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The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1 mut DNMT3A mut ). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1 mut DNMT3A mut patients showed a higher RBC transfusion dependency (92% versus 48%, p = .007), a shorter overall survival (OS) (median, 30 versus 97 months, p = .034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p = .023) than SF3B1 mut DNMT3A wt patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1 mut patients with a negative clinical impact.

Refractory anaemia with ring sideroblasts (RARS) and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organisation 2008 classification and has previously been shown to have a high proportion of JAK2(V617F) (Janus Kinase 2) and SF3B1 (Splicing Factor 3B subunit 1) mutations. The purpose of the present study was to analyse the frequency of SF3B1 mutations in a large cohort of 111 patients with RARS-T and 33 patients with RARS and to explore the prognostic impact of SF3B1 mutational status on RARS-T. The frequency of SF3B1 mutations in RARS-T (96/111, 86.5%) and RARS (28/33, 84.8%) was similar. In RARS-T, median survival was better in SF3B1-mutated patients than in SF3B1-non-mutated patients (6.9 and 3.3 years, respectively, P=0.003). RARS can be differentiated from RARS-T by the frequency of JAK2(V617F) (0% vs 48.6%). In RARS-T patients, SF3B1 (P=0.021) and JAK2 mutations (P=0.016) were independent factors for a better prognosis. Altogether, our results confirm that RARS-T is an independent entity that should be recognised by the next World Health Organisation classification. The assessment of SF3B1 mutations is of prognostic interest in RARS-T patients. Younger age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in RARS-T.

Background: Within the myelodysplastic/myeloproliferative neoplasm (MDS/MPN) category of the WHO (2008), only chronic myelomonocytic leukemia was so far evaluated by multiparameter flow cytometry (MFC)., Methods: To investigate the potential of MFC for MDS/MPNs, unclassifiable (MDS/MPNu), and refractory anemia associated with ring sideroblasts and marked thrombocytosis (RARS-T), we studied 91 patients with these entities (60 males/31 females; 35.3-87.4 years) for MDS-related aberrant immunophenotypes (≥ 2 different cell lineages with ≥ 3 aberrantly expressed antigens). Data were correlated with cytomorphology and cytogenetics., Results: MFC identified MDS-related immunophenotypes in 54/91 (59.3%) of patients. Patients with or without MDS-related immunophenotype did not differ significantly by demographic characteristics, blood values, or median overall survival. MDS-related immunophenotype cases showed a higher number of aberrantly expressed antigens (mean ± SD, 4.9 ± 2.4 vs. 2.0 ± 1.4; P < 0.001). Aberrant karyotypes showed a similar frequency in patients with and without MDS-related immunophenotype (11/54; 20.4% vs. 7/37; 18.9%; P = n.s.)., Conclusions: MDS-related immunophenotype are present in more than half of patients with MDS/MPNu and RARS-T. MFC therefore may be helpful to separate cases into more "MDS-like" or "MPN-like" subgroups., (Copyright © 2012 International Clinical Cytometry Society.)

To characterize bone marrow failure with del(13q), we reviewed clinical records of 22 bone marrow failure patients possessing del(13q) alone or del(13q) plus other abnormalities. All del(13q) patients were diagnosed with myelodysplastic syndrome-unclassified due to the absence of apparent dysplasia. Elevated glycosylphosphatidylinositol-anchored protein-deficient blood cell percentages were detected in all 16 with del(13q) alone and 3 of 6 (50%) patients with del(13q) plus other abnormalities. All 14 patients with del(13q) alone and 2 of 5 (40%) patients with del(13q) plus other abnormalities responded to immunosuppressive therapy with 10-year overall survival rates of 83% and 67%, respectively. Only 2 patients who had abnormalities in addition to the del(13q) abnormality developed acute myeloid leukemia. Given that myelodysplastic syndrome-unclassified with del(13q) is a benign bone marrow failure subset characterized by good response to immunosuppressive therapy and a high prevalence of increased glycosylphosphatidylinositol-anchored protein-deficient cells, del(13q) should not be considered an intermediate-risk chromosomal abnormality.

Background: Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia., Design and Methods: We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases., Results: In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600 × 10(9)/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts., Conclusions: The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.

In 2008, the WHO combined the former categories RCMD (refractory cytopenia with multilineage dysplasia) and RCMD-RS (ring sideroblasts ≥ 15%). We studied the clinical impact and genetic background of RARS, RCMD, and RCMD-RS in 1082 patients. Good karyotypes (IPSS) were similarly frequent in RARS, RCMD, and RCMD-RS. 2-year overall survival (OS) rates were similar in RARS, RCMD, and RCMD-RS (85.9%/89.0%/91.7%; n.s.). The 2-year OS rate was better in good than intermediate or poor karyotypes (p<0.001). These results support to combine RCMD and RCMD-RS as performed by WHO and emphasize the prognostic power of cytogenetic criteria for these MDS subtypes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The severity of neutropenia in myelodysplastic syndrome (MDS) has not been completely studied. We analyzed the prognostic significance of severe neutropenia (neutrophils count <0.5×10(9)/L) at diagnosis in 1109 patients with de novo MDS and low/intermediate-1 IPSS included in the Spanish MDS Registry. Severe neutropenia was present at diagnosis in 48 of 1109 (4%). Patients with severe neutropenia were most strongly represented within the groups of refractory cytopenia with multilineage dysplasia (40%) and refractory anemia with excess of blast type 1 (29%). Severe neutropenia had negative effects on the low/intermediate-1 risk group. A significant difference in overall survival was observed between patients with severe neutropenia (28 months) and patients with a neutrophil count higher than 0.5×10(9)/L (66 months) (p<0.0001). Also, severe neutropenia predicted a significantly reduced on leukemia-free survival (p<0.0001). In the multivariate analysis, severe neutropenia retained its independent prognostic influence on overall survival [HR: 2.19, 95% CI (1.41-3.10), p<0.0001] and leukemia free survival [HR: 3.51, 95% CI (1.97-6.26), p<0.0001]. The degree of neutropenia should be considered as additional prognostic factor in low/intermediate-1 IPSS MDS., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)-RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (∼ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations.

