Evolving classifications of the myelodysplastic syndromes

PURPOSE OF REVIEW: The classification of myelodysplastic syndrome is a continuously evolving process. Every new validated myelodysplastic syndrome classification reflects the better understanding of the disease, its pathogenesis and outcome. The proposed classifications attempt to create more homogenous subtypes of myelodysplastic syndrome, to better predict the prognosis and outcome. RECENT FINDINGS: The myelodysplastic syndrome classifications evolved from the French-American-British to the WHO classification over the last few years. Several new studies validate the WHO classification. The International Prognostic Scoring System is very important to define patient risk of progression to acute myeloid leukemia and predict overall survival. Recent studies suggest International Prognostic Scoring System modifications and a group proposes a new WHO-based prognostic system. SUMMARY: The WHO and International Prognostic Scoring Systems serve as tools to categorize patients in risk groups according to which the goal and type of treatment are different. The myelodysplastic syndrome classifications will continue to be reviewed and modified as we learn more about the disease to better perform this risk stratification.     

Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry

The World Health Organization (WHO) classification contributes to refined classification and prognostication of myelodysplastic syndromes (MDSs). Flow cytometry might add significantly to diagnostic and prognostic criteria. Our analysis of bone marrow samples from 50 patients with MDS showed aberrant expression of differentiation antigens in the myelomonocytic lineage. This also accounted for refractory anemia (RA) with or without ringed sideroblasts (RS), indicating multilineage dysplasia. In 38% of patients, CD34(+) myeloid blasts expressed CD5, CD7, or CD56. Flow cytometry data were translated into a numerical MDS flow-score. Flow-scores increased significantly from RA with or without RS, refractory cytopenia with multilineage dysplasia (RCMD) with or without RS up to refractory anemia with excess of blasts-1 (RAEB-1) and RAEB-2. No significant differences were observed between WHO cytogenetic subgroups. Flow-scores were highly heterogeneous within International Prognostic Scoring System (IPSS) subgroups. Patients in progression to advanced MDS or acute myeloid leukemia had a significantly higher flow-score compared with non-transfusion-dependent patients. In 60% of patients with transfusion dependency or progressive disease, myeloid blasts expressed CD7 or CD56, in contrast to only 9% of non-transfusion-dependent patients. Moreover, all patients with pure RA with or without RS with aberrant myeloid blasts showed an adverse clinical course. In conclusion, flow cytometry in MDS identified aberrancies in the myelomonocytic lineage not otherwise determined by cytomorphology. In addition, flow cytometry identified patients at risk for transfusion dependency and/or progressive disease independent of known risk groups, which might have impact on treatment decisions and the prognostic scoring system in the near future.     

Evolving treatment options of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid stem cell disorders characterized by peripheral cytopenias and dysplasia of bone marrow progenitor cells. A clonal evolution can result in progressive bone marrow failure and transformation towards acute myelogenous leukemia. A patient's prognosis as estimated by the International Prognostic Scoring System, age, and co-morbidities have to be considered for the selection of various treatment options. Although supportive care remains standard therapy for low-risk MDS, a number of treatment approaches that aim to improve cytopenia in transfusion-dependent patients are currently under investigation. Among others, immunosuppressive, anticytokine, and antiangiogenic therapy will be discussed. The demethylating agents 5-azacytidine and decitabine are promising for the treatment of elderly patients with high-risk MDS. An increase of the upper age limit for allogeneic stem cell transplantation, the only curative treatment option, by the development of dose-reduced conditioning regimens may have implications for the treatment of MDS patients in the future.     

The current approach to the diagnosis of myelodysplastic syndromes☆

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic neoplasms that share key clinical and biologic features, including peripheral blood cytopenias, morphologic dysplasia, ineffective and clonal hematopoiesis, and a variable risk of transformation to acute myeloid leukemia. Diagnostic evaluation of MDS relies on morphologic assessment of the peripheral blood and bone marrow, conventional cytogenetics, and exclusion of secondary causes of dysplasia. The diagnosis of MDS has important clinical consequences, but it can be challenging and requires distinction from mimics. In this review, the principles of bone marrow interpretation with respect to the diagnosis and classification of MDS in the current era will be discussed, including accurate morphologic interpretation, use of flow cytometry and immunohistochemistry, appropriate use of cytogenetics, and the emerging role of molecular genetics.     

