Leukemia Research Vol. 16, No, 1, pp. 109-115, 1992. Printed in Great Britain.
0145--2126/92 $5.00 + .00 Pergamon Press plc
PROGNOSTIC FACTORS IN THE MYELODYSPLASTIC SYNDROMES GUIDO J. TPocoT Division of Hematology/Oncology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, U.S.A. Abstract--The myelodysplastic syndromes are acquired clonal hematologic malignancies characterized by progressive cytopenia and an increased risk of evolution to acute myeloid leukemia. It mainly affects elderly people, but may also be found in younger patients and children. MDS represents a heterogeneous group of disorders. Some patients will experience prolonged survival, whereas a substantial number of patients will die within the first year after diagnosis. Treatment of patients should be based on life expectancy. Patients with pancytopenia, excess of bone marrow blasts, complex chromosome abnormalities, abnormal chromosome 7, older age and secondary MDS have a poor prognosis. Several simple scoring systems are available, based on peripheral counts, percent of bone marrow blasts and age, that provide significant prognostic information about life expectancy in patients with MDS. The most widely used is the Bournemouth scoring system. The prognostic factors and the scoring systems are reviewed.
Key words: Myelodysplastic syndromes, prognostic factors, pancytopenia, bone marrow blasts, acute myeloid leukemia, cytogenetics, oncogenes.
INTRODUCTION
The diagnosis of MDS is a clinical one, which is largely based on morphologic changes seen in the peripheral blood, bone marrow smears and trephine biopsies. None of the morphologic findings, however, are diagnostic. Chromosome abnormalities are found in 40-70% of MDS patients [6]. MDS represents a heterogeneous group of disorders. Some patients will experience prolonged survival, whereas a substantial number of patients will die within the first year after diagnosis [7-9], due to leukemic transformation or infectious and/or bleeding complications. It is important to be able to identify those patients with a good prognosis, since even low-dose chemotherapy may lead to unacceptable morbidity and mortality. In poor-prognosis patients, however, the potential benefits of chemotherapy may justify the risks.
THE TERMmyelodysplastic syndromes (MDS) is now reserved for acquired hematologic disorders that precede the onset of acute leukemia, sometimes by many years. They are now generally accepted to represent early stages of acute myeloid leukemia (AML). MDS are malignant hematologic neoplasms, resulting from neoplastic transformation at the level of the pluripotent stem cell or a very early progenitor cell [1--4]. MDS is essentially a disease of later life, about half of the patients being 70 years or older [5]. Disease progression is very likely the result of a multistep process with consecutive genetic insults, leading to irreversible changes in the affected progenitor cells. The consecutive mutations provide increasing growth advantage to the new clones, which become genetically increasingly unstable and lose more and more of their capacity to differentiate.
CLINICAL PARAMETERS
Abbreviations: MDS, myelodysplastic syndromes; RA, refractory anemia; RA-S, refractory anemia with ringsideroblasts; RAEB, refractory anemia with excess of blasts; CMML, chronic myelomonocytic leukemia; RAEB-t, refractory anemia with excess of blasts in transformation; AML, acute myeloid leukemia. Correspondence to: Guido J. Tricot, M.D., Ph.D., Division of Hematology/Oncology, Indiana University Hospital, Room W608, 926 West Michigan Street, Indianapolis, IN 46202-5250, U.S.A.
