Critical Reviews in Oncology/Hematotogy. 1992; 12: 193-215 0 1992 Elsevier Science Publishers B.V. AI1 rights reserved.
ONCHEM
193 1040-84281921S15.00
022
Myelodysplastic Pathogenesis,
syndromes
diagnosis and treatment
Pierre No&l” and Lawrence A. Solberg Jr.b “Division of Hematology and Internal Medicine, Mayo Clinic and Mavo Foundation, Rochester, MN, and bSection of Hematology and Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA (Accepted
4 December
1991)
Contents 194
I.
Introduction
II.
Historical
III.
Classification
194
IV.
Etiology
195
V.
Clinical
VI.
.__....,..._......,._.,..,_.._........_._...,...__....
194
perspective
and pathogenesis
..
features
Laboratory
..
198 198
features
A. Peripheral
198
blood
,..._.................
B. Bone marrow C. Cellular
199 199
dysfunction
D. Cytogenetics
200
E.
200
Cell culture
VII.
Differential
VIII.
Prognosis
IX.
Treatment
201
diagnosis ..,.___.,,.,,__.._,..____..,._._........__....___._.....
201
............................................... A. Supportive care ....................................... ........................................ B. Glucocorticoids
202
C. Androgens
...........................................
203
D. Danazol
203
E.
............................................ Retinoic acid ......................................... 1,25Dihydroxyvitamin D, ...............................
203
F.
202 202
204
............................. ....................................... I. Erythropoietin 2. Granulocyte colony-stimulating factor .....................
G. Recombinant
growth
Pierre NotI received a B.S. degree from McGill University, Canada, brooke, tology
and an M.D. degree Canada.
He is currently
and Internal
and an Assistant
from University
Medicine. Professor
a consultant Mayo
Sher-
in the Division of Hemaat Mayo
Rochester,
MN. Lawrence A. Solberg. Jr., received
University
of California,
Berkeley,
Montreal,
of Sherbrooke,
Clinic and Mayo
of Medicine
204
factors
Foundation.
Medical
Louis University Head
.
204
School of Medicine,
of the Section
Jacksonville, tine, Mayo
204
of Hematology
Jacksonville, Medical
St. Louis, MO. He is currently and Oncology
FL, and an Associate
School,
Rochester,
at Mayo
Professor
Clinic
of Medi-
MN.
School.
a PhD. from the
CA and an M.D. degree from St.
Correspondence: Rochester,
Dr. P. Noel,
MN 55905, USA.
Mayo
Clinic,
200 First
Street
S.W.,
194 3. Granulocyte-macrophage colony-stimulating 4. IL-3 ........................................................
factor ......................
x.
Interferons
XI.
Chemotherapy ..................................................... A. Low-dose cytarabine .............................................. B. Cytarabine and granulocyte-macrophage colony-stimulating factor C. 5-Azacytidine ................................................... D. Conventional antileukemic therapy ....................................
206 206 206 207 207
XII.
Antithymocyte globulin and cyclosporine
208
XIII.
Bone marrow transplantation
208
XIV.
Summary
208
. ..__......._......_.,...................__,..___....._
. . . .._.......__.....__.....__............___..._._.....
References................................................................