According to the revised WHO classification of 2008, dysplasia in > or = 10% of one bone marrow lineage and one cytopenia constitutes the low-risk category of unilineage cytopenia and unilineage dysplasia (UCUD). We retrospectively reclassified, according to WHO, low-risk MDS from our database and found 126 subjects with these features at diagnosis: 79 patients were categorized as refractory anemia (RA), 23 patients as refractory neutropenia (RN), and 24 as refractory thrombocytopenia (RT). We did not find differences between the three subgroups as regards sex, median age, and cytogenetic aberrations. Lower PMN count (0.8 x 10(9)/L) was observed in the RN category, as well as lower platelet count in the RT category (51 x 10(9)/L). Moreover, we found a lower rate of patients requiring RBC transfusions, during the disease course, in the RT category (45.8%) as compared to RA (62%) and RN (69%) groups (p = 0.05); a lower incidence of infections at diagnosis in the RT category (20.8%) compared to RA (32%) and RN (43%) categories (p = 0.03); and a higher incidence of hemorrhagic symptoms at diagnosis in the RT category (41.6%) and RN category (26%) as compared to the RA group (5%) (p = 0.001). Application of different scoring systems (Bournemouth and Spanish scores, WPSS) revealed a low OS in high-risk patients within the RT category, compared to RA and RN categories, although unlikely to reflect the consequences of low OS found in the former category. Statistically significant differences were also evidenced in the incidence of acute myeloid leukemia (AML) evolution and overall survival: 7/79 (8%) patients with the RA category evolved to AML in a median time of 89 months, whereas 4/23 (17%) of the RN category and 1/24 (4%) of the RT category experienced disease progression, in a median time of 33.8 and 12.8 months, respectively (p = 0.03). The RT category had a lower overall survival (15.9 months) as compared to RA (48.2 months) and RN (35.9 months) categories (p < 0.001). In conclusion, in our study, application of the revised 2008 WHO classification confirmed the importance of separating patients with unilineage dysplasia for prognostic disease assessment; from our results it seems that the RT category has a worse outcome.

Background: Although hematopoietic stem cell transplantation (HSCT) is offered as a curative therapy for pediatric myelodysplastic syndrome (MDS), it may cause severe complications and mortality. Several reports have shown the efficacy of immunosuppressive therapy (IST) in adult patients with refractory anemia (RA), but its safety and efficacy remains to be fully elucidated in childhood RA., Procedure: Eleven children diagnosed with RA and enrolled on a prospective multicenter trial conducted by the Japanese Childhood MDS Study Group were eligible for analysis. If patients showed transfusion dependent or suffered from infection due to neutropenia, they received IST consisting of antithymocyte globulin (ATG), cyclosporine (CyA), and methylprednisolone (mPSL)., Results: Eight children received IST, 2 received only supportive therapy, and one underwent HSCT without IST. Five (63%) of eight children who received IST showed hematological response. Of note, one patient showed the disappearance of monosomy 7 after IST. Responders were significantly younger than non-responders (29 months vs. 140 months; P = 0.03). No severe adverse events related to IST were reported in this study. Of 6 children with chromosomal abnormalities who received IST, four showed hematological response. The probability of failure-free and overall survival at 5 years was 63 +/- 17% and 90 +/- 9% respectively., Conclusion: IST is likely to be a safe and effective modality for childhood RA.

Allogeneic stem cell transplantation (alloSCT) for patients with refractory anaemia may result in a 50% event-free survival, but the high non-relapse mortality (NRM) precludes a general application of this therapeutic modality. This study evaluated the impact of various pre-transplant variables, including disease duration, intensity of the conditioning regimen, type of donor and year of transplantation on outcome. The study population consisted of 374 patients; 244 were transplanted from human leucocyte antigen (HLA)-identical siblings and 130 patients from matched unrelated donors. The median age was 39 years. One hundred and two patients were transplanted after reduced intensity conditioning (RIC). The overall 4-year survival was 52%. The 4-year survival of patients transplanted with HLA-identical sibling donors and matched unrelated donors was 52% and 50%, respectively. Multivariate analysis showed an improved survival (P = 0.05) and a lower NRM (P = 0.02) when the transplantation was performed in recent years. Increasing age, and disease duration of >12 months were associated with inferior survival. RIC resulted in a similar survival despite an increased relapse risk (P = 0.02). This improved outcome permits alloSCT in patients older than 50 years of age, even with the use of matched unrelated donors. AlloSCT should be preferentially performed early after diagnosis after careful analysis of prognostic variables.

We carried out the cytogenetic investigation of bone marrow aspirate from 32 patients with different types of MDS. The patients were from 8 regions of Ukraine. 11 patients had abnormal karyotype, and the transformation to AML were observed in 5 of them (45.5%). 27% of all patients had chromosomal changes with 3 or more chromosomes involved. The highest percentage of the patients with chromosomal anomalies (66.7%) was in cases of RAEB. Chromosome deletions were the most frequently detected karyotype abnormalities. We consider the phenomenon of chromosome fragmentation as the cytogenetic approval of the increased level of apoptosis in patients with MDS. The risk of the transformation to AML was measured using new international score system IPSS.