Increasing age has been associated with poor prognosis [6, 10, 11]. In our study on 85 patients, patients under the age of 50 experienced less fatal infectious and/or bleeding complications than people over 70, while the percentage of patients transforming to A M L was similar in all age groups [12]. Since 1980 MDS has been reported in hundreds of patients previously treated for malignant and non109
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110
TABLE 1. MEDIAN SURVIVAL (MONTHS) IN THE DIFFERENT SUBGROUPS, ACCORDING TO F A D
CLASSIFICATION
Coiffier et al. [17] W e i s d o r f e t a l . [58] Varella et al. [59] Todd et al. [60] Mufti et al. [20] Sanz et al. [11] Foucar et al. [8] Kerkhofs et al. [55] Tricot etal. [7]
N
RA
RAS
193 69 60 326 141 370 109 237 85
41.0 52.0 47.0 42.0 32.0 26.0 64.0 50.0 18.5 42.0
52.5 29.0 52.0 36.0 76.0 34.0 71.0 60.0+ 21.0 52.0
Median
malignant disorders with chemotherapeutic agents, usually alkylating agents with or without radiotherapy [13, 14]. Patients with secondary MDS have a poor prognosis with an average survival of only 6 months [15, 16]. P A R A M E T E R S OF THE P E R I P H E R A L BLOOD Anemia [11, 17-19], neutropenia [7, 15, 17, 20] and thrombocytopenia [11, 17-20] have been found to have prognostic significance in some studies, but not in others. Pancytopenia is invariably associated with poor prognosis [11, 12, 20]. In our study, however, the most important factor associated with poor survival was the presence of I>5 % blasts in the peripheral blood smear [7]. Those patients to have a median survival time of only 2.5 months, which is comparable to the survival of untreated AML patients [21]. The poor outcome of patients with a high percentage of blasts in the peripheral blood was also observed in other studies [17, 22]. P A R A M E T E R S OF THE BONE M A R R O W ASPIRATE AND BIOPSY The FAD classification into 5 subgroups [23] has been shown to be significantly correlated with survival in many studies [11,20]. The median survival for the 5 subtypes observed in different studies is provided in Table 1. All those studies demonstrate a better survival for patients with refractory anemia (RA) and R A with ringsideroblasts (RA-S) than in patients with R A with excess of blasts (RAEB) and R A E B in transformation (RAEB-t). The survival of patients with chronic myelomonocytic leukemia (CMML) is comparable to that of patients with RAEB. The survival of patients with RAEB-t is extremely poor and only half that of patients with R A E B and CMML. In some studies survival of RA-S is extremely long while in other studies survival is
RAEB
CMML
RAEB-t
14.5 12.0 14.0 17.5 10.5 12.0 7.0 9.0 11.0 12.0
11.5 2.0 15.0 17.5 22.0 9.0 7.0 60.0+ 9.5 11.5
6.5 11.0 3.0 -5.0 5.0 5.0 6.0 4.5 5.0
comparable to that of patients with RA. The difference is very likely due to the type of patients included. On a cytologic basis two subtypes of sideroblastic anemia can be distinguished: pure sideroblastic anemia, which is confined to dyserythropoiesis, and sideroblastic anemia characterized by additional dysplastic features of granulopoiesis and/or megakaryopoiesis. In a follow-up study of 94 patients with sideroblastic anemia a striking difference was observed in survival and risk of leukemic transformation. The 5-year cumulative chance of survival was 69% in the pure sideroblastic anemia compared to only 19% in those with additional dysplastic features. The cumulative risk of leukemic transformation was 1.9% and 48% respectively [24]. It is very likely that pure sideroblastic anemia is not a myelodysplastic syndrome in the sense of a clonal hematologic malignancy and has a very good prognosis. In Table 2,418 patients from 3 different studies [7, 17, 20] are grouped according to FAB classification. Patients with RAEB and RAEB-t show a high incidence of evolution to AML, 42% and 59% respectively, in contrast to R A and RA-S cases with respectively 12.5% and 11.5% respectively. Mortality of infections and/or bleeding are considerable in RA, RAEB and RAEB-t patients and relatively low in RA-S and CMML cases, probably due to the higher platelet count in RA-S and the higher granulocyte count in CMML. Although there is a significant correlation between FAD classification and survival, this sophisticated classification is not mandatory for prognostic purposes. A more simple classification dividing patients in two groups, cases with 5% bone marrow blasts, has at least an equal prognostic value [7, 11, 17, 20]. Some studies observed a difference in survival between patients with 5-10% and those >10% bone marrow blasts [11], while other studies did not [7, 20]. The presence of Auer rods was considered a
111
