of CMML.23-2P5rogress in understanding the pathobiology of these disorders has shown that unique biologic features such as increased sensitivity to growth factor regulation appear to distinguish CMML from other MDS types (see articles by Greenberg and List and Jacobs in this issue). The pathogenesis of these disorders remains unclear. However, recognition that both MDS and acute myeloid leukemia (AML) may develop following treatment with chemotherapy and/or radiotherapJ63' has provided a fertile area to investigate the pathobiology of these disorders. The risks associated with specific exposures are addressed by Levine and Bloomfield. Environmental exposure to potential leukemogens may also represent contributing factors. Nonetheless, the application of sensitive probes to assess clonality suggests that such exposures may enhance host susceptibility to malignant conversion by limiting stem cell reserve and restricting clonality, and inducing somatic mutations of cellular oncogenes (see article by List and Jacobs in this issue). Interaction with host factors such as age may determine susceptibility and influence disease expression. Detection of nonrandom, cytogenetic abnormalities in MDS confirmed the clonal nature of these disorders, and provided important information regarding disease biology (see article by Nowell). The development of marrow culture techniques has shown that these disorders share a disturbance in progenitor growth and maturation, independent of FAB type (see article by Greenberg). Progress in the last decade suggests that the abnormalities in progenitor growth relate in large part to decreased responsiveness to cytokine stimulation. Supersaturating concentrations of hematopoietic growth factors and certain pharmacologic agents restore progenitor growth in vitro and provide new avenues for clinical applications (see articles by Greenberg, and Kizaki and Koeffler).Indeed, the introduction of recombinant hematopoietins into clinical trials has shown that this new class of agents hold particular promise to ameliorate the cytopenias in MDS. For patients with high initial leukemicburden (eg, M B - T ) and those patients experiencing leukemic conversion, induction chemotherapy offers the prospect for hematologic remission (see article by Cheson). The traditionally higher rate of induction failure due to primary chemoresistance may be less pronounced in patients with RAEB-T, but has limited success in patients with acute leukemia. Recognition that specific biologic phenotypes such as multidrug resistance (MDR) may contribute to treatment failure has provided new inroads for innovative protocol designs. The myelodysplastic syndromes are an extremely heterogenous group of bone marrow disorders with unique biologic features. Further progress with the management of these disorders remains inextricably linked to continued developments in their biology. We hope that this issue of Seminars in Oncology will highlight present results of such efforts and stimulate further development. We are grateful to the contributing authors for their superb and timely reviews. We would like to also express our appreciation to Burroughs Wellcome Company for their generous educational grant providing color photomicrograph reproductions for this issue of Seminars. MYELODYSPLASTIC SYNDROMES 3 REFERENCES 1. Rhoads CP, Barker WH: Refractory anemia: An analysis of one hundred cases. JAMA 110:794-796, 1938 2. Hamilton-Paterson JL: Pre leukemic anemia. Acta Haematol2:309-316, 1949 3. Block M, Jacobsen LO, Bethard WF: Preleukemic acute human leukemia. JAMA 152:1018-1028,1953 4. Bjorkman SE: Chronic refractory anemia with sideroblastic bone marrow. A study of four cases. Blood 11:250259,1956 5. Rheingold JJ, Kaufman R, Adelson E, et al: Smoldering acute leukemia. N Engl J Med 268:812-815,1963 6. Miescher PA, Farquet JJ: Chronic myelomonocytic leukemia. Semin Hematol 11:129-139,1974 7. Geary CG, Catovsky D, Wiltshaw E, et al: Chronic myelomonocytic leukemia. Br J Haematol30:289-302. 1975 8. Zittoun R: Subacute and chronic myelomonocytic leukemia: A distinct haematological entity. Br J Haematol 32:1-7, 1976 9. Dreyfus B: Preleukemic states. I. Definition and classification. 11. Refractory anemia with an excess of myeloblasts in the bone marrow (smoldering acute leukemia). Blood Cells 2:33-55, 1976 10. Dacie JV,Smith MD, White JC, et al: Refractory normoblastic anemia: A clinical and haematological study of 7 cases. Br J Haematol5:56-82,1959 11. Beard M U , Bateman CJT, Crowther DC, et al: Hypoplastic acute myelogenous leukemia. Br J Haematol 31:167-176,1975 12. Cohen JR, Creger WP, Greenberg PL, et al: Subacute myeloid leukemia: A critical review. Am J Med 66:959-966, 1979 13. Sexauer J, Kass L, Schnitzer B: Subacute myelomonocytic leukemia. Clinical, morphologic and ultrastructural studies of 10 cases. Am J Med 572353461, 1974 14. Dameshek W: The DiGuglielmo syndrome revisited. Blood 34567-572, 1969 15. Linman JW, Bagby GC Jr: The preleukemic syndrome (hematopoietic dysplasia). Cancer 42:852-864. 1978 16. Saarni MI, Linman JW: Preleukemia: The hematologic syndrome preceding acute leukemia. Am J Med 55~38-48,1973 17. Streuli RA, Testa JR, Vardiman JW, et al: Dysmyelopoietic syndrome: Sequential, clinical, and cytogenetic studies. Blood 55:636-644,1980 18. Bennett JM, Catovsky D, Daniel M-T, et al: Proposals for the classification of the acute leukemias. Br J Haematol33:451-458. 1976 19. Bennett JM, Catovsky D, Daniel M-T, et al: Proposals for the classification of the myelodysplastic syndrome. Br J Haematol51:189-199,1982 20. Greenberg P, Bagby G: Biological rather than morphologic markers in myelodysplastic syndromes. Br J Haematol53:532-534,1983 21. Spitzer TR, Goldsmith G H Jr: Myelodysplastic syndromes: Is another classification necessary? Br J Haematol 52:343-344, 1982 22. Seigneurin B: Refractory anemia with excess of blasts in transformation: Is a new category necessary? Br J Haematol55:196-197,1983 23. Pugh WC, Pearson M, Vardiman JW, et al: Philadelphia chromosome-negative chronic myelogenous leukemia: A morphological reassessment. Br J Haematol 60:457-467, 1985 24. Travis LB, Pierre RV, DeWald GW: Ph-negative chronic granulocytic leukemia: A non-entity. Am J Pathol 85:186-193,1986 25. Kantarjian HM, Shtalrid M, Kurzrock R, et al: Significance and correlation of molecular analysis results in patients with Philadelphia chromosome-negative chronic myelogenous leukemia and chronic myelomonocytic leukemia. Am J Med 85:639-644,1988 26. Casciato DA, Scott J L Acute leukemia following prolonged cytotoxic agent therapy. Medicine 58:32-47, 1979 27. Michels SD, McKenna RW, Arthur DC, et al: Therapy-related acute myeloid leukemia and myelodysplastic syndrome: A clinical and morphologic study of 65 cases. Blood 65:1364-1372, 1985 28. Koeffler HP: Myelodysplastic syndromes (Preleukemia). Semin Hematol23:284-299,1986 29. Levine EG, Bloomfield CD: Secondary myelodysplastic syndromes and leukemias. Clin Haematol 15:1037-1080. 1986 30. Kantarjian HM, Keating MJ: Therapy-related leukemia and myelodysplastic syndrome. Semin Oncol 14:435443,1987 31. Pedersen-Bjergaard J, Philip P: Therapy-related malignancies: A review. Eur J Haematol42:39-47, 1989 (suppl 48)