- Email: [email protected]
Refractory anemia with ringed sideroblasts with a low IPSS score progressed rapidly with de novo appearance of multiple karyotypic abnormalities and into acute erythroleukemia (AML-M6A)
Leukemia Research 24 (2000) 597 – 600 www.elsevier.com/locate/leukres
Case of the month
Refractory anemia with ringed sideroblasts with a low IPSS score progressed rapidly with de novo appearance of multiple karyotypic abnormalities and into acute erythroleukemia (AML-M6A) Osamu Iwase *, Hirosi Iwama, Seiichi Okabe, Keiko Ando, Makoto Yaguchi, Keisuke Miyazawa, Yukihiko Kimura, Atsushi Kodama, Katsuyuki Fukutake, Kazuma Ohyashiki Chromosome Unit, Central Laboratory, First Department of Internal Medicine, Tokyo Medical Uni6ersity, 6 -7 -1 - Nishi-shinjuka, Shinjuku-ku, Tokyo, 160 -0023, Japan Received 29 September 1999; accepted 5 February 2000
Abstract We report here a case of refractory anemia with ringed sideroblasts (RARS) with a low risk group by the International Prognostic Scoring System (IPSS) at the time of diagnosis but had a rapid disease progression. Although the patient showed a normal male karyotype at the time of RARS diagnosis, his marrow cells had del(5)(q14) and add(17)(p12) abnormalities 2 months after the diagnosis, and later the marrow cells had multiple abnormalities and the patient expired 6 months after the initial diagnosis of RARS. The patient was diagnosed as having RARS with a low risk group by the IPSS classification, however, one should keep in mind that some patients with myelodysplastic syndromes with low risks by either the French – American–British (FAB) classification or the IPSS classification may have progressive disease and subsequential cytogenetic analysis could predict the disease progression. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Myelodysplastic syndrome; Refractory anemia with ringed sideroblasts; Karyotypic abnormalities
1. Introduction Myelodysplastic syndromes (MDS) are categorized based on the percentages of blasts in the peripheral blood and bone marrow by the FAB classification [1]. Refractory anemia (RA) and RA with ringed sideroblasts (RARS) are believed to classified as a low risk group, when compared to RA with excess of blasts (RAEB) and REAB in transformation (RAEB-T) [2– 8]. Recently, the International Prognostic Scoring System (IPSS) has been proposed for the prediction of the prognosis and leukemia evolution of MDS patients [9]. The IPSS utilized cytopenia patterns in the blood,
chromosome abnormalities, and percentages of blasts in the marrow for scoring. Cytogenetic abnormality is an important factor in predicting survival period, while percentages of marrow blasts is a major factor for transformation into acute leukemia. We report here a case of RARS with a normal karyotype at the time of diagnosis, thus indicating a low risk for either leukemic transformation or survival period, however, the patient’s disease deteriorated within 6 months after the diagnosis. We should emphasize the careful attention in monitoring cytogenetics in such MDS patients to predict exact prognosis.
2. Case report * Corresponding author. Tel.: + 81-3-33426111 (ext. 5895); fax: +81-3-53816651. E-mail address: [email protected] (O. Iwase)
A 59-year-old man was referred to our hospital because of anemia and thrombocytopenia on June 29th,
0145-2126/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 0 ) 0 0 0 2 9 - 1
598
O. Iwase et al. / Leukemia Research 24 (2000) 597–600
1998. He did not have any exposure to carcinogenic/ mutagenic agents. At this time, his hemoglobin (Hb) was 11.5 g/dl, a white blood cell (WBC) count was 5.6 ×109/l (neutrophils 67%) without blast cells, and a platelet count was 89×l09/l. On July 8th, a bone marrow examination revealed a hypercellular marrow with 0.8% blasts, and erythroid hyperplasia with 32.7% ringed sideroblasts (Fig. 1A, B). He was tentatively diagnosed as having RARS by the FAB classification, but dysplastic features were not prominent. Cytogenetic examination revealed a normal male karyotype, thus he had a Low risk group for IPSS (score 0 point) (Table 1). The patient was treated with oral vitamin B6 therapy (started on August 17, 1998). On September 4th, he was hospitalized because of progressive thrombocytopenia (39 ×l09/l) and fever. Physical examination revealed neither hepatosplenomegaly nor lymphadenopathy. At this time, his Hb was 9.4 g/dl, a WBC count of 3.1 × l09/l, and a platelet count was 40× l09/l. Detailed examination revealed infectious enteritis and the patient was treated with antibiotics with good response. On September 21st, the second bone marrow examinations did not show apparent dysplastic features, however, chromosome abnormalities [46,XY,del(5)(ql4),add(l7)(pl2)] were detected in 9/19 mitoses in the marrow (Table 1). One month later, his bone marrow had 4.0% myeloblasts and dysplastic features in tri-lineage were prominent on October 30, (hypogranulation and pseudo-Pelger anomaly, multi-nucleated erythroblasts,
micromegakaryocyte and giant platelets) (Fig. 1C–F). Chromosome analysis revealed multiple abnormalities with a karyotypic instability (Table 1). Although vitamin B6 therapy was discontinued on October 31st, pancytopenia has deteriorated, and he required periodic blood transfusions. Low dose enocitabine therapy followed by CAG (cytarabine, aclarubicin, and filgrastim) therapy was started without prominent effect. High fever has repeated by discontinuation of antibiotic therapy. In December, his WBC became below 1.0× l09/l, and he died of septic shock on January 11th, 1999. The bone marrow on January 8th, 1999 revealed the patient developed into acute erythroleukemia (AML-M6A) [10].