Prognostic factors in MDS TABLE 2. OUTCOME IN THE DIFFERENTF A B TYPES
RA AISA RAEB CMML RAEB-t Total
Number
Alive
AML (%)
Death of infections/ bleeding (%)
138 53 136 57 34 418
59 (43) 22 (41.5) 16 (12) 24 (42) 4 (11.5) 125 (30)
17 (12.5) 6 (11.5) 57 (42) 16 (28) 20 (59) 116 (28)
47 (34) 9 (17) 55 (40.5) 9 (16) 10 (29.5) 130 (31)
Other causes 15 (10.5) 16 (30) 8 (5.5) 8 (14) 0 (0) 47 (11)
Coiffier et al. [17] (192 patients). Mufti et al. [20] (141 patients). Our study [7] (85 patients). marker of poor prognosis and patients with Auer rods were therefore placed in the RAEB-t subgroup. Two studies dealing with the prognostic value of the Auer rods in patients with MDS have not found any difference in survival between those with and without Auer rods [25, 26]. By using plastic-embedded trephine biopsies we found that the presence or absence of ALIP (abnormal localization of immature myeloid precursors) has strong prognostic significance [7, 61]. Since all patients with an excess of blasts in their bone marrow smears were also ALIP-positive in our study [7], we do not consider a biopsy essential in these patients. However, the trephine biopsy has a strong prognostic value in those patients who have 50% of these patients having ras-mutations. The incidence in other subgroups of MDS is probably around 20-25% [43, 45]. Mutations may occur in N-, K- and H-ras and may involve codons 12, 13 and 61. Although some studies suggest a poor prognosis in patients with point mutations in ras [41-44], other investigators have failed to confirm this correlation [45-47]. E r b - B amplification of DNA and R N A sequences have been associated with MDS and t(1;7) [48]. I N V I T R O BONE M A R R O W CULTURES
The colony-forming capacities of all hematopoietic precursor cells (CFU-GEMM, BFU-E, CFU-E, CFU-GM, CFU-Meg) are low or absent in the majority of MDS patients [49, 50]. An increased proportion of CFU-GMs from MDS patients are of light buoyant density, and abortive myeloid cluster formation and defective cellular maturation occur within the colonies. A large review of 440 patients with MDS found that 45% of patients had poor clonal growth in soft gel culture and the disease transformed in AML in 50% of these patients; in contrast, 55% of patients had a normal growth pattern in vitro and only 25% of these patients had transformed to AML [51l. Another review of 99 patients correlated clinical outcome with in vitro marrow growth. These were 17 patients with an excess of bone marrow blasts and 83 without an excess of bone marrow blasts. In the RAEB group 70% had a non-leukemic growth pattern; the incidence of evolution to AML was 29% and median survival 21 months; thirty percent showed a leukemic growth pattern with 100% of these patients progressing to AML and median survival of 10 months. In the group without excess of bone marrow blasts 54% had a non-leukemic growth
pattern with 20% progressing to AML and a median survival of 47 months; 46% of these patients had a leukemic growth pattern with 60% evolution to AML and 8 months median survival [5]. Although this study suggests a prognostic value for in vitro bone marrow cultures, it is difficult to understand why the incidence of leukemic growth pattern is lower in the group with excess of bone marrow blasts. An analysis of the data of Spitzer and Verma [52, 53] reveals that the presence or absence of leukemic growth pattern largely coincides with the presence or absence of excess of bone marrow blasts: of a patient with 5% blasts. In vitro bone marrow cultures in an individual with MDS is of limited diagnostic value because of the large variability in the plating efficiency in normal as well as in MDS patients; therefore, the normal range of CFU-GM overlaps with the range seen in MDS patients. However, progressive decrease in cloning efficiency on sequential studies in the same patient is a bad prognostic sign [49, 50]. In a P H A agar-liquid double-layer colony assay in which myeloid leukemia colony-forming cells require the presence of both PHA and CSF for in vitro proliferation, progression to AML in MDS patients was shown to be directly related to PHA dependency for colony formation [54]. In PHA-independent cases the course of the disease was more stable, but again PHA-dependent colony formation was associated with higher bone marrow blast counts. SCORING SYSTEMS Several scoring systems have been devised in an attempt to construct prognostic categories based on quantitative features. The most widely used scoring system is that introduced by Mufti et al. and is based
