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PubMed1997

Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation.

Intensive chemotherapy followed by autologous bone marrow transplantation (ABMT) may provide an alternative therapy for young patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS (sAML) lacking a suitable donor. We report the results for 79 patients with MDS/sAML transplanted with autologous marrow in first complete remission (CR). Within the total group of 79, a cohort of 55 patients for whom the duration of first CR was known were compared with a matched control group of 110 patients with de novo AML. The 2-year survival, disease-free survival (DFS), and relapse rates for the 79 patients transplanted in first CR were 39%, 34%, and 64%, respectively. The relapse risk was greater than 55% for all stages and all disease categories. Patients younger than 40 years had a significantly (P = .04) better DFS (39%) than patients older than 40 years (25%). The DFS at 2 years was 28% for the cohort of 55 patients transplanted for MDS/sAML and 51% for those transplanted for de novo AML (P = .025). Relapse rates were 69% for patients with MDS/sAML and 40% for those with de novo AML (P = .007). ABMT for MDS or secondary leukemia results in a lower DFS when compared with similarly treated patients with de novo AML due to a higher relapse rate. The DFS of 28% for these patients suggests that autotransplantation may be a valuable therapy for this disease. The low treatment-related mortality rate of less than 10% supports the view that sufficient numbers of hematopoietic stem cells are present in patients with MDS to allow adequate repopulation after autologous stem-cell transplantation.

Acute Disease↗
PubMed1993

De novo myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 20: a subtype of MDS with distinct hematological and prognostic features?

We report on 8 cases of de novo myelodysplastic syndromes (MDS) with deletion of the long arm of chromosome 20 (del 20q), who represented about 2% (8/392) of our cases of de novo MDS with cytogenetic analysis seen during a period of 9 yr. Median age was 69 yr, and there were 7 males and 1 female. Anemia was absent or very mild (Hb > 11 g/dl) in 5 patients. Only 1 patient had neutrophils < 0.5 x 10(9)/l, and none had platelets < 50 x 10(9)/l. Four patients had refractory anemia (RA), 2 had refractory anemia with ringed sideroblasts (RARS), and 2 had refractory anemia with excess of blasts (RAEB). Del 20q was isolated in 5 patients, and associated with other chromosomal rearrangement(s) in 3 patients. Only 1 patient progressed to ANLL and 2 showed an increase in bone marrow blasts during evolution. The 5 other patients had stable disease after 18-77 months. By comparison with de novo MDS patients with other cytogenetic findings, patients with del 20q had a tendency towards lower incidence of anemia and excess of marrow blasts, lower incidence of progression to AML and more prolonged survival, although differences were not significant. Only patients with isolated del 5q had a more prolonged survival than patients with del 20q.

Aged↗
PubMed2003

MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants.

Cytogenetic abnormalities (CA), especially of chromosome 13, have been used to identify a subgroup of previously untreated multiple myeloma (MM) patients with very poor prognosis despite high-dose therapy (HDT). We examined the prognostic implications of CA in 1000 MM patients receiving melphalan-based tandem autotransplants (median follow-up, 5 years). Negative consequences for both overall survival (OS) and event-free survival (EFS) in the presence of any CA were confirmed, especially when detected within 3 months of HDT. In the context of standard prognostic factors (SPF), 'MM-MDS' (MM karyotype that contains, in addition, CA typical of MDS) imparted a poor OS and EFS, after adjusting for any CA and all individual CA. One-year mortality was also high, especially for the MM-MDS subgroup with trisomy 8 within a MM signature karyotype (87%vs 34% in its absence, P < 0.001). No patient remained event free 5 years post transplant in the presence of these baseline high-risk CA. However, certain trisomies (e.g. chromosomes 7 and 9) and del 20 had favourable clinical consequences. The higher risk that is associated with CA compared with SPF justifies routine cytogenetic studies in all patients with MM at diagnosis and whenever additional treatment decisions are considered, such as in planning HDT either for initial response consolidation, at the time of primary unresponsiveness to induction therapy, or at relapse.

Antineoplastic Agents, Alkylating↗
PubMed1998

Molecular pathogenesis and targets for therapy in myelodysplastic syndrome (MDS) and MDS-related leukemias.