3. Discussion In general, RARS patients are believed to be consist of two subtypes considering their prognosis. Oguma et al. demonstrated that RARS patients with worse prognosis had a higher percentage of blasts and/or metamyelocytes in the blood than those with a favorable prognosis [11]. More recently, we have reported that RARS patients with complex chromosome changes (] 3 chromosome abnormalities) had a significant high percentage of leukemic transformation and had an unfavorable prognosis [12]. Therefore, a relatively high percentage of blast cells in the marrow and the presence
Fig. 1. Sequential morphologic features in the patient with refractory anemia with ringed sideroblasts. The bone marrow examination dated on July 8, showing an increasing number of erythroblasts (A: × 1000 Wright – Giemsa staining) and 32.7% of them were ringed sideroblasts (B: × 1000 iron staining). The bone marrow examination dated on October 30th, showing myelodysplastic features, including hypogranulated granulocytes (C) and pseudo-Pelger anomaly (D), multinucleated erythroblasts (E), and a giant platelet (F) ( × 1000 Wright – Giemsa staining).
O. Iwase et al./Leukemia Research 24 (2000) 597–600
599
Table 1 The hematologic cytogenetic features during the couse of the RARS patienta Date of examination
Marrow blasts (%)
Marrow blast/NEC (%)
Marrow erythroblasts (%)
Karyotype
Cell number
IPSS score
8 July 1998 21 September 1998
0.8 0.8
1.7 1.4
53.6 44.4
46, XY 46, XY
18 10
0 1
46, XY, del (5)(q14), add(17)(p12)
9
46, XY
4
44, XY, −5, −7, add(17)(p12), −20, +2 5661, X, −Y, +1, +2, +4, del(5)(q14) or −5, +6, +6, add(7)(q35), +8 add(11)(q23), +14, +15, add(17)(p12), +21, +22, +5 7 makers
1
46, XY
3
45, X, −Y 46, XY, add(17)(p12) 45, X, −Y, add(17)(p12) 46, XY, del(5)(q14), add(17)(p12) 5759, X, ×Y, +1, +2, +4, ×5 or del(5)(q14), +6, +6, add(7)(q35), +8, +14, +15, add(17)(p12), +21, +21, +22, +2, ×5, + makers
1 5 2 1
46, XY
1
30 October 1998
19 November 1998
16 December 1998
4.0
2.4
2.8
8.3
4.8
13.7
51.6
50.4
79.6
1.5
16
1.5
8
1.5
45, X, −Y, add(17)(p12) 2 5762, X, −Y, +1, +2, 16 +del(3)(p21), +4, del(5)(q14), +6, +6, add(7)(q35), +8, +14, +15, add(17)(p12), +19, +21, +22, +14 makers 08 January 1999 0.0
0.0
92.4
44, XY, −4, del(5)(q31), −7, −16, add (17)(p12), −20, +21, +21 4960, X, −Y, +1, +2, +del(3)(p21), +4, −5, +6, add(7)(q35), +8,add(11)(q23), +14, add(17)(p12), +19, +21, +22, +14 makers
1
16
a
NEC, non-erythroid cell.