Background: Patients with myelodysplastic syndrome (MDS) display a very diverse pattern. In this study, we investigated prognostic factors and survival rate in adult patients with MDS refractory anaemia (MDS-RA) diagnosed according to French-American-British classification and evaluated the International Prognostic Scoring System (IPSS) for Chinese patients., Methods: A multi-center study on diagnosis of MDS-RA was conducted to characterize the clinical features of Chinese MDS patients. The morphological criteria for the diagnosis of MDS-RA were first standardized. Clinical data of 307 MDS-RA patients collected from Shanghai, Suzhou and Beijing from 1995 to 2006 were analyzed using Kaplan-Meier curve, log rank and Cox regression model., Results: The median age of 307 MDS-RA cases was 52 years. The frequency of 2 or 3 lineage cytopenias was 85.6%. Abnormal karyotype occurred in 35.7% of 235 patients. There were 165 cases (70.2%) in the good IPSS cytogenetic subgroup, 44 cases (18.7%) intermediate and 26 cases (11.1%) poor. IPSS showed 20 (8.5%) categorized as low risk, 195 cases (83.0%) as intermediate-I risk and 20 cases (8.5%) as intermediate-II risk. The 1-, 2-, 3-, 4- and 5-year survival rates were 90.8%, 85.7%, 82.9%, 74.9% and 71.2% respectively. Fifteen cases (4.9%) transformed to acute myeloid leukaemia (median time 15.9 months, range 3 - 102 months). Lower white blood cell count (< 1.5 x 10(9)/L), platelet count (< 30 x 10(9)/L) and cytogenetic abnormalities were independent prognostic factors by multivariate analysis, but age (= 65 years), IPSS cytogenetic subgroup and IPSS risk subgroup were not independent prognostic factors associated with survival time., Conclusions: Chinese patients were younger, and had lower incidence of cytogenetic abnormalities, more severe cytopenias but a more favourable prognosis than Western patients. The major prognostic factors were lower white blood cell count, lower platelet count and fewer abnormal karyotypes. The international prognostic scoring system risk group was not an independent prognostic factor for Chinese myelodysplastic syndrome patients with refractory anaemia patients.

The WHO classification for myelodysplastic syndromes (MDS) has introduced new categories with prognostic relevance. Our aim was to examine the predictive value of the WHO and the FAB classification compared to parameters of peripheral blood, bone marrow and IPSS. Clinical data, peripheral blood counts, bone marrow (BM) cytology and histology and survival were analyzed in consecutive newly diagnosed adult patients with MDS. All cases were diagnosed according to FAB criteria and reclassified by the WHO proposal. Among 150 patients entering the study median age was 58 years (12-90). According to FAB, 90 patients had refractory anemia (RA), 18 sideroblastic anemia, 34 refractory anemia with excess of blasts (RAEB), three RAEB-t and five chronic myelomonocytic leukemia. Using the WHO proposal, one half of the patients with RA changed category. One patient had the 5q-syndrome. There were 25 cases with refractory cytopenias with multilineage dysplasia (RCMD) and 23 WHO "unclassified". These last patients presented few cell atypias, favorable IPSS and a good survival as has been described for refractory cytopenias in pediatric MDS. Hypocellular BM was found in 24% of the patients. Karyotype was available in only 85 cases. In the univariate analysis, both classifications, hemoglobin values, hypercellular bone marrow and IPSS had an influence on survival. Using the bootstrap resampling as stability test for the model created by the multivariate analysis, the WHO classification entered the model in 73%, FAB in 38% and IPSS in only 7%. Therefore, in a setting with a high number of low-risk MDS, the WHO classification is the best predictor of survival of the patients.

The deletion (5q) karyotype [del (5q)] in patients with myelodysplastic syndrome (MDS) is considered a good risk feature, while the impact of del (5q) combined with other karyotypic abnormalities [del (5q)+] is less well defined. We analysed the outcome of haematopoietic cell transplants (HCT) in patients with MDS with del (5q) or del (5q)+. Fifty-seven patients, aged 6-72 years, with MDS and del (5q) abnormalities received HCT from related (n = 32) or unrelated (n = 25) donors. By French-American-British (FAB) criteria, 27 patients had refractory anaemia (RA), 10 RA with excess blasts (RAEB), eight RAEB in transformation (RAEB-T) and 12 acute myeloid leukaemia evolving from MDS (tAML). Non-relapse mortality at 1-year post-transplantation was 30% for del (5q) and 38% for del (5q)+ patients. Relapse occurred in one of 20 del (5q) patients and 15 of 37 del (5q)+ patients (P = 0.001). After adjusting for del (5q) status, blast count (<5%) was the only factor significantly associated with relapse-free survival. Patients with del (5q), either as a '5q- syndrome' or with MDS in general, had better outcomes than did patients with del (5q)+. The indication for transplantation in patients with del (5q) was generally severe cytopenias, compared with disease progression to a more advanced FAB stage in patients with del (5q)+. Conceivably, outcome for patients with del (5q)+ would be improved with transplantation earlier in the disease course.

Primary myelodysplasia (MDS) without an increased number of blasts is a rare finding in childhood. We performed a retrospective analysis of 67 children with a diagnosis of primary MDS to determine the clinical and hematologic course of the disease. The median age at diagnosis was 8.3 years (range, 0.3-18.1 years). In contrast to refractory anemia in adults, 44% of patients had hemoglobin levels greater than 10 g/100 mL. The median white blood cell count and the absolute neutrophil count were 3.6 x 109/L and 0.9 x 109/L, respectively. Seventy-five percent of patients had thrombocytopenia. Bone marrow was hypocellular in 43% of the patients. Results of cytogenetic analysis showed monosomy 7 in 49%, trisomy 8 in 9%, and other abnormalities in 9% of the patients. The probability of survival 10 years after diagnosis was 0.48 (standard error [SE] = 0.10). Patients with monosomy 7 had significantly higher estimated probabilities of progression to advanced MDS than did patients with other chromosomal anomalies or normal karyotype. Of the 67 children, 41 underwent allogeneic stem cell transplantation (SCT). Patients whose disease did not progress to advanced MDS before SCT had significantly greater probability of survival than patients who experienced progression (0.76 [SE = 0.09] vs 0.36 [SE = 0.16]). SCT improved the outcomes for patients with monosomy 7 and should be offered early in the course of the disease. Recommendations for best treatment options for children with other chromosomal abnormalities or normal karyotype may have to await results of prospective clinical trials.