The myelodysplastic syndromes (MDS) are a family of disorders that are characterized by ineffective hematopoiesis and evolution to acute myelogenous leukemias (AMLs) that are strikingly refractory to current therapeutic approaches. A substantial proportion of these complex diseases arise in the setting of exposures to environmental or occupational toxins, including cytotoxic therapy for a prior malignancy or other disorder (secondary MDS/AML). On the genomic level, MDS is typified by losses and translocations involving certain key gene segments, with disruption of the normal structure and function of genes that control the balance of proliferation and differentiation in hematopoietic precursors. In addition, MDS cells display impaired responses to diverse cytokines in terms of activating signaling intermediaries that trigger both proliferation and differentiation, and the disruption of the normal flow of biochemical information along the pathways translates into ineffective multilineage hematopoiesis and bone marrow failure. MDS/AMLs provide a fertile testing ground for the development of novel agents and the concomitant molecular dissection of the mechanisms by which these agents induce growth inhibition, terminal differentiation, and eventual cell death.

Chromosome Aberrations↗
PubMed1995

The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS.

Although molecular and cytogenetic studies strongly point to the role of oncogenes, the mechanisms underlying the development of MDS and their progressive evolution to AML are still largely unknown. It has been postulated that AML has a preleukemic stage and a multi step pathogenesis, with the preleukemic stem cell able to undergo clonal evolution, with the acquisition of karyotypic abnormalities, leading to the development of acute leukemic subclones. The activations of the ras oncogenes or inactivation of the p53 anti-oncogene by point mutations have been described recently in several cases of MDS as well as AML, suggesting a critical role for these alterations in the development of these myelogenous leukemias. We reported previously establishment of a leukemic cell line, SKM-1, from the patient who initially possessed multiple point mutations of ras genes but lost these mutations during disease progression to myelomonocytic leukemia with acquisition of chromosomal abnormalities involving the p53 anti-oncogene. This process is characterized by genetic instabilities probably due to the failure of their DNA repairment leading to abnormal control of cell proliferation and differentiation. Studying this cell line, SKM-1, is a promising approach to understand the mechanisms of the initiation, disease progression, alterations of DNA repairment, and genetic instability in MDS and myelogenous malignancies.

Disease Progression↗
PubMed1995

Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG).

We conducted a prospective, multicenter pilot study of remission induction therapy in patients with poor prognosis MDS and AML evolving from a preceding phase of MDS. Fifty evaluable patients from 15 institutions were treated with one or two remission-induction courses consisting of i.v. idarubicin 12 mg/m2/day on days 1, 2, and 3 combined with a continuous i.v. infusion of cytarabine of 200 mg/m2/day on days 1 to 7. Of the 27 complete remitters (54%), 23 received a consolidation course which was identical to the remission-induction course except for the idarubicin 12 mg/m2 which was given on day 1 only. Fifteen patients received maintenance therapy consisting of six courses of cytarabine 10 mg/m2, s.c. twice daily, for 14 days. Two complete remitters were allografted and five patients received an ABMT. The median survival of all 50 treated patients was 14 months. The median duration of disease-free survival was 11 months with two patients in CR more than 2 years after entering CR. Twenty-four of the 27 remitters have relapsed. Four patients died during remission-induction therapy, but no patient died as a result of persisting hypoplasia. No fatal complications occurred during the consolidation and maintenance courses. Age and stage of disease had no significant impact on CR rate nor on remission duration. The CR rate was significantly (P = 0.03) higher in patients with only normal metaphases compared to patients with cytogenetic abnormalities. The DFS at 2 years was 33 vs 8%, respectively, for patients without or with cytogenetic abnormalities (P = 0.02). This study shows that patients below the age of 60 years with poor risk features are candidates for treatment with combination chemotherapy. A complete remission rate of more than 50% may be expected. Maintaining remission after remission-induction chemotherapy is a difficult issue. Patients not eligible for allogeneic BMT may be treated with intensive post-remission chemotherapy or autologous BMT.

Adolescent↗
PubMed2004

Granulocyte colony-stimulating factor receptors on CD34++ cells in patients with myelodysplastic syndrome (MDS) and MDS-acute myeloid leukemia.

We studied surface expression of granulocyte colony-stimulating factor receptor (G-CSFR) on CD34++ progenitor cells of myelodysplastic patients. Late stages of disease showed a higher proportion of high or low G-CSFR expression than early stages. Most of the patients with the low expression had neutropenia. Neutropenia was relatively less present in the normal group, but it reappeared in the high group. All the neutropenic patients in the high group showed response to G-CSF, while response in the normal group was minor. These findings suggest that lowered expression of G-CSFR leads to neutropenia in myelodysplastic patients. This article reviewed the knowledge of the G-CSFR and its role in the disorders of granulopoiesis, including myelodysplastic syndrome (MDS).