of multiple cytogenetic changes in RARS patients might be an indicator for poorer prognosis [12]. Of note is that the presence of multiple chromosome changes links to not only leukemic transformation but also poorer prognosis. However, it is unclear whether the evolution of leukemia in RARS is associated with a poorer prognosis and these clinical characteristics are related to certain cytogenetic abnormality. We presented a patient with RARS with a normal male karyotype and obtained a score compatible with a
Low risk score at the time diagnosis. At the time of MDS diagnosis for this patient, the FAB criteria and the IPSS judgment resulted in good prognosis. Therefore, we administered vitamin B6. However, this therapy failed to obtain hematologic improvement and very shortly the patient’s disease deteriorated. Of note is that the percentage of blasts in the marrow during his course did not increase dramatically: the percentage of blasts in non-erythroid component slightly increased during the course (Table 1) without the presence of
600
O. Iwase et al. / Leukemia Research 24 (2000) 597–600
acute leukemia evolution. As mentioned above, multiple cytogenetic abnormalities in the marrow link to the evolution of leukemia and poorer prognosis. In the current case, multiple chromosome changes were detected at the time of hematologic deterioration representing by multiple cytopenia, while he never experienced leukemic transformation. His marrow finding terminated into erythremic features. Nakamura et al. reported that erythroleukemia with multiple chromosome changes had poorer prognosis compared to those with normal karyotypes, thus indicating that either erythremic or erythroleukemic transformation with multiple cytogenetic changes may link to poor prognosis without development of acute leukemia [13]. Another issue that we should address is that this patient was firstly judged as a low risk group by the IPSS, but the score in this patient increased rapidly within 6 months after the initial diagnosis. Thus, some MDS patients showing progressive hematologic deterioration should be re-assessed and obtained correct information, including cytogenetics. Although our case might be a rare, one should pay careful attention that some MDS patients might develop erythroid type of M6, and repeated cytogenetic studies will predict such patients.
Acknowledgements O. Iwase, H. Iwama, S.Okabe, K. Ando, and M. Yaguchi provided clinical data. A. Kodama and K. Fukutake provided cytogenetic data. K. Miyazawa and Y. Kimura provided critical revision of the manuscript. O. Iwase, M. Kiyasawa, and K. Ohyashiki drafted the manuscript and provided study design. This work has been supported in part by Grant-in-Aid of the Ministry of Helath and Welfare (Intractable Hematopoietic Diseases) (K.O.).
.
References [1] Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;5l:189 – 99. [2] Coiffier B, Adeleine P, Viala JJ, et al. Dysmyelopoietic syndromes: a search for prognostic factors in 193 patients. Cancer 1983;52:83– 90. [3] Juneja SK, Imbert M, Jouault H, Scoazec JY, Sigaux F, Sultan C. Haematological features of primary myelodysplastic syndromes (PMDS) at initial presentation: a study of 118 cases. J Clin Pathol 1983;36:129 – 35. [4] Mufti GJ, Stevens JR, Oscier DG, Hamblin TJ, Machin D. Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 1985;59:425 – 33. [5] Varela BL, Chuang C, Woll JE, Bennett JM. Modifications in the classification of primary myelodysplastic syndromes: the addition of a scoring system. Hematological Oncol 1985;3:55 – 63. [6] Foucar K, Langdon RM, Armitage JO, Olson DB, Carroll TJ Jr. Myelodysplastic syndromes: a clinical and pathologic analysis of 109 cases. Cancer 1985;56:553 – 61. [7] Tricot G, Vlietinck R, Boogaerts MA, et al. Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br J Haematol 1985;60:19 – 32. [8] Sanz GF, Sanz MA, Vallespi T, et al. 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 1989;74:395 – 408. [9] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079 – 88. [10] Garand R, Duchayne E, Blanchard D, et al. Minimally differentiated erythroleukaemia (AML M6 ‘variant’): a rare subset of AML distinct from AML M6. Br J Haematol 1995;90:868 – 75. [11] Oguma S, Yoshida Y, Uchino H, Maekawa T. Factors influencing nonleukemic death in refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess of blasts. Cancer Res 1987;47:3559 – 602. [12] Toyama K, Ohyashiki K, Yoshida Y, et al. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia 1993;7:499– 508. [13] Nakamura H. Cytogenetic heterogeneity in erythroleukemia defined as M6 by the French – American – British (FAB) Cooperative Group criteria. Leukemia 1989;3:305 – 9.
