The myelodysplastic syndromes: morphology,risk assessment,and clinical management (2002)

The Myelodysplastic Syndromes (MDS) represent a group of potentially acute myeloid leukemic disorders. There exists a delicate balance between increased apoptosis and proliferation of the leukemic hematopoietic stem cell that permits many patients to survive for years. When the balance shifts towards proliferation AML develops with a poor outcome for most but not all patients. I will review the latest proposals from the W.H.O. in classification, including pediatric MDS, prognostic factors and response criteria. Then I will present a strategy for the management of low risk patients with supportive care or low intensity treatment (cytokines, Immune modulation, anti-VEGF agents) and finally chemotherapy and intensive therapy with auto and allo BMT.     

Chromosome and molecular abnormalities in myelodysplastic syndromes

Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.     

Prognostic molecular markers in myelodysplastic syndromes

Cytogenetic findings in myelodysplastic syndromes play an important role in diagnosis, prognostication and clinical decision making. Therefore, they became an important aspect in scoring systems such as the International Prognostic Scoring System (IPSS) and the WHO-adapted Prognostic Scoring System (WPSS). Ongoing efforts to refine the categorization of karyotypes with regard to prognosis and therapeutic options will change scoring systems in the near future. In order to learn more about the pathophysiology of myelodysplastic syndromes, various molecular genetic aberrations are identified and their impact on prognosis discussed. New screening methods such as gene expression or single nucleotide polymorphism analysis are good candidates to find entrance in clinical practice in the future as they are useful tools in further elucidation of the underlying defects in myelodysplastic syndromes and the development of more specific classifications of the disease concerning risk assessment.     

Flow cytometry for diagnosis and assessment of prognosis in patients with myelodysplastic syndromes

The Myelodysplastic Syndrome (MDS) comprises a spectrum of hematopoietic stem cell disorders. Identification of additional parameters that might distinguish different risk groups or entities would be useful. Flow cytometric studies have begun to characterize individual or composite immunophenotypic abnormalities as well as light scatter properties that may be helpful for diagnosis and of prognostic value for the natural course of the disease and for outcome after therapy. Here we review the current state of the art of the use of flow cytometry in patients with MDS.     

The myelodysplastic syndromes

The myelodysplastic syndromes constitute a fascinating model for monoclonal premalignant disorders. Haemopoiesis is 'dysplastic' with inefficient maturation of a slowly expanding or sometimes of a stable population, of blood cell precursors. About one third of the patients evolve into acute leukaemia, the result of either a progressive expansion of the original clone or a new mutation producing a more malignant subclone. The majority of patients suffer from the results of bone-marrow insufficiency, with pancytopenia and possibly immune deficiency. Characteristic karyotype anomalies involving mainly chromosomes 5, 7 and 8 are seen in half the patients. These same chromosomes are known to carry different oncogenes. The myelodysplastic syndrome occurs mainly in the aged and there is a moderate male preponderance. The incidence is still unknown but is probably similar to that of acute leukaemia. The etiology is also unknown; however, a secondary myelodysplastic syndrome precedes acute myeloid leukaemia, as a late consequence of chemo- and radio-therapy in treated Hodgkin's disease. This suggests that environmental mutagens might also be involved in primary myelodysplastic syndromes. Treatment remains highly unsatisfactory but a few recent developments improve prognosis, at least in the younger patient.     

The role of angiogenesis in the biology and therapy of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by peripheral cytopenias in the setting of a normocellular or hypercellular bone marrow that morphologically shows trilineage dysplasia. Mechanisms of disease include pluripotent stem cell damage, abnormalities in proliferation, differentiation, and apoptosis leading to an ineffective hematopoiesis. A growing body of evidence support angiogenesis as having a key role in the pathophysiology of hematologic malignancies, including MDS. Knowledge and interest in angiogenesis and its interactions with proliferation and apoptosis have provided the rationale for the use of antiangiogenic drugs, such as thalidomide and its analogue CC5013, with hematologic improvement. Although the results are modest, other drugs with somewhat novel antiangiogenic mechanisms of action are under development, such as the vascular endothelial growth factor-receptor blocker SU5416, the antivascular endothelial growth factor antibody bevacizumab, arsenic trioxide, metalloproteinase inhibitors, such as AG3340, and farnesyl transferase inhibitor R115777. This review attempts to provide an overview of the evidence of increased angiogenesis and the status of drug development targeting angiogenesis in patients with MDS.     

The genetics of the myelodysplastic syndromes: classical cytogenetics and recent molecular insights

Myelodysplastic syndromes (MDS) are a complex group of clonal hematopoietic disorders with an attendant diverse array of associated genetic changes. Conventional cytogenetics plays a prominent and well-established role in determining the contemporary diagnosis and prognosis of these disorders. More recently, molecular approaches have been useful in further characterizing this group of diseases, albeit in a largely experimental context, with the detection of changes at the single gene level including mutations, amplification and epigenetic phenomena. Nevertheless, we remain largely ignorant of the genetic underpinnings of MDS. Here we briefly review the established role of cytogenetics in MDS, and emphasize recent advances in unraveling the genetics of MDS, with a view towards how such findings might facilitate our ability to understand, diagnose and treat these disorders in a more rational manner.     

