The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes.

The Wilms' tumor gene, WT1, is a tumor marker for leukemic blast cells. The WT1 expression levels were examined for 57 patients with myelodysplastic syndromes (MDS) (refractory anemia (RA), 35; RA with excess of blasts (RAEB) 14; RAEB in transformation (RAEB-t), six; and MDS with fibrosis, two) and 12 patients with acute myeloid leukemia (AML) evolved from MDS. These levels significantly increased in proportion to the disease progression of MDS from RA to overt AML via RAEB and RAEB-t in both bone marrow (BM) and peripheral blood (PB). WT1 expression levels in PB significantly correlated with the evolution of RAEB or RAEB-t to overt AML within 6 months. Therefore, WT1 expression levels in PB were superior to those in BM for early prediction of the evolution to AML by means of quantitation of the WT1 expression levels. Furthermore, WT1 expression in PB of patients with overt AML evolved from MDS was significantly decreased by effective chemotherapy or allogeneic stem cell transplantation and became undetectable in long-term survivors. These results clearly showed that WT1 expression levels are a tumor marker for preleukemic or leukemic blast cells of MDS and thus reflect the disease progression of MDS. Therefore, monitoring of WT1 expression levels has made continuous assessment of the disease progression of MDS possible, as well as the prediction of the evolution of RAEB or RAEB-t to overt AML within 6 months. The results also showed that quantitation of WT1 expression levels is useful for diagnosis of minimal residual disease of MDS with high sensitivity, thus making it possible to evaluate the efficacy of treatment for MDS.     

Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS).

We reviewed the clinical features, treatment, and outcome of 100 children with myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (-7) or deletion of the long arm of chromosome 7 (7q-). Patients with therapy-induced disease were excluded. The morphologic diagnoses according to modified FAB criteria were: MDS in 72 (refractory anemia (RA) in 11, RA with excess of blasts (RAEB) in eight, RAEB in transformation (RAEB-T) in 10, JMML in 43), and AML in 28. The median age at presentation was 2.8 years (range 2 months to 15 years), being lowest in JMML (1.1 year). Loss of chromosome 7 as the sole cytogenetic abnormality was observed in 75% of those with MDS compared with 32% of those with AML. Predisposing conditions (including familial MDS/AML) were found in 20%. Three-year survival was 82% in RA, 63% in RAEB, 45% in JMML, 34% in AML, and 8% in RAEB-T. Children with -7 alone had a superior survival than those with other cytogenetic abnormalities: this was solely due to a better survival in MDS (3-year survival 56 vs 24%). The reverse was found in AML (3-year survival 13% in -7 alone vs 44% in other cytogenetic groups). Stable disease for several years was documented in more than half the patients with RA or RAEB. Patients with RA, RAEB or JMML treated with bone marrow transplantation (BMT) without prior chemotherapy had a 3-year survival of 73%. The morphologic diagnosis was the strongest prognostic factor. Only patients with a diagnosis of JMML fitted what has previously been referred to as the monosomy 7 syndrome. Our data give no support to the concept of monosomy 7 as a distinct syndrome.     

Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group.

PURPOSE: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children's Cancer Group protocol 2891. PATIENTS AND METHODS: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML. RESULTS: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30% +/- 18%; antecedent MDS, 50% +/- 25%; and de novo AML, 45% +/- 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML. CONCLUSION: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.     

High prevalence of human T-lymphotropic virus type I carriers among patients with myelodysplastic syndrome refractory anemia with excess of blasts (RAEB), RAEB in transformation and acute promyelocytic leukemia.

We examined human T-lymphotropic virus type I (HTLV-I) infection among patients with myelodysplastic syndrome (MDS), refractory anemia with excess of blasts (RAEB)/RAEB in transformation (RAEBt) and acute myelogenous leukemia (AML). The study population consisted of 151 patients: 46 with MDS RAEB/RAEBt and 105 with AML (M1, n = 15; M2, n = 39; M3, n = 18; M4, n = 19; M5, n = 9; M6, n = 3; M7, n = 2). As a reference, we examined 92 patients with refractory anemia (RA) and 405 patients with cardiovascular diseases (CVD). Thirteen patients with RAEB/RAEBt (28.3%), 11 with AML (11.6%), 27 with RA (29.3%), and 45 with CVD (11.0%) were positive for HTLV-I. Seven AML patients with HTLV-I infection had M3 acute promyelocytic leukemia (APL). The prevalences of HTLV-I infection among patients with RAEB/RAEBt (P < 0.001), APL (P = 0.001), and RA (P < 0.001) were significantly higher than that in patients with CVD. The prevalences of HTLV-I infection were still significantly higher in patients with RAEB/RAEBt (P = 0.007), APL (P = 0.017) and RA (P < 0.001) than in those with CVD matched by sex and age. Platelet counts and survival times of RAEB/RAEBt patients with infection were significantly lower than those of patients without infection.     