We analyzed effects of successive changes in prevention and treatment of chronic GVHD in 405 patients with aplastic anemia and refractory anemia given HLA-matched hematopoietic stem cell transplantation (HSCT) from 1970-1997. For analysis, patients were divided into group I, transplantations from 1970-1976; group II, 1977-1983; group III, 1984-1990; and group IV, 1991-1997. The overall incidence of chronic GVHD was 28%. Incidences of chronic GVHD for groups I through IV were 20%, 46%, 41%, and 22%, respectively, reflecting added buffy coat infusions in groups II and III. Five-year survival rates of patients with chronic GVHD for groups I through IV were 58%, 74%, 82%, and 76%, respectively (NS). Among group I patients, 50% were alive off immunosuppression, none were alive on immunosuppression, and 50% died. These figures were 76%, 0%, and 24% in group II; 80%, 10%, and 10% in group III; and 64%, 21%, and 14% in group IV patients. More serious infections and skin contractures were seen in group I than in groups II, III, and IV (P = .0001, .02, .01 and P =.0003, .001, .05, respectively). Lung complications, aseptic necroses, depression, and Karnofsky scores were comparable among groups. Gastrointestinal complications seemed less frequent among groups II through IV. Diabetes mellitus was more frequent in group IV than in groups I through III (P = .008). Secondary malignancies occurred in 33%, 6%, 3%, and 0% of patients in the 4 groups, respectively. In conclusion, over 28 years, chronic GVHD has remained challenging, with only slight improvements in quality of life. Decisive improvements in therapy and survival will have to await both a better understanding of the immunological events underlying chronic GVHD and better infection prevention and control.

Decitabine (5-aza-2'-deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low-dose decitabine ameliorates cytopenias including induction of trilineage responses in approximately 50% of patients with high-risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention-to-treat) after a median of three courses (range, 2-6) until best cytogenetic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7.5 months (range, 3-15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic responses (60%) in the IPSS 'low-risk' group, 6 out of 30 with 'intermediate risk' (20%) and 10 out of 26 in the 'high-risk' group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative risk of death in patients achieving a major cytogenetic response was 0.38 (95% confidence interval 0.17-0.88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0.0213). In conclusion, repeated courses of low-dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre-existing chromosomal abnormalties; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with 'high-risk' chromosomal abnormalities may particularly benefit from this treatment.

Patients with the refractory anemia (RA) subtype of myelodysplastic syndrome who undergo allogeneic bone marrow transplantation (BMT) have a low risk of relapse, but they have a high risk of nonrelapse mortality when prepared with conventional preparative regimens. To try to reduce nonrelapse mortality, we treated 14 RA patients with a modified approach to total body irradiation (TBI) followed by cyclophosphamide (CY) and HLA-identical sibling BMT. Median patient age was 44 years (range, 28 to 65 years). Patients received TBI with shielding of the right lobe of the liver and both lungs followed by electron beam boosts to shielded ribs. Total radiation exposure in nonshielded areas was 12 Gy (n = 10), 10 Gy (n = 3), or 6 Gy (n = 1). After TBI, patients received CY at 120 mg/kg over 2 days, followed by transplantation of unmanipulated bone marrow. All patients initially achieved engraftment with donor cells, although 2 patients had subsequent reemergence of host hematopoiesis without evidence of disease relapse. Five patients died of transplantation-related causes between 22 and 1262 days post-BMT. Four patients relapsed between 157 and 1096 days post-BMT. These 14 patients were compared with 46 historical controls with RA who received conventional CY/TBI or busulfan/CY preparative regimens. Patients in the experimental group had a similar nonrelapse mortality rate compared with the historical control group (29% versus 37%, respectively; P = .8), but a higher relapse rate (34% versus 2%, P = .0004) and a lower disease-free survival (38% versus 61%, P = .16). We conclude that this modified TBI approach is associated with an unacceptably high risk of relapse for patients with RA undergoing BMT.

Refractory anemia (RA) is a very heterogeneous disease regarding biological and clinical features. The International Prognostic Scoring System (IPSS) was useful for assessing the prognosis in the whole group of 219 myelodysplastic syndrome (MDS) patients. However, the IPSS was not sufficient in 132 RA patients. To predict survival and freedom from acute myeloid leukemia (AML) evolution, we investigated individual prognostic factors based on the clinical parameters (age, gender, morphologic features, cytopenias and cytogenetics) of 132 RA patients using univariate and multivariate analyses. Based on the results, we devised a new system for assessing the prognosis of RA patients. In our system, RA patients with pseudo-Pelger-Huët anomalies >/=3% were classified as high risk (12 patients); of patients without pseudo-Pelger-Huët anomalies >/=3%, those with intermediate/poor karyotype according to IPSS, Hb /=10% were classified as intermediate risk (57 patients); and those without high or intermediate risk were classified as low risk (67 patients). In our system, the analyses of both survival times and leukemia-free survival times revealed significant differences among the three groups (P < 0.0001).