Case of the month
Refractory anemia with ringed sideroblasts with a low IPSS score progressed rapidly with de novo appearance of multiple karyotypic abnormalities and into acute erythroleukemia (AML-M6A) Osamu Iwase *, Hirosi Iwama, Seiichi Okabe, Keiko Ando, Makoto Yaguchi, Keisuke Miyazawa, Yukihiko Kimura, Atsushi Kodama, Katsuyuki Fukutake, Kazuma Ohyashiki Chromosome Unit, Central Laboratory, First Department of Internal Medicine, Tokyo Medical Uni6ersity, 6 -7 -1 - Nishi-shinjuka, Shinjuku-ku, Tokyo, 160 -0023, Japan Received 29 September 1999; accepted 5 February 2000
Abstract We report here a case of refractory anemia with ringed sideroblasts (RARS) with a low risk group by the International Prognostic Scoring System (IPSS) at the time of diagnosis but had a rapid disease progression. Although the patient showed a normal male karyotype at the time of RARS diagnosis, his marrow cells had del(5)(q14) and add(17)(p12) abnormalities 2 months after the diagnosis, and later the marrow cells had multiple abnormalities and the patient expired 6 months after the initial diagnosis of RARS. The patient was diagnosed as having RARS with a low risk group by the IPSS classification, however, one should keep in mind that some patients with myelodysplastic syndromes with low risks by either the French – American–British (FAB) classification or the IPSS classification may have progressive disease and subsequential cytogenetic analysis could predict the disease progression. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Myelodysplastic syndrome; Refractory anemia with ringed sideroblasts; Karyotypic abnormalities
1. Introduction Myelodysplastic syndromes (MDS) are categorized based on the percentages of blasts in the peripheral blood and bone marrow by the FAB classification [1]. Refractory anemia (RA) and RA with ringed sideroblasts (RARS) are believed to classified as a low risk group, when compared to RA with excess of blasts (RAEB) and REAB in transformation (RAEB-T) [2– 8]. Recently, the International Prognostic Scoring System (IPSS) has been proposed for the prediction of the prognosis and leukemia evolution of MDS patients [9]. The IPSS utilized cytopenia patterns in the blood,
chromosome abnormalities, and percentages of blasts in the marrow for scoring. Cytogenetic abnormality is an important factor in predicting survival period, while percentages of marrow blasts is a major factor for transformation into acute leukemia. We report here a case of RARS with a normal karyotype at the time of diagnosis, thus indicating a low risk for either leukemic transformation or survival period, however, the patient’s disease deteriorated within 6 months after the diagnosis. We should emphasize the careful attention in monitoring cytogenetics in such MDS patients to predict exact prognosis.
2. Case report * Corresponding author. Tel.: + 81-3-33426111 (ext. 5895); fax: +81-3-53816651. E-mail address: [email protected] (O. Iwase)
A 59-year-old man was referred to our hospital because of anemia and thrombocytopenia on June 29th,
0145-2126/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 0 ) 0 0 0 2 9 - 1
598
O. Iwase et al. / Leukemia Research 24 (2000) 597–600
1998. He did not have any exposure to carcinogenic/ mutagenic agents. At this time, his hemoglobin (Hb) was 11.5 g/dl, a white blood cell (WBC) count was 5.6 ×109/l (neutrophils 67%) without blast cells, and a platelet count was 89×l09/l. On July 8th, a bone marrow examination revealed a hypercellular marrow with 0.8% blasts, and erythroid hyperplasia with 32.7% ringed sideroblasts (Fig. 1A, B). He was tentatively diagnosed as having RARS by the FAB classification, but dysplastic features were not prominent. Cytogenetic examination revealed a normal male karyotype, thus he had a Low risk group for IPSS (score 0 point) (Table 1). The patient was treated with oral vitamin B6 therapy (started on August 17, 1998). On September 4th, he was hospitalized because of progressive thrombocytopenia (39 ×l09/l) and fever. Physical examination revealed neither hepatosplenomegaly nor lymphadenopathy. At this time, his Hb was 9.4 g/dl, a WBC count of 3.1 × l09/l, and a platelet count was 40× l09/l. Detailed examination revealed infectious enteritis and the patient was treated with antibiotics with good response. On September 21st, the second bone marrow examinations did not show apparent dysplastic features, however, chromosome abnormalities [46,XY,del(5)(ql4),add(l7)(pl2)] were detected in 9/19 mitoses in the marrow (Table 1). One month later, his bone marrow had 4.0% myeloblasts and dysplastic features in tri-lineage were prominent on October 30, (hypogranulation and pseudo-Pelger anomaly, multi-nucleated erythroblasts,
micromegakaryocyte and giant platelets) (Fig. 1C–F). Chromosome analysis revealed multiple abnormalities with a karyotypic instability (Table 1). Although vitamin B6 therapy was discontinued on October 31st, pancytopenia has deteriorated, and he required periodic blood transfusions. Low dose enocitabine therapy followed by CAG (cytarabine, aclarubicin, and filgrastim) therapy was started without prominent effect. High fever has repeated by discontinuation of antibiotic therapy. In December, his WBC became below 1.0× l09/l, and he died of septic shock on January 11th, 1999. The bone marrow on January 8th, 1999 revealed the patient developed into acute erythroleukemia (AML-M6A) [10].