Myelodysplastic Syndromes—A Population-Based Study on Transformation and Survival

A retrospective analysis was done on 113 patients (median age 73 years) with myelodysplastic syndromes (MDS), consecutively diagnosed at our center during a 10-year period. Patients with refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) had significantly longer survival than patients with refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML) or refractory anemia with excess blasts in transformation (RAEB-T). Thirty-seven patients (33%) subsequently developed acute myelogenous leukemia (AML). The percentages of AML transformation for the subgroups were: RA: 26%, RARS: 14%, RAEB: 38%, CMML: 25% and RAEB-T: 69%. A total of 9 patients received high-dose chemotherapy, 7 of them already at the time of MDS diagnosis. Six of the RAEB-T patients entered complete and two partial remission. The median age in the group of RAEB-T patients was significantly lower (62 years) than in the other MDS subgroups. It seems that high-dose chemotherapy, at least in RAEB-T, may induce complete remission and improve survival time.     

Myelodysplastic syndromes in patients under 50 years old: a single institution experience

We report on our experience relating to 62 patients with myelodysplastic syndrome (MDS) aged less than 50 years, seen at our Institution and conservatively treated from July 1983 to December 2000. Patients demographics and clinical features at diagnosis were analysed for their prognostic value on survival and on risk of transformation to acute leukaemia. The median age at diagnosis was 43 years (range 21-50). According to FAB criteria there were 30 patients with refractory anaemia (RA), 3 with refractory anaemia with ringed sideroblasts (RARS), 18 with refractory anaemia with excess of blasts (RAEB), 6 with refractory anaemia with excess of blasts in transformation (RAEB-t) and 5 with chronic myelomonocytic leukaemia (CMML). Fifty patients had evaluable cytogenetic analysis: the most frequent karyotypic change was trisomy of chromosome 8 (10%), followed by monosomy 7 (6%); partial chromosome deletions and translocations were also common abnormalities, occurring on the whole in 16% of patients. At a median follow-up of 15 months 19 patients (31%) progressed to acute myeloid leukaemia (AML). From univariate analysis we identified some features, which appeared to be predictive of outcome and risk of transformation to AML. Age above 40 years (p = 0.002) and high risk according to IPSS score (p = 0.002) were found to be predictive for a shorter survival; FAB grouping (p = 0.0001), percentage > 5% of blasts in the bone marrow (p = 0.001) and high risk by IPSS score (p = 0.0003) were found to be predictive for a higher risk of transformation to AML. Presenting features in young MDS patients may identify subjects at higher risk of unfavourable outcome.     

Presence of peripheral blasts in refractory anemia and refractory cytopenia with multilineage dysplasia predicts an unfavourable outcome

The World Health Organization (WHO) assigns myelodysplastic syndrome (MDS) to RA/RCMD/RARS/RSCM/5q- syndrome, if medullary blasts are <5% and peripheral blast (PB) count < or =1%. In 1103 patients with these diagnoses, we analysed survival and risk of AML evolution depending on the presence of PB. Median survival in the group with 1% PB (n=74) was significantly lower as compared to those without PB (20 versus 47 months, p<0.00005). Cumulative risk of AML was significantly higher in patients showing PB (p<0.00005). Median survival of patients with PB was not different from that of RAEB I. We therefore propose to consider patients with PB, regardless of medullary blast, as RAEB I.     

Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse. PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients. RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P =.006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P =.0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P =.02). CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.     

Spontaneous remission in adults with primary myelodysplastic syndromes

Reports on spontaneous remissions in patients with primary myelodysplastic syndromes (MDS) occasionally appear in the literature. We report five adult patients with spontaneous remission of MDS, achieved without cytotoxic or any other treatment. These five patients represent 1.6% of 307 MDS patients, diagnosed in our Institute since 1987. According to FAB criteria, three patients had RA, and one patient had RARS and RAEB, each. All patients were women, median age of 63 yr (range 32-68 yr). Patients were without significant complaints and peripheral cytopenia was mild. Bone marrow dyshematopoiesis was also mild, mostly affecting erythroid and megakaryocytic series. At diagnosis, three patients had cytogenetic abnormalities [+8,+12; +15 and del(16)(q22)]. Median time to complete hematological and cytogenetical remission was 51 mo, while median duration of spontaneous remission was 45 mo (range 44-60 mo). As for the follow-up, none of the patients relapsed. In conclusion, although spontaneous remissions (i.e., "regression") of MDS are uncommon, better understanding of their basis may lead to crucial advances in the study of leukemogenesis.     