Prognosticfactors in MDS on conventional hematologic features [20]. The major advantage of this system is that the parameters are easy to obtain even for community physicians and the scoring system is very simple. One point is awarded to each of the following: a hemoglobin of 1 0 % bone marrow blasts and a platelet count of ~60 years. Group A has a score of 0 or 1, group B 2 or 3 and group C 4 or 5. The differences in survival for the three groups are highly significant. The advantage of the latter scoring system is that it could segregate patients with 1>5% bone marrow blasts in three risk groups with a median survival of 51 months in group A, 15 months in group B, and 4 months with group C. When we applied the Bournemouth scoring system to our patients we had very few patients in group A. We found a major difference in survival in group B patients based on the presence or absence of ALIP. The median survival of ALIP-positive patients was 16 months, compared to 34 months for the ALIP-negative patients [56]. CONCLUSION The most important prognostic factors in patients with MDS are the extent of the cytopenia, the presence or absence of excess of bone marrow blasts,
113
the presence or absence of complex chromosome abnormalities or abnormal chromosome 7, primary or secondary MDS and to a lesser extent age. Based on these prognostic factors a fairly good idea about survival time can be formed and therapy can be instituted accordingly. REFERENCES 1. Raskind W. H., Tirumaly N., Jacobson R., et al. (1984) Evidence for a multistep pathogenesis of a myelodysplastic syndrome. Blood 63, 1318-1323. 2. Prchal J. T., Trockmorton D. W., Carrol A. J., et al. (1978) A common progenitor for myeloid and lymphoid cells. Nature 274, 590-591. 3. Janssen W. G., Buschle M., Layton M., et al. (1989) Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. Blood 73, 248254. 4. Wiederman C. J., Bilgeri R., Petzer A., et al. (1989) Multipotent stem cell origin of myelodysplastic syndromes. Blood 73, 2230. 5. Galton D. A. G. (1984) The myelodysplastic syndromes. Clin. Lab. Haemat. 6, 99-112. 6. Second International Workshop on Chromosomes in Leukemia (1980) Chromosomes in preleukemia. Cancer Genet. Cytogenet. 2, 108. 7. Tricot G., Vlietinck R., Boogaerts M. A., et al. (1985) Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br. J. Haemat. 60, 19-32. 8. Foucar K., Langdon R. M., Armitage J. O., et al. (1985) Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases. Cancer 56, 553-561. 9. Vallespi T., Torrabadella A., Julia A., et al. (1985) Myelodysplastic syndromes: a study of 101 cases according to the FAB classification. Br. J. Haemat. 61, 83-92. 10. Kerkhofs H., Hermans I., Haak H. L., et al. (1987) Utility of the FAB classification for myelodysplastic syndromes: investigation of prognostic factors in 237 cases. Br. J. Haemat. 65, 73-81. 11. Sanz G. F., Sanz M. A., Vallespi T., etal. (1989) Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 74, 395--408. 12. Tricot G., Vlietinck R. & Verwilghen R. L. (1986) Prognostic factors in the myelodysplastic syndromes: a review. Scand. J. Haemat. 36 (suppl 45), 107-113. 13. Rosner F. & Grunwald H. W. (1980) Cytotoxic drugs and leukaemogenesis. Clin. Haemat. 9, 663-681. 14. Kantarjian H. M. & Keating M. J. (1987) Therapyrelated leukemia and myelodysplastic syndrome. Semin. Oncol. 4, 435--443. 15. Michels S. D., McKenna R. W., Arthur D. C., et al. (1985) Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. B l o o d 65, 1364-1372. 16. Le Beau M. M., Albain K. S., Larson R. A. et al. (1986) Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute non-lymphocytic leukemia: further
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0145--2126/92 $5.00 + .00 Pergamon Press plc
PROGNOSTIC FACTORS IN THE MYELODYSPLASTIC SYNDROMES GUIDO J. TPocoT Division of Hematology/Oncology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, U.S.A. Abstract--The myelodysplastic syndromes are acquired clonal hematologic malignancies characterized by progressive cytopenia and an increased risk of evolution to acute myeloid leukemia. It mainly affects elderly people, but may also be found in younger patients and children. MDS represents a heterogeneous group of disorders. Some patients will experience prolonged survival, whereas a substantial number of patients will die within the first year after diagnosis. Treatment of patients should be based on life expectancy. Patients with pancytopenia, excess of bone marrow blasts, complex chromosome abnormalities, abnormal chromosome 7, older age and secondary MDS have a poor prognosis. Several simple scoring systems are available, based on peripheral counts, percent of bone marrow blasts and age, that provide significant prognostic information about life expectancy in patients with MDS. The most widely used is the Bournemouth scoring system. The prognostic factors and the scoring systems are reviewed.