Serial assessment of suspected myelodysplastic syndromes: significance of flow cytometric findings validated by cytomorphology,cytogenetics, and molecular genetics

The significance of flow cytometry indicating myelodysplasia without proof of myelodysplasia by cytomorphology remains to be clarified. We evaluated follow-up analyses in 142 patients analyzed in parallel by flow cytometry, cytomorphology and cytogenetics for suspected myelodysplasia without proof of myelodysplasia by cytomorphology. At initial assessment, flow cytometry indicated myelodysplasia in 64 of 142 (45.1%) patients. In 9 of 142 (6.3%) patients, cytogenetics revealed aberrant karyotypes at first evaluation that were found in 5 of 64 (7.8%) patients rated with myelodysplasia by flow cytometry. The remaining 133 patients without proof of myelodysplasia by cytomorphology and with normal karyotype underwent follow-up analyses that confirmed myelodysplasia by cytomorphology, cytogenetics or molecular genetics in 47 (35.3%) after a median interval of nine months (range 1-53 months). As far as initial flow cytometry results are concerned, this applied to 30 of 59 (50.1%) with myelodysplasia, 10 of 42 (23.8%) with “possible myelodysplasia” (minor antigen aberrancies only) and 7 of 32 (21.9%) without myelodysplasia (P=0.004). Notably, in these latter 7 patients, flow cytometry results changed at follow up to “possible myelodysplasia” (n=4) and “myelodysplasia” (n=2). These data argue in favor of including flow cytometry along with cytomorphology, cytogenetics and molecular genetics to diagnose myelodysplasia, and suggest a closer monitoring of patients with myelodysplasia-typical aberrant antigen expression found by flow cytometry.     

The myelodysplastic syndromes: classification and prognosis

Myelodysplastic syndrome is a neoplastic clonal stem cell disorder characterized clinically by bone marrow failure and a tendency to progress to acute myelogenous leukemia. Dysplasia is the pathologic hallmark. The French-American-British classification served as the gold standard for more than two decades. Under the auspice of the World Health Organization, more than 100 hematopathologists in a 3-year cumulative effort issued the new World Health Organization classification, which recognizes multilineage dysplasia. Refractory anemia with excess blasts is divided into two groups. Chronic myelomonocytic leukemia is reclassified under a separate category. Refractory anemia with excess blasts in the transformation group was omitted. Finally, 5q-syndrome is a new subgroup. In addition to the pathologic classification, various prognostic predictors were formatted into scoring systems. Bone marrow blast percentage, cytopenias, and cytogenetics are the backbone for those prognostic models. The International Prognostic Scoring System is a product of pooled data from previous scoring systems and a useful tool to predict survival and acute myelogenous leukemia evolution. This paper discusses the classification and prognosis of myelodysplastic syndromes and their evolution.     

The challenge of individualised risk assessment and therapy planning in elderly high-risk myelodysplastic syndromes (MDS) patients

Myelodysplastic syndromes (MDS) represent one of the most frequent and serious haematologic diseases of the elderly. Effective therapies exist ranging from best supportive care to haematologic stem cell transplantation (HSCT). Decision making, however, is rather complex in this group of patients because ageing is a multidimensional process involving not only physiological changes but also changes in functional, social, emotional and cognitive capacities. All these factors can have a significant impact on the efficacy and tolerability of a potential therapy and therefore have to be thoroughly assessed before deciding on individual treatment regimens. Risk assessment tools are available both to classify the stage and prognosis of MDS and to meet the needs of elderly patients. A tool explicitly focussing on elderly MDS patients, however, is still missing. The current report approached this issue by combining the well established MDS-risk score 'International Prognostic Scoring System' (IPSS) with the 'Multidimensional Geriatric Assessment' (MGA). As decision making is most complex in high-risk MDS patients, the new algorithm is presented exemplarily for this group of patients. In a first step, MDS-related risk is identified using IPSS, in a second step, patients are assigned to one of three risk categories of the MGA (go-go/fit, slow-go/vulnerable, no-go/frail). While go-go patients might be subjected to therapies comparable to those given to younger patients, in no-go patients, a palliative therapy combined with best supportive care will probably be most appropriate. In slow-go patients, age-related life expectancy taken from public age statistics should be compared to the MDS-related life expectancy. Based on this combined assessment procedure and also on treatment tolerance in terms of the expectations/wishes of the patient and his/her family, an individualised therapeutic approach should be developed. Specific treatment recommendations for these three groups of patients are given, including HSCT, azanucleosides and best supportive care. To illustrate its practicability, i.e. the implementation of the novel algorithm in clinical practice, the case of an elderly high-risk MDS patient is presented and discussed in detail. This new algorithm will facilitate the identification of the very particular needs and conditions of elderly MDS patients in clinical practice. Based on this, individually tailored therapeutic approaches can be developed--the prerequisite for the best possible clinical outcome.     