I. Introduction
Myelodysplastic syndromes (MDS) are clonal hemopathies characterized by ineffective hematopoiesis and cellular dysfunction. The majority of patients die of complications of marrow failure or acute leukemia. Several problems face the clinician managing patients with MDS. Diagnosis can be difficult because several diseases are associated with bone marrow dysplasia. In the absence of karyotypic abnormalities, it is often difficult to be confident of a diagnosis of refractory anemia. Some laboratory tests are available to establish the prognosis and risk of leukemic conversion. Unfortunately, few patients benefit from the results of these tests because of lack of effective therapy. Bone marrow transplantation and high-dose chemotherapy are the only current treatments that have the potential of reestablishing normal hematopoiesis. These are generally useful in the small subset of patients less than 45 years of age. II. Historical
205 205
perspective
The first cases of MDS were described by Luzzatto in 1907 [l] and Di Guglielmo in 1917 [2]. In 1941, Bomford and Rhoads [3] described 100 cases of refractory anemia (RA). In 1942, Chevallier [4] described the odoleucoses (frontiers of leukemia). Mallarme [5] described the hematologic findings preceding acute leukemia in 1949. In the same year, Hamilton-Paterson [6] described preleukemic anemia. In 1953, Block et al. [7] coined the term ‘preleukemia’. RA with ringed sideroblasts was first described by Bjijrkman in 1956 [8]. The presence of a double red cell population in this disorder was
206
208
observed by Dacie et al. in 1959 [9]. The term ‘smouldering leukemia’ was applied by Rheingold et al. [IO] in 1963 to the disease affecting elderly patients with 20% to 40% blasts in the bone marrow but only occasional blasts in the peripheral blood. RA with excess blasts was first described by Dreyfus et al. in 1970 [ll]. In 1972, Zittoun et al. [12] recognized chronic myelomonocytic leukemia (CMML) as a specific preleukemic state. In 1973, Saarni and Linman [13] described 34 patients in whom acute myeloid leukemia was preceded by a preleukemic phase. In 1976, the French-American-British Cooperative Group (FAB) [ 141 classified dyshematopoietic syndromes into two categories: RA with excess blasts and CMML. In 1982, the FAB defined the current five categories of MDS [15]. III. Classification
MDS have been classified by the FAB group [ 151into five categories: RA; RA with ringed sideroblasts (RARS); RA with excess blasts (RAEB); RA with excess blasts in transformation (RAEBIT); and CMML. This classification applies only to primary MDS and is based on the percentage of peripheral blood and bone marrow blasts as well as the presence or absence of ringed sideroblasts or Auer rods (Table 1). The FAB defines two types of blasts: Type I blasts have a prominent nucleolus with uncondensed chromatin pattern and absence of cytoplasmic granules. The nuclear/cytoplasmic ratio of the smaller blasts tends to be higher than that of the larger ones. Type II blasts have a few primary granules; their nuclear/cytoplasmic ratio tends to be lower and their nucleus remains in a central position. The Morphologic, Immunologic, and Cytogenetic
195 TABLE I Classification of the myelodysplastic syndromes, as proposed by the French-American-British Subtype
RA RARS RAEB RAEBIT CMML
Monocytes (~1). peripheral blood
no no no no > 1000
Ringed sideroblasts (%). marrow
< 15 > 15 no no no
Cooperative Group
Blast cells (%)
Auer rods, marrow
peripheral blood
marrow
ONCHEM
193 1040-84281921S15.00
022
Myelodysplastic Pathogenesis,
syndromes
diagnosis and treatment
Pierre No&l” and Lawrence A. Solberg Jr.b “Division of Hematology and Internal Medicine, Mayo Clinic and Mavo Foundation, Rochester, MN, and bSection of Hematology and Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA (Accepted
4 December
1991)
Contents 194
I.
Introduction
II.
Historical
III.
Classification
194
IV.
Etiology
195
V.
Clinical
VI.
.__....,..._......,._.,..,_.._........_._...,...__....
194
perspective
and pathogenesis
..
features
Laboratory
..
198 198
features
A. Peripheral
198
blood
,..._.................
B. Bone marrow C. Cellular
199 199
dysfunction
D. Cytogenetics
200
E.
200
Cell culture
VII.
Differential
VIII.
Prognosis
IX.
Treatment
201
diagnosis ..,.___.,,.,,__.._,..____..,._._........__....___._.....
201
............................................... A. Supportive care ....................................... ........................................ B. Glucocorticoids
202
C. Androgens
...........................................
203
D. Danazol
203
E.
............................................ Retinoic acid ......................................... 1,25Dihydroxyvitamin D, ...............................
203
F.
202 202
204
............................. ....................................... I. Erythropoietin 2. Granulocyte colony-stimulating factor .....................
G. Recombinant
growth
Pierre NotI received a B.S. degree from McGill University, Canada, brooke, tology
and an M.D. degree Canada.
He is currently
and Internal
and an Assistant
from University
Medicine. Professor
a consultant Mayo
Sher-
in the Division of Hemaat Mayo
Rochester,
MN. Lawrence A. Solberg. Jr., received
University
of California,
Berkeley,
Montreal,
of Sherbrooke,
Clinic and Mayo
of Medicine
204
factors
Foundation.
Medical
Louis University Head
.
204
School of Medicine,
of the Section
Jacksonville, tine, Mayo
204
of Hematology
Jacksonville, Medical
St. Louis, MO. He is currently and Oncology
FL, and an Associate
School,
Rochester,
at Mayo
Professor
Clinic
of Medi-
MN.