Key words: Myelodysplastic syndromes, prognostic factors, pancytopenia, bone marrow blasts, acute myeloid leukemia, cytogenetics, oncogenes.
INTRODUCTION
The diagnosis of MDS is a clinical one, which is largely based on morphologic changes seen in the peripheral blood, bone marrow smears and trephine biopsies. None of the morphologic findings, however, are diagnostic. Chromosome abnormalities are found in 40-70% of MDS patients [6]. MDS represents a heterogeneous group of disorders. Some patients will experience prolonged survival, whereas a substantial number of patients will die within the first year after diagnosis [7-9], due to leukemic transformation or infectious and/or bleeding complications. It is important to be able to identify those patients with a good prognosis, since even low-dose chemotherapy may lead to unacceptable morbidity and mortality. In poor-prognosis patients, however, the potential benefits of chemotherapy may justify the risks.
THE TERMmyelodysplastic syndromes (MDS) is now reserved for acquired hematologic disorders that precede the onset of acute leukemia, sometimes by many years. They are now generally accepted to represent early stages of acute myeloid leukemia (AML). MDS are malignant hematologic neoplasms, resulting from neoplastic transformation at the level of the pluripotent stem cell or a very early progenitor cell [1--4]. MDS is essentially a disease of later life, about half of the patients being 70 years or older [5]. Disease progression is very likely the result of a multistep process with consecutive genetic insults, leading to irreversible changes in the affected progenitor cells. The consecutive mutations provide increasing growth advantage to the new clones, which become genetically increasingly unstable and lose more and more of their capacity to differentiate.
CLINICAL PARAMETERS
Abbreviations: MDS, myelodysplastic syndromes; RA, refractory anemia; RA-S, refractory anemia with ringsideroblasts; RAEB, refractory anemia with excess of blasts; CMML, chronic myelomonocytic leukemia; RAEB-t, refractory anemia with excess of blasts in transformation; AML, acute myeloid leukemia. Correspondence to: Guido J. Tricot, M.D., Ph.D., Division of Hematology/Oncology, Indiana University Hospital, Room W608, 926 West Michigan Street, Indianapolis, IN 46202-5250, U.S.A.
Increasing age has been associated with poor prognosis [6, 10, 11]. In our study on 85 patients, patients under the age of 50 experienced less fatal infectious and/or bleeding complications than people over 70, while the percentage of patients transforming to A M L was similar in all age groups [12]. Since 1980 MDS has been reported in hundreds of patients previously treated for malignant and non109
G. J. TRICOT
110
TABLE 1. MEDIAN SURVIVAL (MONTHS) IN THE DIFFERENT SUBGROUPS, ACCORDING TO F A D
CLASSIFICATION
Coiffier et al. [17] W e i s d o r f e t a l . [58] Varella et al. [59] Todd et al. [60] Mufti et al. [20] Sanz et al. [11] Foucar et al. [8] Kerkhofs et al. [55] Tricot etal. [7]
N
RA
RAS
193 69 60 326 141 370 109 237 85
41.0 52.0 47.0 42.0 32.0 26.0 64.0 50.0 18.5 42.0
52.5 29.0 52.0 36.0 76.0 34.0 71.0 60.0+ 21.0 52.0
Median
malignant disorders with chemotherapeutic agents, usually alkylating agents with or without radiotherapy [13, 14]. Patients with secondary MDS have a poor prognosis with an average survival of only 6 months [15, 16]. P A R A M E T E R S OF THE P E R I P H E R A L BLOOD Anemia [11, 17-19], neutropenia [7, 15, 17, 20] and thrombocytopenia [11, 17-20] have been found to have prognostic significance in some studies, but not in others. Pancytopenia is invariably associated with poor prognosis [11, 12, 20]. In our study, however, the most important factor associated with poor survival was the presence of I>5 % blasts in the peripheral blood smear [7]. Those patients to have a median survival time of only 2.5 months, which is comparable to the survival of untreated AML patients [21]. The poor outcome of patients with a high percentage of blasts in the peripheral blood was also observed in other studies [17, 22]. P A R A M E T E R S OF THE BONE M A R R O W ASPIRATE AND BIOPSY The FAD classification into 5 subgroups [23] has been shown to be significantly correlated with survival in many studies [11,20]. The median survival for the 5 subtypes observed in different studies is provided in Table 1. All those studies demonstrate a better survival for patients with refractory anemia (RA) and R A with ringsideroblasts (RA-S) than in patients with R A with excess of blasts (RAEB) and R A E B in transformation (RAEB-t). The survival of patients with chronic myelomonocytic leukemia (CMML) is comparable to that of patients with RAEB. The survival of patients with RAEB-t is extremely poor and only half that of patients with R A E B and CMML. In some studies survival of RA-S is extremely long while in other studies survival is