Epidemiology and risk factors for infections in myelodysplastic syndromes

We conducted a case–control study to describe the epidemiology and risk factors for infections requiring hospitalization in patients with myelodysplastic syndromes (MDS). Of 497 patients identified, 103 patients developed 201 episodes of infection. The probability of acquiring an infection 1 year from date of MDS diagnosis was 15% (95% confidence interval [CI] 12–18%). Patients developing infections had decreased survival compared to those who did not (P = 0.007). Significant risk factors for infection were higher risk MDS (hazard ratio [HR] = 2.7, 95% CI = 1.7–4.1, P < 0.0001), nadir absolute neutrophil count <500/mL (HR = 1.8, 95% CI = 1.2–2.7, P < 0.007), chronic obstructive pulmonary disease (HR = 2.6, 95% CI = 1.4–4.9, P < 0.003), history of other malignancy (HR 2.0, 95% CI = 1.3–3.1, P < 0.003), and autoimmune disease (HR 2.9, 95% CI = 1.4–6.0, P < 0.005). Age, nadir platelet count <20,000/mL, diabetes mellitus, and MDS treatment were not significant risk factors. Pneumonia was the most common infection, and bacteria the predominant pathogens.     

骨髓增生异常综合征诊断与分型的新认识

骨髓增生异常综合征（ＭＤＳ）是全潜能干细胞水平上的分化障碍引起的一组克隆性恶性血液病。法美英（ＦＡＢ）三国协作组根据血象和骨髓象内的原始细胞数量、髓内环形铁粒幼细胞的多寡,以及周围血单核细胞的增多与否,将ＭＤＳ分为５种亚型（期）,即难治性贫血（Ｒ...     

Management of patients with higher risk myelodysplastic syndromes

Higher risk myelodysplastic syndromes (MDS) include patients in the Intermediate-2 and high-risk categories of the International Prognostic Scoring System, as well as patients with MDS secondary to radiation or chemical exposure. Ideally, the goal of therapy is to alter the natural history of disease in these patients to achieve cure or durable remission. High-intensity chemotherapy can achieve moderate rates of complete remission, however, durability of remission and overall survival tend to be short. Hematopoietic stem cell transplantation (HSCT) offers the possibility of cure, with long-term disease-free survival inversely related to age. Patients who are elderly or have poor functional status are candidates for reduced intensity HSCT, although this is still an experimental modality. Azacitidine is a hypomethylating agent that is a reasonable option for many patients ineligible for high-intensity therapies. Other therapies, such as immunomodulatory agents, arsenic trioxide, and farnesyl transferase inhibitors have thus far shown limited usefulness in higher risk MDS. This paper reviews the various therapeutic options for higher risk MDS, providing rationale for specific management approaches for these patients.     

The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990

In this review I have outlined the molecular basis and prenatal diagnosis of alpha-thalassemia and then concentrated on the state of our knowledge of the molecular basis of beta-thalassemia and its prenatal diagnosis. I discussed the improved but more complicated genetic counselling now available as a result of our increased knowledge of the effects of various defects in the beta-globin gene. Our knowledge of the heterogeneous molecular basis of the thalassemia syndromes has become very impressive and it is hoped that effective therapy will soon follow. For the present, however, prevention of the birth of affected children is the most effective means of reducing the suffering associated with the thalassemia syndromes, and prevention of this type is succeeding in many parts of the world, including North America.     

Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options

Myelodysplastic syndromes (MDS) and the mixed myelodysplastic/myeloproliferative disorder juvenile myelomonocytic leukaemia (JMML) are rare haematopoietic stem cell diseases in children. While MDS-initiating events remain largely obscure, a growing body of clinical, genetic and laboratory evidence suggests that JMML is, at least in part, caused by aberrant signal transduction resulting from mutations of components of the RAS signalling pathway. To date, haematopoietic stem cell transplantation cures more than half of children diagnosed with MDS or JMML. Research on genetic conditions predisposing to MDS in young age, such as inherited syndromes with bone marrow failure, may present important insights into MDS pathogenesis.     

骨髓增生异常综合征FAB和WHO分型的临床评价

目的:评价和分析骨髓增生异常综合征(MDS)从FAB分型到WHO分型的发展和临床意义。方法:对MDS患者分别用FAB分型及WHO分型进行分型,并对形态学、临床、实验室检查及预后资料进行对比分析。结果:MDS和急性髓性白血病(AML)均可出现病态造血。FAB分型中难治性贫血(RA)、原始细胞过多难治性贫血(RAEB)、转化中的原始细胞过多难治性贫血(RAEB-T)及AML之间生存率差异有统计学意义。WHO分型中RA与难治性血细胞减少伴多系增生异常(RCMD)之间生存率差异无统计学意义,RA与RAEB、RCMD与RAEB之间生存率差异有统计学意义,RAEB-Ⅰ与RAEB-Ⅱ之间生存率有显著差异。结论:WHO分型将FAB分型中的RA分为RA和RCMD并未显示出临床优越性。RAEB-T生存期比AML更短,因而将RAEB- T归为急性白血病,对临床治疗有好处。WHO分型按照原始细胞百分比将RAEB分为RAEB-Ⅰ和RAEB-Ⅱ,对临床诊断、治疗和预后有益。