Acute Disease↗
PubMed1991

Consecutive chromosomal studies in patients with myelodysplastic syndrome (MDS). Czechoslovak MDS Cooperative Group.

In order to detect a possible relationship between clonal chromosomal abnormalities acquired during the course of the disease and its prognosis in patients with myelodysplastic syndrome (MDS) the authors have performed consecutive analyses in 77 patients with this disease. They were part of the large series of 209 patients cytogenetically examined during the last ten years. According to the cytogenetic findings we have distinguished three groups: 1) sixteen patients who has a normal karyotype in bone marrow cells at the beginning of the investigation and this finding remained unchanged during the course of the disease. Three of them progressed into acute leukemia (AL) without any detectable change in the chromosomal complement of the bone marrow cells; 2) twenty-five patients who had at the beginning of the study, different pathological chromosomal clones in bone marrow cells. There was no chromosomal evolution detectable during the disease; eight of them progressed into acute leukemia; 3) thirty-six patients who had either normal or pathological chromosomal findings at the first examination and in whom further clonal abnormalities had developed during the course of the disease. Twelve of them progressed into acute leukemia. Two to nine cytogenetic examinations were successfully performed with a mean of three studies per patient. The results confirmed strictly individual development of chromosomal abnormalities during the course of the disease, with an unfavorable prognosis for the patients with complex chromosomal changes. Three patients with del 7q had very poor prognosis with rapid progression of the disease. Two cases with the same acquired abnormalities (del 20q, +8, -22) transformed into acute leukemia within the period of 36 months from the onset of the disease.

Acute Disease↗
PubMed1989

An autopsy case of myelodysplastic syndrome (MDS): diagnostic problems between MDS and the other haematopoietic disorders including acute myelofibrosis.

We report an autopsy case of myelodysplastic syndrome (MDS) in a 35-year-old male, who presented with pancytopenia and bleedings. Bone marrow specimens disclosed myelofibrosis and hypercellular marrow with more than 60% atypical erythroblasts in the bone marrow cells. Type I or type II blasts were less than 10% of the peripheral blood and bone marrow cells during the clinical course. At autopsy, infiltration by myeloid and erythroid cells and megakaryocytes was noted in the liver, spleen and lymph nodes. According to the FAB classification, this case might be classified into refractory anemia with excess of blasts (RAEB) or RAEB in transformation. However, the remarkable neoplastic proliferation of three haematopoietic cell lines also indicates acute myeloproliferative disorder such as acute myelofibrosis or acute panmyelosis.

Acute Disease↗
PubMed1990

Bestatin treatment of myelodysplastic syndromes (MDS) and the effects of bestatin on hematopoiesis in MDS.

A high remission rate (75%) was achieved in a preliminary study using bestatin in patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-t). One of 2 patients with RAEB-t and 3 of 6 patients with RAEB obtained complete response. Two patients with RAEB achieved good response, but one with refractory anemia failed. Clonogenic marrow cell culture studies in patients with myelodysplastic syndromes have demonstrated intrinsic hematopoietic stem cell abnormalities, in particular defective erythroid colony formation. After bestatin treatment, these abnormalities as well as hematologic findings were markedly improved. The results suggest that bestatin has an enhancing effect on burst promoting activity production of helper (CD4 positive) T lymphocytes and the effect on hematopoiesis of bestatin may be mediated by T lymphocytes.

Aged↗
PubMed1997

Comprehensive clinical assessment in community setting: applicability of the MDS-HC.