RAEB
CMML
RAEB-t
14.5 12.0 14.0 17.5 10.5 12.0 7.0 9.0 11.0 12.0
11.5 2.0 15.0 17.5 22.0 9.0 7.0 60.0+ 9.5 11.5
6.5 11.0 3.0 -5.0 5.0 5.0 6.0 4.5 5.0
comparable to that of patients with RA. The difference is very likely due to the type of patients included. On a cytologic basis two subtypes of sideroblastic anemia can be distinguished: pure sideroblastic anemia, which is confined to dyserythropoiesis, and sideroblastic anemia characterized by additional dysplastic features of granulopoiesis and/or megakaryopoiesis. In a follow-up study of 94 patients with sideroblastic anemia a striking difference was observed in survival and risk of leukemic transformation. The 5-year cumulative chance of survival was 69% in the pure sideroblastic anemia compared to only 19% in those with additional dysplastic features. The cumulative risk of leukemic transformation was 1.9% and 48% respectively [24]. It is very likely that pure sideroblastic anemia is not a myelodysplastic syndrome in the sense of a clonal hematologic malignancy and has a very good prognosis. In Table 2,418 patients from 3 different studies [7, 17, 20] are grouped according to FAB classification. Patients with RAEB and RAEB-t show a high incidence of evolution to AML, 42% and 59% respectively, in contrast to R A and RA-S cases with respectively 12.5% and 11.5% respectively. Mortality of infections and/or bleeding are considerable in RA, RAEB and RAEB-t patients and relatively low in RA-S and CMML cases, probably due to the higher platelet count in RA-S and the higher granulocyte count in CMML. Although there is a significant correlation between FAD classification and survival, this sophisticated classification is not mandatory for prognostic purposes. A more simple classification dividing patients in two groups, cases with 5% bone marrow blasts, has at least an equal prognostic value [7, 11, 17, 20]. Some studies observed a difference in survival between patients with 5-10% and those >10% bone marrow blasts [11], while other studies did not [7, 20]. The presence of Auer rods was considered a
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Prognostic factors in MDS TABLE 2. OUTCOME IN THE DIFFERENTF A B TYPES
RA AISA RAEB CMML RAEB-t Total
Number
Alive
AML (%)
Death of infections/ bleeding (%)
138 53 136 57 34 418
59 (43) 22 (41.5) 16 (12) 24 (42) 4 (11.5) 125 (30)
17 (12.5) 6 (11.5) 57 (42) 16 (28) 20 (59) 116 (28)
47 (34) 9 (17) 55 (40.5) 9 (16) 10 (29.5) 130 (31)
Other causes 15 (10.5) 16 (30) 8 (5.5) 8 (14) 0 (0) 47 (11)
Coiffier et al. [17] (192 patients). Mufti et al. [20] (141 patients). Our study [7] (85 patients). marker of poor prognosis and patients with Auer rods were therefore placed in the RAEB-t subgroup. Two studies dealing with the prognostic value of the Auer rods in patients with MDS have not found any difference in survival between those with and without Auer rods [25, 26]. By using plastic-embedded trephine biopsies we found that the presence or absence of ALIP (abnormal localization of immature myeloid precursors) has strong prognostic significance [7, 61]. Since all patients with an excess of blasts in their bone marrow smears were also ALIP-positive in our study [7], we do not consider a biopsy essential in these patients. However, the trephine biopsy has a strong prognostic value in those patients who have 50% of these patients having ras-mutations. The incidence in other subgroups of MDS is probably around 20-25% [43, 45]. Mutations may occur in N-, K- and H-ras and may involve codons 12, 13 and 61. Although some studies suggest a poor prognosis in patients with point mutations in ras [41-44], other investigators have failed to confirm this correlation [45-47]. E r b - B amplification of DNA and R N A sequences have been associated with MDS and t(1;7) [48]. I N V I T R O BONE M A R R O W CULTURES