Purpose: To investigate whether the abnormalities observed on femoral marrow magnetic resonance images are related to the development of leukemia and survival of patients with myelodysplastic syndromes (MDS)., Patients and Methods: The findings on magnetic resonance images of the femoral marrow were evaluated over periods of 1 to 92 months (median, 18 months) in 42 consecutive adult patients with newly diagnosed MDS. Magnetic resonance images were obtained by the T1-weighted spin echo method and the short T1 inversion recovery technique., Results: Magnetic resonance images showed that the femoral marrow patterns changed from fatty, faint, or nodular to scattered or uniform as the disease progressed. Development of acute myeloid leukemia was observed in only 13 patients whose marrow exhibited a scattered or uniform pattern. The overall survival of the 29 patients with a scattered or uniform marrow pattern was significantly shorter than that of the 13 patients with a fatty, faint, or nodular marrow pattern (10.7% v 73.3% at 7 years; P < .01). The period of leukemia-free survival was also significantly shorter in the patients with a scattered or uniform marrow pattern versus a fatty, faint, or nodular pattern (37.7% v 100% at 7 years; P < .01)., Conclusion: Magnetic resonance images of the femoral marrow can provide valuable information for assessing the prognosis and determining the most appropriate management of patients with MDS.

Ultrastructural abnormalities of erythroblasts in 30 patients with refractory anemia (RA) according to FAB classification were studied. Nuclear clefts, iron-laden mitochondria, and myelin figures in cytoplasm were most frequently observed. Eleven patients (36.7%) with nuclear clefts of erythroblasts had a higher platelet count and higher incidence of cytogenetic abnormalities linked to poor prognosis than the patients without nuclear clefts. They also had a higher frequency of leukemic transformation and shorter survival than the patients without nuclear clefts. The nuclear clefts of erythroblasts, which are the result of impairment of DNA metabolism or nuclear formation and fusion during mitosis, may be one of the adverse prognostic factors for patients with RA.

We report on 71 consecutive patients with de novo myelodysplastic syndromes referred to physicians belonging to the Société française de greffe de moelle from 1982 through 1991 and transplanted with marrow from HLA-identical siblings. There were 16 cases of refractory anemia, 27 of refractory anemia with excess of blast cells, and 28 of refractory anemia with excess of blast cells in transformation. Seventeen patients had received cytoreductive chemotherapy before the graft. The disease progressed in 17 patients between diagnosis and grafting. Twenty-three patients are alive with a median follow-up of 6 years, whereas 24 died from relapse and 24 from transplant-related complications. Kaplan-Meier estimates of event-free survival, relapse and transplant-related mortality at 7 years were 32%, 48%, and 39%, respectively. The log-rank test and Cox's model revealed better outcome among young patients, patients in an early stage of the French-American-British (FAB) classification or with a low percentage of marrow blasts before transplantation, patients who did not undergo cytoreductive chemotherapy before transplantation, and patients conditioned with total body irradiation and cyclophosphamide. The high rate of relapse in advanced FAB stages has led us to graft patients earlier in the course of the disease, and we are currently conducting a multicenter, randomized study to determine the value of intensive chemotherapy before grafting in patients with an excess of marrow blasts.

Purpose: Myelofibrosis is a common, poor-prognosis feature of myelodysplastic syndromes (MDS). The aim of this work was to evaluate quantitatively the extent of the juxtatrabecular fibrosis in primary MDS and in secondary myelodysplasias, along with the presence of immature precursor cells in anomalous position, that is, the displacement of granulopoiesis from the paratrabecular area to central positions., Patients and Methods: Twenty-seven bone marrow samples were examined: 9 from primary MDS, 9 from secondary myelodysplasias, and 9 normal. The percentage of myeloblasts and promyelocytes with nucleoli located in the central areas was estimated, in an attempt to correlate such feature with the degree of juxtatrabecular fibrosis. The analysis of data was performed with the Kruskal-Wallis test, values of p < 0.01 being significant., Results: Sectorial juxtatrabecular fibrosis was present in all the myelodysplastic samples, ranging from 6% to 55% of the trabecular surface; the highest values found in the controls were about 3.6% (p < 0.01). Although the juxtatrabecular fibrosis figures are higher in secondary MDS, the difference is not significant with regard to the primary MDS in the number of patients studied here. The count of myeloblasts and promyelocytes with nucleoli present in the MDS was significantly greater than that of the control group. The number of promyelocytes with nucleoli was significantly higher in the primary MDS with respect to the secondary ones, whereas no significant difference was seen between the two types of MDS regarding the myeloblast count., Conclusions: The increased number of central immature precursor cells in MDS was not directly correlated with the extent of the juxtatrabecular fibrosis. Although the number of cases is small, the fact that the juxtatrabecular fibrosis was higher in the two deceased patients in the series (49% and 56%, respectively) suggests a poor-risk prognosis for such finding.

Thirty-four patients with myelodysplastic syndromes, 23 men and 11 women, aged between 47 and 80 years, with all types of myelodysplastic syndromes were treated with 13-cis-retinoic acid. The dose of retinoic acid ranged between 10 and 60 mg/m2/daily and was administered in combination with vitamin E to diminish side effects. The duration of treatment was 3 months to 5 years. Partial remission was achieved in 4 patients, 1 with RA type, 2 with RAEB and 1 with CMML. Survival ranged from 1 to 5 years. Patients who received retinoic acid developed mild side effects. In conclusion, the administration of 13-cis-retinoic acid improves the hematological picture in a small number of MDS patients (11.7%).

We studied the platelets of 8 patients with myelodysplasia aged 49-77 years, using both ultrastructural and functional techniques. Five of the 8 patients were classified as having refractory anaemia, and 3 as refractory anaemia with excess of blasts (RAEB). Electron microscopically, the myelodysplastic patients had in addition to normal ones, platelets containing significantly less alpha-granules. In part of these hypogranular platelets, the dense tubular system was abundant, but in contrast with normal platelets, it was not dispersed between the other organelles, nor did it form a membrane complex with the open cannalicular system. From a functional point of view, collagen-induced shape change was the most frequently disturbed parameter: there was a total loss of collagen-induced shape change in 5 patients. In 2 patients, there was a complete lack of response to collagen in platelet-rich plasma (both shape change and aggregation); in one of them, there was also a total loss of adenosine triphosphate secretion in response to all inducers tested. After 4 years of follow-up, 5 patients had died, of whom 3 were RAEB patients. An initial complete absence of collagen-induced shape change was found in these 5 patients, while in the 3 patients who were still alive at the end of the follow-up period, collagen-induced shape change was normal in 2 and slightly diminished in one.