School.
a PhD. from the
CA and an M.D. degree from St.
Correspondence: Rochester,
Dr. P. Noel,
MN 55905, USA.
Mayo
Clinic,
200 First
Street
S.W.,
194 3. Granulocyte-macrophage colony-stimulating 4. IL-3 ........................................................
factor ......................
x.
Interferons
XI.
Chemotherapy ..................................................... A. Low-dose cytarabine .............................................. B. Cytarabine and granulocyte-macrophage colony-stimulating factor C. 5-Azacytidine ................................................... D. Conventional antileukemic therapy ....................................
206 206 206 207 207
XII.
Antithymocyte globulin and cyclosporine
208
XIII.
Bone marrow transplantation
208
XIV.
Summary
208
. ..__......._......_.,...................__,..___....._
. . . .._.......__.....__.....__............___..._._.....
References................................................................
I. Introduction
Myelodysplastic syndromes (MDS) are clonal hemopathies characterized by ineffective hematopoiesis and cellular dysfunction. The majority of patients die of complications of marrow failure or acute leukemia. Several problems face the clinician managing patients with MDS. Diagnosis can be difficult because several diseases are associated with bone marrow dysplasia. In the absence of karyotypic abnormalities, it is often difficult to be confident of a diagnosis of refractory anemia. Some laboratory tests are available to establish the prognosis and risk of leukemic conversion. Unfortunately, few patients benefit from the results of these tests because of lack of effective therapy. Bone marrow transplantation and high-dose chemotherapy are the only current treatments that have the potential of reestablishing normal hematopoiesis. These are generally useful in the small subset of patients less than 45 years of age. II. Historical
205 205
perspective
The first cases of MDS were described by Luzzatto in 1907 [l] and Di Guglielmo in 1917 [2]. In 1941, Bomford and Rhoads [3] described 100 cases of refractory anemia (RA). In 1942, Chevallier [4] described the odoleucoses (frontiers of leukemia). Mallarme [5] described the hematologic findings preceding acute leukemia in 1949. In the same year, Hamilton-Paterson [6] described preleukemic anemia. In 1953, Block et al. [7] coined the term ‘preleukemia’. RA with ringed sideroblasts was first described by Bjijrkman in 1956 [8]. The presence of a double red cell population in this disorder was
206
208
observed by Dacie et al. in 1959 [9]. The term ‘smouldering leukemia’ was applied by Rheingold et al. [IO] in 1963 to the disease affecting elderly patients with 20% to 40% blasts in the bone marrow but only occasional blasts in the peripheral blood. RA with excess blasts was first described by Dreyfus et al. in 1970 [ll]. In 1972, Zittoun et al. [12] recognized chronic myelomonocytic leukemia (CMML) as a specific preleukemic state. In 1973, Saarni and Linman [13] described 34 patients in whom acute myeloid leukemia was preceded by a preleukemic phase. In 1976, the French-American-British Cooperative Group (FAB) [ 141 classified dyshematopoietic syndromes into two categories: RA with excess blasts and CMML. In 1982, the FAB defined the current five categories of MDS [15]. III. Classification
MDS have been classified by the FAB group [ 151into five categories: RA; RA with ringed sideroblasts (RARS); RA with excess blasts (RAEB); RA with excess blasts in transformation (RAEBIT); and CMML. This classification applies only to primary MDS and is based on the percentage of peripheral blood and bone marrow blasts as well as the presence or absence of ringed sideroblasts or Auer rods (Table 1). The FAB defines two types of blasts: Type I blasts have a prominent nucleolus with uncondensed chromatin pattern and absence of cytoplasmic granules. The nuclear/cytoplasmic ratio of the smaller blasts tends to be higher than that of the larger ones. Type II blasts have a few primary granules; their nuclear/cytoplasmic ratio tends to be lower and their nucleus remains in a central position. The Morphologic, Immunologic, and Cytogenetic
195 TABLE I Classification of the myelodysplastic syndromes, as proposed by the French-American-British Subtype
RA RARS RAEB RAEBIT CMML
Monocytes (~1). peripheral blood
no no no no > 1000
Ringed sideroblasts (%). marrow
< 15 > 15 no no no
Cooperative Group
Blast cells (%)
Auer rods, marrow
peripheral blood
marrow