The colony-forming capacities of all hematopoietic precursor cells (CFU-GEMM, BFU-E, CFU-E, CFU-GM, CFU-Meg) are low or absent in the majority of MDS patients [49, 50]. An increased proportion of CFU-GMs from MDS patients are of light buoyant density, and abortive myeloid cluster formation and defective cellular maturation occur within the colonies. A large review of 440 patients with MDS found that 45% of patients had poor clonal growth in soft gel culture and the disease transformed in AML in 50% of these patients; in contrast, 55% of patients had a normal growth pattern in vitro and only 25% of these patients had transformed to AML [51l. Another review of 99 patients correlated clinical outcome with in vitro marrow growth. These were 17 patients with an excess of bone marrow blasts and 83 without an excess of bone marrow blasts. In the RAEB group 70% had a non-leukemic growth pattern; the incidence of evolution to AML was 29% and median survival 21 months; thirty percent showed a leukemic growth pattern with 100% of these patients progressing to AML and median survival of 10 months. In the group without excess of bone marrow blasts 54% had a non-leukemic growth
pattern with 20% progressing to AML and a median survival of 47 months; 46% of these patients had a leukemic growth pattern with 60% evolution to AML and 8 months median survival [5]. Although this study suggests a prognostic value for in vitro bone marrow cultures, it is difficult to understand why the incidence of leukemic growth pattern is lower in the group with excess of bone marrow blasts. An analysis of the data of Spitzer and Verma [52, 53] reveals that the presence or absence of leukemic growth pattern largely coincides with the presence or absence of excess of bone marrow blasts: of a patient with 5% blasts. In vitro bone marrow cultures in an individual with MDS is of limited diagnostic value because of the large variability in the plating efficiency in normal as well as in MDS patients; therefore, the normal range of CFU-GM overlaps with the range seen in MDS patients. However, progressive decrease in cloning efficiency on sequential studies in the same patient is a bad prognostic sign [49, 50]. In a P H A agar-liquid double-layer colony assay in which myeloid leukemia colony-forming cells require the presence of both PHA and CSF for in vitro proliferation, progression to AML in MDS patients was shown to be directly related to PHA dependency for colony formation [54]. In PHA-independent cases the course of the disease was more stable, but again PHA-dependent colony formation was associated with higher bone marrow blast counts. SCORING SYSTEMS Several scoring systems have been devised in an attempt to construct prognostic categories based on quantitative features. The most widely used scoring system is that introduced by Mufti et al. and is based
Prognosticfactors in MDS on conventional hematologic features [20]. The major advantage of this system is that the parameters are easy to obtain even for community physicians and the scoring system is very simple. One point is awarded to each of the following: a hemoglobin of 1 0 % bone marrow blasts and a platelet count of ~60 years. Group A has a score of 0 or 1, group B 2 or 3 and group C 4 or 5. The differences in survival for the three groups are highly significant. The advantage of the latter scoring system is that it could segregate patients with 1>5% bone marrow blasts in three risk groups with a median survival of 51 months in group A, 15 months in group B, and 4 months with group C. When we applied the Bournemouth scoring system to our patients we had very few patients in group A. We found a major difference in survival in group B patients based on the presence or absence of ALIP. The median survival of ALIP-positive patients was 16 months, compared to 34 months for the ALIP-negative patients [56]. CONCLUSION The most important prognostic factors in patients with MDS are the extent of the cytopenia, the presence or absence of excess of bone marrow blasts,
113
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