We statistically analyzed the hematologic findings of patients with refractory anemia (RA) to identify parameters associated with a poor prognosis. We first separated the RA patients into two groups: one group with disease progression and one without. The patients with disease progression were predominantly male and had a significantly higher percentage of bone marrow (BM) blasts at the time of diagnosis (3.06 +/- 1.29% vs. 1.44 +/- 1.38%, P < 0.005). This finding was confirmed when the patients were separated into the two groups; those who survived and those who expired (BM blasts: 2.68 +/- 1.59% vs. 1.37 +/- 1.27%, P < 0.005). The survival probabilities were calculated depending on whether or not the RA patients had > or = 3% BM blasts. The RA patients with > or = 3% BM blasts had a significantly worse prognosis (P < 0.01) than the patients with < 3% BM blasts. Notably, the RA patients with > or = 3% BM blasts did not show any significant differences in the incidence of disease progression, mortality rate, or survival probability, when compared with the patients with RA with an excess of blasts (RAEB). The present findings indicate that RA patients are heterogeneous with regard to prognosis, and the RA patients with > or = 3% BM blasts might have a poorer prognosis than those with fewer BM blasts. Thus we propose a general approach in predicting the prognosis of RA patients: those with complex chromosomal changes will expire shortly. Secondly, when the patients do not have any complex changes, the prognosis might be linked to the percentage of BM-blasts at the MDS diagnosis.

Refractory anemia (RA) is the only myelodysplastic syndrome (MDS) devoid of quantitative marrow diagnostic criteria. The diagnosis rests mainly on the subjective identification of qualitative abnormalities according to the French-American-British criteria (FAB) involving one or more bone marrow hematopoietic cell lineages. The occurrence of nonrandom chromosome abnormalities remains the hallmark of the disease and the only means of investigation which confirms the disease objectively. With the purpose in mind to further characterize RA among MDS, we have undertaken a prospective high resolution banding chromosome analyses of bone marrow cells in patients with primary refractory anemia (PRA) with the aim of defining a cytogenetic phenotype and of assessing the clinical relevance of clonal abnormalities at initial diagnosis. Of 39 patients consecutively referred for chromosome analyses with a diagnosis of RA according to the FAB criteria, 27 patients had PRA and fulfilled our criteria for adequate chromosome analyses. Median age was 68 years. Fourteen of 27 patients (52%) had clonal chromosomal abnormalities at diagnosis. None of the patients showed a complex karyotype; 9/14 (64%) had a mixture of normal and abnormal cells. Interstitial or terminal deletions, involving chromosomes 5, 6, 7, 9, 11, 12, and 20, were found in 11/14 (79%) of the patients. Comparison of survival between patients with and without abnormalities showed no difference. The presence of clonal abnormalities did not predict transformation to acute myeloblastic leukemia (AML) nor was it associated with poor survival. In this study, patients with PRA were found to have a predominant pseudodiploid karyotypic pattern characterized by interstitial and/or terminal deletions as opposed to derivatives, specific and non-specific balanced translocations, or other structural and numerical abnormalities. We were unable to reveal any prognostic significance to the presence of these clonal abnormalities at initial diagnosis.

Cytogenetic studies were performed in 112 untreated cases of myelodysplastic syndrome (MDS) between 1985 and 1990. Among 112 patients who were examined at the time of diagnosis, 54 had an abnormal karyotype (48%). The highest frequency of chromosome abnormalities was observed in refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-t) and the lowest in refractory anemia with ring sideroblasts (RARS) and chronic myelomonocytic leukemia (CMMoL). Numerical changes were observed in 19 cases and structural in 17; chromosome 8 was most frequently gained (11 cases), whereas chromosome 7 was most frequently lost (6 cases), 5q- in 14 (4 as a sole anomaly); involvement of 7q22 was seen in 3 cases, 11p in 2 patients, 11q in 3 (one patient as a sole anomaly), 12p in 4 (2 patients as a sole anomaly), i(17q) in 4 (3 patients as a sole anomaly), and complex chromosomal defects in 10 patients. If one takes into account the prognosis value, a complex karyotype and the presence of ring chromosomes were correlated with the worst prognosis, followed by -7/7q-; an intermediate prognosis corresponds to i(17q), 12p as a sole anomaly, +8 (as a sole anomaly or plus other anomalies), and involvement of 12p. Patients with a 5q- as a sole anomaly or with a normal karyotype, had the best prognosis.

Eighty-one of 473 patients with refractory myelodysplastic anemias registered by the Japanese Cooperative Study Group prior to January 1987 survived more than 5 years. At presentation, most patients had mild cytopenia, a less aggressive form of the disease (48 with refractory anemia, 23 with refractory anemia with ring sideroblasts, 10 with refractory anemia with excess of blasts), less blast cells in the marrow and blood, and onset at younger ages. Their clinical profiles 5 years after presentation showed no significant improvement. The results suggest that the long-term survivors were found in a subpopulation of patients with a favorable prognosis and that it is a part of the natural course rather than the results of treatment.