Re-evaluation of refractory anemia with excess blasts in transformation

The category 'refractory anemia with excess blasts in transformation (RAEBt)' consists of two sub-sets; one group is categorized based on the percentage of blasts in the marrow (> or =20%) and other is based on the percentage of blasts in the peripheral blood (> or =5%). We separated RAEBt patients based on these two criteria and compared hematologic and clinical relevance to assess the reasonable basis for the new classification. All RAEBt patients showing peripheral blood (PB) blasts of > or =5% were re-classified as RAEB by the WHO classification. This subset of RAEBt patients had lower percentages of bone marrow (BM) blasts, and notably they showed frequent complex cytogenetic abnormalities, including -5/5q- and/or -7/7q-. Moreover, the RAEBt patients of this group had shorter survivals compared to RAEBt patients with BM blasts between 20 and 30%. We next assessed hematologic and clinical relevance between refractory anemia with excess blasts (RAEB) and RAEBt patients with PB blasts of > or =5%. Except for the percentage of blasts in the PB (P=0.0037) and BM (P=0.0073), there was no significant difference in hematologic or clinical features between RAEB patients with BM blasts of > or =11% and RAEBt patients with PB blasts of > or =5%. When MDS patients with PB blasts of > or =5% (RAEBt by the FAB classification) were included as RAEB-II based on the "MDS 2000 classification', there was a high frequency of patients with complex chromosome changes, involving 5q and 7q, with significant poorer outcome compared to those with RAEB-I. Although it is still controversial whether MDS patients with BM blasts 20% or more should be considered as acute leukemia, the utilization of the 'MDS 2000 classification' might be useful to designate MDS patients diagnosed based on the percentage of blasts in the peripheral blood.     

骨髓增生异常综合征的免疫表型特征分析

 【摘要】　目的　评价免疫表型在骨髓增生异常综合征（MDS）诊断中的价值。方法　采用流式细胞术对27例MDS患者的骨髓细胞进行免疫表型检测。结果　随着MDS疾病的进展,CD+34细胞比例逐渐升高,分别为：难治性贫血／环形铁粒幼细胞性难治性贫血（RA／RAS）7.43 %,难治性贫血伴原始细胞增多（RAEB）36.81 %,难治性贫血伴原始细胞增多转化型（RAEB-T）56.45 %,3组差异有统计学意义（F＝51.197,P＝0.000）,且各组间差异均有统计学意义（P＜0.05）;髓系抗原CD33、CD13、HLA-DR表达逐渐增高,CD14、CD15抗原表达随着疾病的进展逐渐降低,3组间差异有统计学意义（P＜0.05）;B淋巴细胞表面抗原CD19、CD10的表达随着疾病进展而降低;T淋巴细胞表面抗原CD7表达随着疾病进展而增高,分别为RA／RAS 2.63 %、RAEB 10.79 % 和RAEB-T 11.00 %,3组间差异有统计学意义（F＝10.439,P＝0.001）,其中RA／RAS组与RAEB组、RAEB-T组之间差异有统计学意义（P＝0.000,P＝0.001）。结论　检测MDS患者骨髓细胞的免疫表型有助于MDS的诊断、分型和判断预后,从而为治疗提供依据。     

CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine.

5-Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes (MDS). Whether responses to 5-Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia (AML) treated with 5-Azacytidine, 7 achieved complete remissions (CR) (21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow (BM) blasts at the time of haematological improvements (HI) (2 had pre-existing refractory anaemia (RA), 4 had refractory anaemia with excess blasts (RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven (71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival (OS) (median 23 versus 9 months, P=0.015). Bisulphite genomic sequencing (BGS) of the CDKN2B (p15(INK4b)) promoter showed low level, heterogeneous pretreatment methylation (mean 12.2%) in 14/17 (82%) patients analysed. Lower baseline methylation occurred in responders (9.8% versus 16.2% in non-responders P=0.07). No response was seen in patients with >24% methylation, in whom p15(INK4b) mRNA was not expressed. 5-Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/17 (47%) patients, but this did not correlate with response. At 75 mg/m(2), cell death (reduced BM cellularity (P=0.001) and increased apoptosis (P=0.02)) rather than demethylation of CDKN2B correlates with response. Patients with >24% methylation may benefit from alternative dosing or combination strategies.     