OBJECTIVE: To describe the results of an international trial of the home care version of the MDS assessment and problem identification system (the MDS-HC), including reliability estimates, a comparison of MDS-HC reliabilities with reliabilities of the same items in the MDS 2.0 nursing home assessment instrument, and an examination of the types of problems found in home care clients using the MDS-HC. DESIGN: Independent, dual assessment of clients of home-care agencies by trained clinicians using a draft of the MDS-HC, with additional descriptive data regarding problem profiles for home care clients. SETTING AND PARTICIPANTS: Reliability data from dual assessments of 241 randomly selected clients of home care agencies in five countries, all of whom volunteered to test the MDS-HC. Also included are an expanded sample of 780 home care assessments from these countries and 187 dually assessed residents from 21 nursing homes in the United States. MEASUREMENTS: The array of MDS-HC assessment items included measures in the following areas: personal items, cognitive patterns, communication/hearing, vision, mood and behavior, social functioning, informal support services, physical functioning, continence, disease diagnoses health conditions and preventive health measures, nutrition/hydration, dental status, skin condition, environmental assessment, service utilization, and medications. RESULTS: Forty-seven percent of the functional, health status, social environment, and service items in the MDS-HC were taken from the MDS 2.0 for nursing homes. For this item set, it is estimated that the average weighted Kappa is .74 for the MDS-HC and .75 for the MDS 2.0. Similarly, high reliability values were found for items newly introduced in the MDS-HC (weighted Kappa = .70). Descriptive findings also characterize the problems of home care clients, with subanalyses within cognitive performance levels. CONCLUSION: Findings indicate that the core set of items in the MDS 2.0 work equally well in community and nursing home settings. New items are highly reliable. In tandem, these instruments can be used within the international community, assisting and planning care for older adults within a broad spectrum of service settings, including nursing homes and home care programs. With this community-based, second-generation problem and care plan-driven assessment instrument, disability assessment can be performed consistently across the world.

Activities of Daily Living↗
PubMed2005

Peripheral blood MDS score: a new flow cytometric tool for the diagnosis of myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders diagnosed using morphologic and clinical findings supported by cytogenetics. Because abnormalities may be subtle, diagnosis using these approaches can be challenging. Flow cytometric (FCM) approaches have been described; however the value of bone marrow immunophenotyping in MDS remains unclear due to the variability in detected abnormalities. We sought to refine the FCM approach by using peripheral blood (PB) to create a clinically useful tool for the diagnosis of MDS. METHODS: PB from 15 patients with MDS was analyzed by multiparametric flow cytometry using an extensive panel of monoclonal antibodies. Patterns of neutrophil antigen expression were compared with those of normal controls (n = 16) to establish light scatter and/or immunophenotypic abnormalities that correlated with MDS. A scoring algorithm was developed and validated prospectively on a blinded patient set. RESULTS: PB neutrophils from patients with MDS had lower side scatter and higher expression of CD66 and CD11a than did controls. Some MDS PB neutrophils demonstrated abnormal CD116 and CD10 expression. Because none of these abnormalities proved consistently diagnostic, we sought to increase the power of the assay by devising a scoring system to allow the association of multiple abnormalities and account for phenotypic variations. The PB MDS score differentiated patients with MDS from controls (P < 0.0001) in the test set. In a prospective validation, the PB MDS score successfully identified patients with MDS (sensitivity 73%, specificity 90%). CONCLUSIONS: FCM analysis of side scatter and only four additional immunophenotypic parameters of PB neutrophils using the PB MDS score proved more sensitive than standard laboratory approaches and may provide an additional, more reliable diagnostic tool in the identification of MDS.

Aged↗
PubMed2000

[Myelodysplastic syndromes (MDS). Aspects of hematopathologic diagnosis].

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell disorders which generally occur in older adults but may also affect children. Primary MDS should be distinguished from secondary MDS associated with antineoplastic or immunosuppressive therapy (t-MDS), exposure to toxic compounds, or genetic disorders. The establishment of a neoplastic clone is reflected by dysplastic features and impaired function which may affect all three hematopoietic cell lineages. The ineffective hematopoiesis which causes bone marrow failure is accompanied by peripheral blood cytopenia and is considered to result from increased apoptosis, at least in the less advanced MDS stages. The elucidation of the molecular pathogenesis of MDS has provided evidence that chromosomal abnormalities are present in about 50% of patients with primary MDS. They include numerical aberrations such as monosomy 5 or 7, trisomy 8, loss of the Y-chromosome and structural abnormalities such as deletion of the long arm of chromosome 5 (5q-syndrome), 7, or 8. Based on the percentage of blasts (<5%, 5-20%, 20-30%) and the presence of >15% ringed sideroblasts for marrows with <5% blasts, the French-American-British (FAB) classifies MDS into 4 morphologic categories: refractory anemia (RA), refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEB-t), and refractory anemia with ringed sideroblasts. The fifth morphologic type is chronic myelomonocytic leukemia characterized by peripheral blood monocytosis (>1x10(9)/l). However, a modification of this classification will be proposed by the World Health Organization, with the intention of lowering the threshold for the diagnosis of AML from 30% to 20% blast cells. In patients presenting with cytopenias suggesting impaired hematopoiesis, the initial diagnosis depends mainly on the cytological evaluation of bone marrow and blood smears and the histological findings of trephine bone marrow biopsy. In a retrospective analysis we evaluated the occurrence of the distinct FAB-categories as percentage of the total number of MDS cases diagnosed at the Institute of Pathology of the University of Freiburg. A total of 63% fullfilled the criteria of RA/RARS, 17% of RAEB, 14% of RAEB-t, and 6% of CMML. A fibrotic variant of MDS was observed in 7.67% of all cases, ranging from 2.34% in RA up to 15. 42-15.84% in the categories which did not show significant differences with regard to myelofibrosis. The histologic evaluation of a trephine bone marrow biopsy is of critical importance for the evaluation of fibrotic or hypocellular MDS since these patterns are not reflected by the cytological examination. The combined cytological and histological diagnosis of bone marrow and peripheral blood is a reliable tool for the initial diagnosis of MDS. In addition, cytogenetic and molecular analysis should be performed. Presently, the risk of leukemic transformation is evaluated using the International Prognostic Scoring System for MDS, which is the sum of the scores of bone marrow blasts, karyotypes and cytopenia. In the context of clinical trials therapeutic modalities should be considerd according to the age and the general performance state and the prognostic scores of individual patients.