Clinical, haematological and outcome data were studied in 84 patients with acquired idiopathic sideroblastic anaemia (AISA) from a registry of 613 consecutive myelodysplastic syndromes (MDS) recorded by five institutions in western France. Two groups could be identified and compared: 'pure' erythroblastic AISA (AISA-E: 59 pts), and AISA with myelodysplastic features, i.e. dysgranulo and/or dysmegakaryopoiesis (AISA-M: 25 pts). Results were also compared to those of a series of 71 cases of refractory anaemia without sideroblastosis (RA) carried out from the same registry. Dyserythropoiesis was present in 90% of all AISA subtypes, dysgranulopoiesis in 88% of the AISA-M cases; dysmegakaryopoiesis was observed in 44% of AISA-M. Ten patients with both forms of AISA showed high platelet counts. These cases appeared particular in that four of them were associated with a splenomegaly and/or a hyperleucocytosis. They had to be distinguished from myeloproliferative syndromes. Outcome comparison of AISA-E with AISA-M showed a significant discrepancy of survival duration (60 vs 38 months respectively). Progression towards refractory anaemia with excess of blasts or acute leukaemia, was significantly higher for AISA-M than for AISA-E. The risk of transformation increased to 24% for the AISA-M group similarly to those of RA patients (17%). We conclude that AISA must be divided into two categories, 'pure' AISA and AISA-M, because survival duration and risk of transformation are different.

We analysed the course and clinical features of a series of refractory anaemias (RA, RAEB, RAEBt). We could not find evidence to support the hypothesis that these three MDS classes are inevitably subsequent events of a single disease. Therefore aggressive treatment of RA, aimed at avoiding its evolution to RAEB or RAEBt, does not seem justified.

We retrospectively evaluated the efficacy of androgen in the treatment of refractory anemia (RA) and compared patient characteristics and the probability of survival in androgen-responder and nonresponder groups. Forty patients with RA were treated in our hospital between 1975-1989, and 27 were treated with various derivatives of androgen. Eleven of the latter responded effectively to androgen therapy, representing an efficacy rate of 40.7%, higher than that of any other treatments thus far reported. The probability of 10-year survival estimated by the Kaplan-Meier method was 75.0% for the responder group and 41.3% for nonresponders, with a median follow-up of 1202 and 1272 days, respectively. In addition, the percent probability of transformation-free survival was higher among androgen-responders than among nonresponders, though the difference was not significant. Transformation from RA to RAEB or overt leukemia was seen in only one case among the former group, but in six among the latter. With respect to patient characteristics, only the percentage of marrow myeloblasts differed significantly between the groups.

We treated 47 adult patients with de novo myelodysplastic syndrome (MDS) by an anthracycline-AraC regimen. Median age was 54, and M/F 1.3. At diagnosis, 26 patients had refractory anaemia with an excess of blasts in transformation (RAEB-T) three had refractory anaemia (RA), 11 had refractory anaemia with excessive blasts (RAEB) and seven had chronic myelomonocytic leukaemia (CMML). Treatment was started within 3 months of diagnosis in 30 patients, and after more than 3 months in the 17 remaining patients. At the onset of treatment, 16 patients had progressed to acute myeloid leukaemia (AML). Twenty-two patients (47%) reached complete remission (CR), 10 (21%) had hypoplastic death and 15 (32%) had resistant disease. Median actuarial disease-free interval was 11 months. Median actuarial survival was 14 months from diagnosis and 10 months from the onset of treatment. A significantly higher CR rate was found in patients with RAEB-T at diagnosis (69% v 19% in patients with other FAB subtypes: P = 0.008), and in patients treated within 3 months of diagnosis. Using multivariate analysis, RAEB-T at diagnosis emerged as the most powerful prognostic factor of CR achievement. Karyotype was the only significant prognostic factor of disease-free interval, with a median of 16.5 months in patients with normal karyotype versus 4 months in patients with normal findings (P = 0.018). A subgroup of 15 patients with RAEB-T at diagnosis and normal karyotype, who had a CR rate of 80% and a median actuarial disease-free interval of 18 months, could be identified. Our results confirm that, overall, intensive chemotherapy has limited efficacy in MDS, especially when compared with allogeneic bone marrow transplantation (BMT). Relatively favourable results were obtained in our patients with RAEB-T at diagnosis, however, particularly those with normal karyotype. In that subgroup, intensive chemotherapy may be recommended, especially before BMT, as a high risk of relapse after BMT in patients with RAEB-T allografted as first line therapy has been reported.

Cytogenetic studies were performed in 120 patients with de novo myelodysplastic syndrome (MDS) classified according to FAB criteria. Twenty-eight patients had refractory anemia (RA), 14 had refractory anemia with ring sideroblasts (RARS), 45 had refractory anemia with blast excess (RAEB), 19 had refractory anemia with blast excess in transformation (RAEB-t), and 14 had chronic myelomonocytic leukemia (CMMoL). Fifty patients (42%) had clonal chromosome anomalies at initial analysis. The most common cytogenetic anomalies were: 5q- (11 patients), trisomy 8 (nine patients), -7/7q- (6 patients), 12p- (five patients), followed by structural anomalies of chromosome 17 (four patients), and loss of Y chromosome (three patients). The prognostic value of chromosome anomalies was examined by comparison of the significance of single chromosome anomalies (34 patients) versus multiple cytogenetic changes (16 patients). Patients with multiple anomalies had a shorter survival (8 months) than patients with single anomalies (18 months) or those with a normal karyotype (36 months). All these differences were significant. The incidence of multiple anomalies was higher in patients with RAEB and RAEB-t than in those with RA, RARS, and CMMOL (p less than 0.05). However, no chromosome anomaly was specifically associated with any group of FAB classification. Transformation to acute leukemia was observed in 25% of patients with normal karyotype, 41% of patients with single anomalies, and 50% of patients with multiple changes. The incidence of leukemic transformation was significantly higher in patients with multiple anomalies than in those with a normal karyotype (p less than 0.05). Thus, in the present study, FAB classification and chromosome anomalies were of independent prognostic significance. Sequential cytogenetic studies were performed in 23 patients to correlate the cytogenetic and clinical findings during the course of the disease. Six of seven patients with transformation to acute leukemia showed a karyotypic evolution. These findings agree with the view that an unstable karyotype can be associated with a poor prognosis.