Biologic characteristics of 164 patients with myelodysplastic syndromes

Rates of proliferation, apoptosis and cytokine expression were measured in bone marrow (BM) biopsies of 164 myelodysplastic syndrome (MDS) patients. There were 107 males and 57 females. Median age was 69 years and 101 had refractory anemia (RA), 17 RA with ringed sideroblasts (RARS), 38 with RA and excess blasts (RAEB) and 8 with RAEB in transformation (RAEB-t). Apoptosis measured by in-situ end labeling (ISEL) was directly related to the number of macrophages (p = 0.028, n = 83). Mean tumor necrosis factor alpha (TNF-alpha) and ISEL positivity were higher in RAEB + RAEB-t patients (p = 0.0554 and p = 0.06 respectively) while hemoglobin was higher for RA + RARS group (p = 0.0472). Patients with high apoptosis had lower white blood cell counts (p = 0.0009), lower percentage of blasts (p = 0.0009) and higher number of macrophages (p = 0.0086). We conclude that measurements of apoptosis, proliferation and cytokine expression provide important biological information which helps to distinguish RA + RARS patients from RAEB + RAEB-t patients, and may be of additive prognostic significance.     

Combination of 5-azacytidine and thalidomide for the treatment of myelodysplastic syndromes and acute myeloid leukemia

BACKGROUND.

The treatment of myelodysplastic syndromes (MDS) remains a challenge to the clinician despite recent advances. Many patients will either not respond or will have only limited and/or brief responses to single‐agent therapy. Eventually, 30% of patients with MDS will progress and develop acute myeloid leukemia (AML). New strategies are needed for these patients.

METHODS.

5‐Azacytidine (AZA) and thalidomide were administered to 40 patients with MDS or AML. AZA was given at a dose of 75 mg/m² subcutaneously for 5 of 28 days together with thalidomide starting at a dose of 50 mg per day and increasing to 100 mg per. Six patients had refractory anemia (RA), 2 patients had RA with ringed sideroblasts, 10 patients had RA with excess blasts (RAEB), 1 patient had RAEB in transformation, 4 patients had chronic myelomonocytic leukemia, 1 patient had chronic idiopathic myelofibrosis, and 16 patients had AML. Thirty‐six patients were evaluable for outcome.

RESULTS.

A hematologic improvement (HI) was observed in 15 of 36 patients (42%), stable disease was observed in 5 of 36 patients (14%), and 10 of 36 patients (28%) had disease progression. Six patients experienced complete remission (CR), 2 patients experienced an erythroid HI (HI‐E), 1 patient experience an absolute neutrophil count HI (HI‐ANC), 5 patients experienced a platelet HI (HI‐P), and 7 patients had bilineage HI (HI‐P and HI‐ANC or an HI‐E and HI‐ANC). It was noteworthy that 9 of 14 patients with AML had a history of prior MDS, 2 of 9 patients achieved a CR, 4 of 9 patients had HI (HI‐E and bilineage HI), and 1 patient had stable disease and was continuing treatment. DNA microarray analysis of 8 responders and 4 nonresponders revealed that the genes associated with cellular proliferation had higher expression levels in nonresponders.

CONCLUSIONS.

The current findings indicated that a combination of low‐dose AZA and thalidomide was well tolerated and was effective therapy for the treatment of patients with MDS and AML arising from prior MDS. Cancer 2008. © 2008 American Cancer Society.     

Myelodysplastic Syndrome

The myelodysplastic syndromes (MDS) are a heterogeneous group of stem cell malignancies characterized by dysplastic and ineffective hematopoiesis and a variable risk of transformation to acute myeloid leukemia (AML). They usually occur in elderly people with an age at diagnosis of between 60 and 75 years. The natural history of these syndromes ranges from a chronic form spanning years [refractory anemia with or without ring sideroblasts (RARS)] to forms with a rapid evolution to AML [refractory anemia (RA) with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-t)]. Although the relationship between de novo AML and MDS has been controversial, recent evidence suggests that AML (especially AML in the elderly) and MDS are part of the same continuous disease spectrum rather than distinct disorders. MDS are clonal diseases with a step-wise genetic progression leading to secondary acquired, MDS specific-cytogenetic aberrations characterized by gains and loss of specific chromosomal regions. The treatment options for patients with MDS are complex and highly individualized, although, most therapies are poorly effective and the curative approaches are only available for aminority of patients.     