3. Discussion In general, RARS patients are believed to be consist of two subtypes considering their prognosis. Oguma et al. demonstrated that RARS patients with worse prognosis had a higher percentage of blasts and/or metamyelocytes in the blood than those with a favorable prognosis [11]. More recently, we have reported that RARS patients with complex chromosome changes (] 3 chromosome abnormalities) had a significant high percentage of leukemic transformation and had an unfavorable prognosis [12]. Therefore, a relatively high percentage of blast cells in the marrow and the presence
Fig. 1. Sequential morphologic features in the patient with refractory anemia with ringed sideroblasts. The bone marrow examination dated on July 8, showing an increasing number of erythroblasts (A: × 1000 Wright – Giemsa staining) and 32.7% of them were ringed sideroblasts (B: × 1000 iron staining). The bone marrow examination dated on October 30th, showing myelodysplastic features, including hypogranulated granulocytes (C) and pseudo-Pelger anomaly (D), multinucleated erythroblasts (E), and a giant platelet (F) ( × 1000 Wright – Giemsa staining).
O. Iwase et al./Leukemia Research 24 (2000) 597–600
599
Table 1 The hematologic cytogenetic features during the couse of the RARS patienta Date of examination
Marrow blasts (%)
Marrow blast/NEC (%)
Marrow erythroblasts (%)
Karyotype
Cell number
IPSS score
8 July 1998 21 September 1998
0.8 0.8
1.7 1.4
53.6 44.4
46, XY 46, XY
18 10
0 1
46, XY, del (5)(q14), add(17)(p12)
9
46, XY
4
44, XY, −5, −7, add(17)(p12), −20, +2 5661, X, −Y, +1, +2, +4, del(5)(q14) or −5, +6, +6, add(7)(q35), +8 add(11)(q23), +14, +15, add(17)(p12), +21, +22, +5 7 makers
1
46, XY
3
45, X, −Y 46, XY, add(17)(p12) 45, X, −Y, add(17)(p12) 46, XY, del(5)(q14), add(17)(p12) 5759, X, ×Y, +1, +2, +4, ×5 or del(5)(q14), +6, +6, add(7)(q35), +8, +14, +15, add(17)(p12), +21, +21, +22, +2, ×5, + makers
1 5 2 1
46, XY
1
30 October 1998
19 November 1998
16 December 1998
4.0
2.4
2.8
8.3
4.8
13.7
51.6
50.4
79.6
1.5
16
1.5
8
1.5
45, X, −Y, add(17)(p12) 2 5762, X, −Y, +1, +2, 16 +del(3)(p21), +4, del(5)(q14), +6, +6, add(7)(q35), +8, +14, +15, add(17)(p12), +19, +21, +22, +14 makers 08 January 1999 0.0
0.0
92.4
44, XY, −4, del(5)(q31), −7, −16, add (17)(p12), −20, +21, +21 4960, X, −Y, +1, +2, +del(3)(p21), +4, −5, +6, add(7)(q35), +8,add(11)(q23), +14, add(17)(p12), +19, +21, +22, +14 makers
1
16
a
NEC, non-erythroid cell.