The survival of MDS patients without detectable circulating CFU-GM (median = 188 days) was significantly lower than those in whose peripheral blood CFU-GM were detected (median greater than 1000 days) (p less than 0.01). About half of those with detectable PB-CFU-GM died within 2 yr whilst the remainder survived more than ca 3 yr. There was no significant difference in the distribution of patients having 0-5% and greater than 5% marrow blast cells within the three groups.

The association between nonleukemic death and various features recorded at presentation in patients with refractory anemia (RA), RA with ring sideroblasts, and RA with excess of blasts was analyzed in 251 patients using the proportional hazards model. Features associated with higher nonleukemic death rates were: 1% or more metamyelocytes in peripheral blood (PB); lower 59Fe incorporation rate; 1% or more blasts in PB; lower hematocrit or hemoglobin; presence of giant platelets; 1 microgram/liter or higher serum vitamin B12 levels; higher periodic acid-Schiff positive erythroblasts; and 1% or higher promyelocytes in PB. Multivariate analysis was also performed using the following predictor variables: metamyelocytes in PB, micromegakaryocytes, hemoglobin, giant platelets, presence or absence of RA with excess of blasts, and mononuclear large megakaryocytes. Patients were divided arbitrarily into low (hazard ratio, less than 0.55), intermediate (hazard ratio, 0.55-1.5), and high (hazard ratio, greater than 1.5) risk groups. The cumulative nonleukemic death rates in the high and intermediate risk groups reached a median at 602 and 1984 days from presentation, respectively, while the rate reached a plateau level of 49.4% after 2644 days in the low risk group. The risk factors for leukemic transformation and nonleukemic death were found to be different and to need separate consideration.

Two independent observers performed a double review of cytological and histological bone marrow material obtained at diagnosis and during follow up in 34 patients with the myelodysplastic syndrome (MDS), subtypes refractory anaemia (RA) and RA with ringed sideroblasts (RA-S) (26 and 8 patients, respectively). Average values were used for the analyses. Data obtained at diagnosis confirmed earlier observations that a worse prognosis was indicated by high blast cell counts (P less than 0.01), presence of blast foci and clonal cytogenetic abnormalities (P = 0.08). Data obtained during follow up, in addition, showed that an increased probability of progression to FAB-subtype RA with an excess of blasts was related to both the occurrence of blast foci (P less than 0.05) and the occurrence of new or additional clonal abnormalities (karyotype shift) (P less than 0.01). The relationship between parameters investigated at diagnosis, during follow up, and in the pooled material, points to RA-S being a separate entity having a better prognosis than RA, and further substantiates an earlier observed relationship between blast cell accumulation and the frequency of cytogenetically abnormal metaphases.

Between 1980 and 1986, we diagnosed refractory anaemia (RA), according to the FAB classification, in 69 patients, who constituted 22% of the 312 cases of myelodysplastic syndromes (MDS) seen over that period. The haematological features were variable, with pancytopenia in 14 cases (20%), bicytopenia in 24 (36%) and mono-cytopenia in the remaining patients, including 21 (30%) cases of anemia alone, 8 (12%) cases of refractory neutropenia and 2 (3%) cases of refractory thrombocytopenia. Myelodysplastic features were also quite variable, involving one, two or all three lineages. In patients with a single cytopenia or only one dysplastic lineage, FAB criteria appeared insufficient for adequate inclusion among RA and we suggest more precise diagnostic criteria, resulting from the utilization of cytogenetics, ferrokinetics, progenitor cultures and perhaps molecular biology, in such cases. Median survival was 42 months. 12 patients (17%) progressed to RAEB (of whom 7 finally developed ANLL) and 4 patients (6%) to CMML. In spite of the heterogeneity of haematological features, only two factors were associated with poor prognosis, namely age greater than 70 yr at diagnosis and haemoglobin less than 10 g/dl, whereas, to a lesser extent, neutropenia was associated with progression to RAEB.

Several aspects of prognosis of myelodysplastic syndromes were reviewed with special attention to refractory anemia (RA). The median survivals were 14 months in chronic myelomonocytic leukemia, 16 months in RAEB, 42 months in RA, and 58 months in RA with ring sideroblasts (RARS). Cumulative leukemia-free rates at 5 years were 31% in RAEB, 80% in RA, and 92% in RARS. The proportion of cases having very low hazards for leukemic transformation or for nonleukemic death was 92% (RARS), 73% (RA), and 26% (RAEB) for leukemic transformation and 23% (RA) and 29% (RAEB) for nonleukemic death. All RARS cases had hazard for nonleukemic death. In RA, the annual mortality rate was about 5 to 11 times higher than that of age-and sex- matched general population up to 6 years. After which no failure was found in RA cases with survival rate of 33% up to 14 years. The relative importance of hazard from leukemic transformation to nonleukemic death in RA was about one half at presentation, but this declined to less than 10% after 10 years.

Thirty three patients with refractory myelodysplastic anaemias (RMDA) with marrow hypocellularity were reviewed to see whether they differed from those with normocellular or hypercellular marrows. The median age was 65 years with a male:female ratio of 26:7. There were 11 cases of refractory anaemia (RA), four of refractory anaemia with ringed sideroblasts (RARS), and 18 of refractory anaemia with excess of blasts (RAEB). All presented with peripheral cytopenias, mostly pancytopenia or bicytopenia dysplasia in one or more cell lineages, and a marrow biopsy specimen with less than normal numbers of nucleated cells for the age. Twenty four patients died, including 14 of the 16 who developed acute non-lymphocytic leukaemia (ANLL). The results suggest that patients with hypocellular RMDA have a similar prognosis to those with normocellular or hypercellular marrows at presentation.