Cytogenetic studies in 32 patients with myelodysplastic syndrome: insights to specific chromosomal abnormalities and prognosis

Cytogenetic studies were performed on a group of 32 patients with myelodysplastic syndrome (MDS). Five patients had refractory anemia (RA), four RA with ring sideroblasts (RARS), nine RA with excess blasts (RAEB), eight RAEB 'in transformation' (RAEB-T), three chronic myelomonocytic leukemia (CMML) and three secondary MDS (SMDS). Two patients in the SMDS group had been treated with alkylating agents for lung cancer and polycythemia vera, respectively. The other had been exposed to thorotrast. Chromosome analyses were performed with Q and G bandings on bone marrow cells incubated for 24 hr. A clonal chromosomal abnormality was observed in the marrow cells from 19 of the 32 patients (59%). Chromosomal abnormalities of nos. 5 and/or 7 were found in five patients, and were probably specific for RAEB-T and SMDS. Among the twelve patients with solely abnormal metaphases (AA), eight (67%) progressed to acute leukemia, a higher proportion than the three from the 13 patients (23%) with solely normal metaphases (NN) (P less than 0.05). One of the seven patients (14%) with both normal and abnormal metaphases (AN) developed acute leukemia (AA v. AN, P less than 0.03). In only two of the 12 patients who progressed to acute leukemia (17%), was complete remission achieved. The median survival time was only 4.0 months for patients with karyotype AA compared with 18.0 months for AN and 24.0 months for NN (AA v. AN, P less than 0.05, AA v. NN, P less than 0.05). The absence of cytogenetically normal cells indicated a poor prognosis with frequent progression to acute leukemia which is resistant to chemotherapy. Progression to acute leukemia depended not only on chromosomal abnormalities but also on morphological subtype classified according to French-American-British co-operative group criteria. Morphological findings and karyotype combined gave a good indication of the outcome for patients with MDS.     

Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients.

The biological and clinical importance of cytogenetic analysis in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML) is being increasingly recognized. Recently, cytogenetic similarities were noted between elderly de novo AML and secondary AML, suggesting common etiopathogenetic mechanisms. In the present study we analyzed the cytogenetic similarities between patients with AML of different age and patients with MDS consecutively diagnosed during a 5-year period at a single, primary referral, hematologic center. Of 246 patients aged <86 years, 195 (80%) had a cytogenetic study at diagnosis. Informative metaphases were obtained in 182 cases (93%), including 17 (9.3%) with secondary MDS/AML. Patients were classified according to FAB criteria and were subdivided into four groups: (1) 'early MDS': 42 patients with MDS of FAB subtypes other than refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-T); (2) 'late MDS': 35 patients with RAEB and RAEB-T; (3) 'old AML': 48 patients with AML aged 65 to 85 years; (4) 'young AML': 57 patients with AML aged <65 years. Results showed that 'late MDS' and 'old AML' had striking cytogenetic similarities both in the frequency of normal karyotypes (31% and 27%), single abnormalities (14% and 13%), double abnormalities (17% and 14%), complex karyotypes (37% and 46%), and numerical abnormalities (89% and 93%), as well as in the frequency of rearrangements involving chromosome 5 (20% and 31%) and 7 (27% and 27%). The only difference between the two groups was found in the median number of chromosomes involved in complex karyotypes (5 vs 8; P=0.03). 'Early MDS' had significantly less complex karyotypes (21%; P<0.05), but its cytogenetic features resembled otherwise those of 'late MDS' and 'old AML', and any significant difference disappeared when patients with chronic myelomonocytic leukemia (CMML) were excluded. CMML markedly differed from other MDS subtypes in the frequency of normal (57%) and of complex karyotypes (6%). Secondary MDS/AML and AML with trilineage dysplasia shared the same cytogenetic features of 'late MDS' and 'old AML'. 'Young AML' strikingly differed from all other groups, particularly in the higher frequency of balanced translocations (29%; P<0.001) and single karyotype abnormalities (32%; P<0.02), and in the lower frequency of complex karyotypes (19%; P<0.01) and of chromosome 5 (2%; P<0.001) and 7 (9%; P<0.01) involvement. We conclude that in a population-based series of patients, the cytogenetic profile of MDS, particularly of RAEB/RAEB-T, was nearly identical to that of elderly patients with AML both in the frequency and in the type of chromosomal abnormalities. These results support the possibility that MDS and AML of elderly patients may represent the same disease seen at different stages of evolution.     