of multiple cytogenetic changes in RARS patients might be an indicator for poorer prognosis [12]. Of note is that the presence of multiple chromosome changes links to not only leukemic transformation but also poorer prognosis. However, it is unclear whether the evolution of leukemia in RARS is associated with a poorer prognosis and these clinical characteristics are related to certain cytogenetic abnormality. We presented a patient with RARS with a normal male karyotype and obtained a score compatible with a
Low risk score at the time diagnosis. At the time of MDS diagnosis for this patient, the FAB criteria and the IPSS judgment resulted in good prognosis. Therefore, we administered vitamin B6. However, this therapy failed to obtain hematologic improvement and very shortly the patient’s disease deteriorated. Of note is that the percentage of blasts in the marrow during his course did not increase dramatically: the percentage of blasts in non-erythroid component slightly increased during the course (Table 1) without the presence of
600
O. Iwase et al. / Leukemia Research 24 (2000) 597–600
acute leukemia evolution. As mentioned above, multiple cytogenetic abnormalities in the marrow link to the evolution of leukemia and poorer prognosis. In the current case, multiple chromosome changes were detected at the time of hematologic deterioration representing by multiple cytopenia, while he never experienced leukemic transformation. His marrow finding terminated into erythremic features. Nakamura et al. reported that erythroleukemia with multiple chromosome changes had poorer prognosis compared to those with normal karyotypes, thus indicating that either erythremic or erythroleukemic transformation with multiple cytogenetic changes may link to poor prognosis without development of acute leukemia [13]. Another issue that we should address is that this patient was firstly judged as a low risk group by the IPSS, but the score in this patient increased rapidly within 6 months after the initial diagnosis. Thus, some MDS patients showing progressive hematologic deterioration should be re-assessed and obtained correct information, including cytogenetics. Although our case might be a rare, one should pay careful attention that some MDS patients might develop erythroid type of M6, and repeated cytogenetic studies will predict such patients.
Acknowledgements O. Iwase, H. Iwama, S.Okabe, K. Ando, and M. Yaguchi provided clinical data. A. Kodama and K. Fukutake provided cytogenetic data. K. Miyazawa and Y. Kimura provided critical revision of the manuscript. O. Iwase, M. Kiyasawa, and K. Ohyashiki drafted the manuscript and provided study design. This work has been supported in part by Grant-in-Aid of the Ministry of Helath and Welfare (Intractable Hematopoietic Diseases) (K.O.).
.
References [1] Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;5l:189 – 99. [2] Coiffier B, Adeleine P, Viala JJ, et al. Dysmyelopoietic syndromes: a search for prognostic factors in 193 patients. Cancer 1983;52:83– 90. [3] Juneja SK, Imbert M, Jouault H, Scoazec JY, Sigaux F, Sultan C. Haematological features of primary myelodysplastic syndromes (PMDS) at initial presentation: a study of 118 cases. J Clin Pathol 1983;36:129 – 35. [4] Mufti GJ, Stevens JR, Oscier DG, Hamblin TJ, Machin D. Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 1985;59:425 – 33. [5] Varela BL, Chuang C, Woll JE, Bennett JM. Modifications in the classification of primary myelodysplastic syndromes: the addition of a scoring system. Hematological Oncol 1985;3:55 – 63. [6] Foucar K, Langdon RM, Armitage JO, Olson DB, Carroll TJ Jr. Myelodysplastic syndromes: a clinical and pathologic analysis of 109 cases. Cancer 1985;56:553 – 61. [7] Tricot G, Vlietinck R, Boogaerts MA, et al. Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br J Haematol 1985;60:19 – 32. [8] Sanz GF, Sanz MA, Vallespi T, et al. 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 1989;74:395 – 408. [9] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079 – 88. [10] Garand R, Duchayne E, Blanchard D, et al. Minimally differentiated erythroleukaemia (AML M6 ‘variant’): a rare subset of AML distinct from AML M6. Br J Haematol 1995;90:868 – 75. [11] Oguma S, Yoshida Y, Uchino H, Maekawa T. Factors influencing nonleukemic death in refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess of blasts. Cancer Res 1987;47:3559 – 602. [12] Toyama K, Ohyashiki K, Yoshida Y, et al. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia 1993;7:499– 508. [13] Nakamura H. Cytogenetic heterogeneity in erythroleukemia defined as M6 by the French – American – British (FAB) Cooperative Group criteria. Leukemia 1989;3:305 – 9.