Adult↗
PubMed1994

The MDS Cognition Scale: a valid instrument for identifying and staging nursing home residents with dementia using the minimum data set.

OBJECTIVE: We report the development and validation of an MDS-based cognitive index, the MDS Cognition Scale (MDS-COGS), by evaluating it against two popular dementia rating scales, the Global Deterioration Scale (GDS) and the Mini-Mental State Examination (MMSE). DESIGN: A Cross-sectional study. PARTICIPANTS: Two hundred nursing home residents. MEASUREMENTS: Each study participant was assessed on the GDS and the MMSE by trained medical students. At the same time, but independent of the medical students, a geriatric nurse completed the Minimum Data Set (MDS) instrument on each participant. MAIN RESULTS: The Cognitive Performance Scale (CPS), a categorical measure of cognition that uses MDS items, was compared with the GDS in 133 subjects, using a split-sample technique. The GDS was found to be more appropriate as a 4-stage than a 7-stage scale, with GDS stages 1-4 acting as a single stage. The CPS showed very poor percent agreement with GDS stages 5 and 7 (50% or less) and, therefore, was revised by adding other MDS predictors. The new instrument, designated MDS-COGS, is a 0-10 point scale generated from eight MDS cognitive items. The MDS-COGS was then validated against the 4-stage GDS and MMSE in the remaining 67 nursing home residents. Chance-corrected agreement (kappa) between the MDS-COGS and GDS in the 67 subjects was 0.80 (95% CI = 0.70, 0.88), and percent agreement with GDS stages 5 and 7 was 60% and 85%, respectively. The MDS-COGS was also demonstrated to be a valid measure of cognitive impairment as defined by the MMSE, with sensitivity, specificity, chance-corrected agreement (kappa), and area under the ROC curve, all above 0.80. CONCLUSIONS: The MDS Cognition Scale, the MDS-COGS, provides a valid measure of the presence and severity of cognitive impairment in nursing home residents using items from the Minimum Data Set.

Aged↗
PubMed1992

Morphologic classification of the myelodysplastic syndromes (MDS): combined utilization of bone marrow aspirates and trephine biopsies.

In a retrospective and prospective follow-up study from 1975 to 1991, bone marrow biopsies, aspirates and clinical features of 495 patients with MDS were investigated. Sections of undecalcified plastic embedded biopsies and smears of bone marrow aspirates were stained according to Giemsa. Bone marrows with MDS were characterized by three main categories of morphologic alterations: (1) cellular abnormalities, (2) architectural disorganization in the bone marrow and (3) stromal changes; the combined use of aspirates and trephine biopsies enabled a more reliable and accurate diagnosis of MDS than either one alone. The bone marrow findings fell into one of 7 subtypes, with the frequencies and median survivals in brackets: (1) MDS sideroblastic (19%, 62 months), (2) MDS megaloblastoid (13%, 56 months), (3) MDS proliferative (22%, 31 months), (4) MDS blastic (15%, 9 months), (5) MDS hypoplastic (15%, 26 months), (6) MDS fibrotic (6%, 29 months), and (7) MDS inflammatory (10%, 42 months). In follow-up studies patients with secondary MDS were excluded and the prognosis and subsequent evolution for each of the morphologic subtypes were evaluated. The conclusion is drawn that aspirates and trephine biopsies are complementary procedures and both are required for diagnosis, classification and decisions on current treatment modalities of patients with MDS.

Adolescent↗