Mutational analysis of the KIT gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia

The progenitor cells of myelodysplastic syndrome (MDS) are thought to undergo a multistep process during their transformation into overt acute leukemia. In this study, the role of mutation of the KIT gene in the extracellular membrane, juxtamembrane and tyrosine kinase domains was investigated in 75 patients with MDS or MDS-derived leukemia (MDS-AML). Mutation was detected in 2 of 15 (13.3%) patients with refractory anemia with excess blasts transformation (RAEB-T), in 1 of 15 (6.6%) patients with chronic myelomonocytic leukemia (CMML), and in 5 of 26 (19.2%) patients with MDS-AML. However, no mutation was found in any of the nine patients with refractory anemia (RA) or the 10 patients with refractory anemia with excess blasts (RAEB). Of the mutations, five patients had changes at the same codon in tyrosine kinase domain, Asp816, while the remainder had unique mutations. These observations suggest that KIT gene mutations identified in the advanced stage of MDS, and genetic abnormality in the KIT gene, particularly at codon 816, might be additional events that contribute to the progression of MDS to AML.     

Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases

A total of 109 patients with myelodysplastic syndromes (MDS) was analyzed to determine the clinical and pathologic features of the five recently defined French-American-British Cooperative Group (FAB) subtypes, and to assess the utility of this classification system in predicting survival, evolution to acute nonlymphocytic leukemia (ANLL), and cause of death. All patients with MDS presented with anemia; additional cytopenias were present in patients with refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML) and refractory anemia with excess blasts in transformation to ANLL (RAEB/Tr). Thirty-two patients received some form of antileukemic therapy for MDS. ANLL developed in 16 of the 77 remaining untreated patients, including 18% (2/11), 0% (0/21), 22% (5/23), 33% (2/6), and 44% (7/16) of patients with refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), RAEB, CMML, and RAEB/Tr, respectively (P = 0.02). The FAB subtype was highly predictive of survival with median survivals ranging from 71 months for RARS to 5 months for RAEB/Tr (P = less than 0.0001). Patients with RAEB, CMML, and RAEB/Tr frequently died of direct consequences of MDS, while patients with RA and especially RARS generally survived or died from unrelated disorders (P = less than 0.0001). MDS encompass a spectrum of disorders. RA and RARS, are relatively indolent and often do not lead to the patient's demise. RAEB, CMML, and RAEB/Tr are aggressive disorders which are often responsible for the patient's death whether or not actual progression to overt leukemia occurs. FAB subtype predicts survival, evolution to ANLL, and cause of death, although the five morphologic subtypes appear to separate into only two disease groups, especially with regard to survival and cause of death.     

Primary myelodysplasia occurring in adults under 50 years old: a clinicopathologic study of 52 patients.

Although myelodysplastic syndromes (MDSs) are generally thought to be diseases of elderly patients, younger patients also have rarely been diagnosed with MDS. This is a report of the clinical, morphologic and cytogenetic features of 52 cases of primary MDS occurring in adults under the age of 50 years. Cases secondary to chemotherapy or radiotherapy were excluded. There were 31 males and 21 females. The median age at presentation was 39 years (range, 18 to 49 years). The interval between onset of symptoms and diagnosis was brief (median, 4 weeks; range, 1-32 weeks). Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) were asymptomatic. Forty-two (81%) of the patients were classified using FAB criteria for blood and bone marrow morphology: refractory anemia (RA), 11; refractory anemia with ringed sideroblasts (RARS), four; refractory anemia with excess blasts (RAEB), 12; chronic myelomonocytic leukemia (CMML), three; refractory anemia with excess blasts in transformation (RAEB-T), 12 patients. Ten patients could not be categorized. Abnormalities involving chromosome 7 was the most frequent cytogenetic abnormality (31%). Partial chromosomal deletion and chromosome gain were also common abnormalities (22% and 9%, respectively). Translocations accounted for only 9% of the main cytogenetic abnormalities encountered in this patient population. For the 49 patients for whom information regarding AML transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range 3 weeks to 3 years). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. Thirteen patients underwent bone marrow transplantation at the time of presentation of their disease.