Azacitidine for treatment of patients with myelodysplastic syndromes (MDS): practical recommendations of the German MDS Study Group

Myelodysplastic syndromes (MDS) are a group of common bone marrow disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a substantial risk of progression to acute myeloid leukemia (AML). For many years, the main treatment option for MDS was best supportive care which alleviates symptoms, but has no effect on the natural course of the disease. Recently, demethylating agents have become available as a promising new treatment for patients with MDS. In two randomized clinical trials, the demethylating agent azacitidine has demonstrated a reduced risk of transformation to AML, improvement of peripheral blood values, an improved quality of life, and a definite survival advantage compared to conventional care regimens for patients with International Prognostic Scoring System score of intermediate-2 or high-risk MDS. This review aims to provide practical recommendations for the use of azacitidine and the management of its side effects in patients with MDS, assuring safe administration and best efficacy of treatment.     

Can t(8;21) oligoblastic leukemia be called a myelodysplastic syndrome?

The new World Health Organization (WHO) classification of hematologic malignancies has incorporated t(8;21) myelodysplastic syndromes (MDS) according to the French-American-British classification into the category of acute myeloid leukemia (AML) with t(8;21)(q22;q22), while our knowledge about clinicopathological features of t(8;21) oligoblastic leukemia is still limited. We present our experience with 12 patients meeting the FAB diagnostic criteria of MDS and having t(8;21), who were compared to 43 t(8;21) AML patients. The MDS and AML patients shared most hematomorphologic, immunophenotypic, and clinical features, whereas the differences lay along myeloid maturation. The MDS patients had higher percentages of circulating neutrophils and marrow myeloid cells beyond promyelocytes than the AML patients. The incidence of Auer rods in mature neutrophils in MDS was significantly higher than that in AML, and furthermore, the neutrophils in MDS more commonly contain t(8;21) than in AML. Our findings support the rationale for the WHO classification, and future studies on large patient populations should help clarify whether the spontaneous differentiation potential could be actively associated with a hematological manifestation of t(8;21) leukemias.     

Pathobiology, classification, and diagnosis of myelodysplastic syndrome

Recent advances in molecular genetics have advanced the knowledge regarding the mechanisms leading to myelodysplastic syndrome (MDS), secondary acute myeloid leukemia, and therapy-induced MDS. Unfavorable cytogenetics associated with this group of disorders includes monosomy or deletion of the long arm of chromosomes 5 or 7, inversions of chromosome 3, translocations, deletions, and trisomies involving several other chromosomes. These unbalanced chromosomal aberrations result in hemizygosity and unmasking of oncogenes, changes in levels of expressed genes, or inactivation of tumor suppressor genes. It is evident that the cytogenetics associated with MDS is highly complex and heterogeneous, leading to an equally heterogeneous manifestation of the disease. Classifications, initially defined by the French-British-American group followed by the World Health Organization, and now by the International Prognostic Scoring System, have determined prognosis and helped develop treatment strategies for these patients, thus reducing their potential to develop acute leukemia. To date there are seven different prognostic schemas. These are constantly being improved so that MDS patients, who tend to be elderly, can be suitably treated. Additionally, treatment considerations and prognosis are different for patients who develop therapy-related MDS or for the juvenile population than for those with de novo MDS. The genetic alterations in MDS bone marrow and blood cells have been identified and possible models have been proposed for the development and progress of MDS, from the early stage to late-stage MDS evolving to acute myeloid leukaemia. As the functional mechanisms behind these chromosomal changes are being revealed, new therapies based on these mechanisms are currently being made and tested.     

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database

One‐third of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML), with its concomitant poor prognosis. Recently, multiple mutations have been identified in association with MDS‐to‐sAMLtransition, but it is still unclear whether all these mutations are necessary for transformation. If multiple independent mutations are required for the transformation, sAML risk should increase with time from MDS diagnosis. In contrast, if a single critical biological event determines sAML transformation; its risk should be constant in time elapsing from MDS diagnosis. To elucidate this question, we studied a database of 1079 patients with MDS. We classified patients according to the International Prognostic Scoring System (IPSS), using either the French‐American‐British (FAB) or the World Health Organization (WHO) criteria, and statistically analyzed the resulting transformation risk curves of each group. The risk of transformation after MDS diagnosis remained constant in time within three out of four risk groups, and in all four risk groups, when patients were classified according to FAB or to the WHO‐determined criteria, respectively. Further subdivision by blast percentage or cytogenetics had no influence on this result. Our analysis suggests that a single random biological event leads to transformation to sAML, thus calling for the exclusion of time since MDS diagnosis from the clinical decision‐making process. Am. J. Hematol. © 2012 Wiley Periodicals, Inc.     

Does mutational burden add to other prognostic factors in MDS?

Myelodysplastic syndromes (MDS) are clonal bone marrow disorders characterized by complex genomic abnormalities that define disease phenotype, prognosis, and progression. The overall outcomes of MDS patients are very heterogeneous and can be measured in months in some patients and years in others. Several scoring systems have been developed in MDS, with the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) the most widely accepted risk stratification tools in clinical practice and trial eligibility. Recently, somatic mutations have been shown to impact overall survival and the risk of progression to acute myeloid leukemia. Attempts to add this information to current models or develop newer models are underway, but the optimal approach remains controversial. Newer methods to develop a personalized prediction model that provides outcomes specific for a patient were developed and could change the prognostic paradigm for MDS patients in the near future.     

Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution.

In 1999 a working group of the World Health Organization (WHO) published a revised classification for myelodysplastic syndromes (MDS): RA, RARS, refractory cytopenia with multilineage dysplasia (RC+Dys), RAEB I and II, del (5q) syndrome, and MDS unclassifiable. Chronic myelomonocytic leukemia (CMML) and RAEB-t were excluded. Standard French-American-British (FAB) and new WHO classifications have been compared in a series of patients (n = 431) from a single center, analyzing morphologic, clinical, and cytogenetic data. According to the WHO findings, dysgranulocytopoiesis or dysmegakaryocytopoiesis only were found in 26% of patients with less than 5% medullary blasts. These patients are thus unclassified and should remain in the subgroups RA and RARS. Splitting of heterogeneous RAEB into 2 subgroups according to blast count was supported by a trend to a statistically significant difference in the single-center study population. Patients with CMML whose white blood cell counts are above 13 000/microL may be excluded from the MDS classification, as warranted by WHO, but a redistribution of patients with dysplastic CMML according to medullary blast count leads to more heterogeneity in other WHO subgroups. Although the natural courses of RAEB-T and acute myeloid leukemia (AML) with dysplasia are different, comparable median survival durations after treatment in patients with RAEB-T and AML were in favor of the proposed 20% medullary blast threshold for AML. The homogeneity of subgroups was studied by evaluating prognostic scores. A significant shift into lower IPSS risk groups was evident in the new classification. These data cannot provide evidence for the new WHO proposal, which should not be adopted for routine clinical use at present. Some of its aspects can provide a starting point for further studies involving refined cytogenetics and clinical results.     

Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis

The International Prognostic Scoring System (IPSS) has been widely used to predict the prognosis of patients with myelodysplastic syndrome (MDS). However, IPSS does not always provide a sufficiently precise evaluation of patients to allow the appropriate choice of clinical interventions. Here, we analyzed the expression of Bmi-1, which is required to regulate the self-renewal in CD34+ cells from 51 patients with cases of MDS and acute myeloid leukemia preceded by MDS (MDS-AML). Higher positivity rate of Bmi-1 was preferentially seen in refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and MDS-AML compared with refractory anemia (RA) and RA with ringed sideroblasts (RARS). IPSS score was positively correlated with the percentage of Bmi-1 expression. Patients with RA and RARS with a higher percentage of Bmi-1+ cells showed disease progression to RAEB. Here, we propose Bmi-1 as a novel molecular marker to predict the progression and prognosis of MDS.     

骨髓增生异常综合征患者骨髓CD34+细胞亚群及细胞周期分析

目的 探讨骨髓增生异常综合征(MDS)患者骨髓CD34+细胞亚群及细胞周期分布异常的临床意义.方法 采用流式细胞术检测50例(17例低危、33例高危)MDS患者、8例MDS转化的急性髓系自血病(MDS-AML)及25例对照组原代骨髓CD34+CD38+、CD34+CD38-细胞亚群及G0/G1期、S期和G2/M期细胞比例.结果 高危和MDS-AML组骨髓CD34+细胞比例[(2.29±2.17)%、(18.69±17.47)%]明显高于对照组[(0.36±0.49)%,P＜0.05].低危、高危及MDS-AML组CD34+CD38+细胞相对比例[(86.09±7.79)%、(81.68±11.82)%、(82.88±2.60)%]显著低于对照组[(92.21±3.85)%,P＜0.05],而CD34+CD38-细胞比例[(13.91±7.79)%、(18.32±11.82)%、(17.13±2.60)%]显著高于对照组[(7.79±3.85)%,P＜0.05].MDS组CD34+CD38-细胞比例与国际预后积分系统(IPSS)(r=0.493,P=0.001)、WHO分型预后积分系统(WPSS)积分(r=0.586,P=0.000)均呈正相关.低危、高危及MDS-AML组骨髓单个核细胞(BMMNC)中G0/G1期细胞比例[(94.52±4.32)%,(96.07±3.88)%,(94.65±4.55)%]明显高于对照组[(88.94±7.30)%,P＜0.01],而3组S期[(4.63±3.34)%,(3.45±3.80)%,(5.12±4.55)%]和G2/M期[(0.84±1.52)%,(0.48±0.74)%,(0.22±0.34)%]细胞比例明显低于对照组[(9.06±6.50)%,(2.00±2.93)%,P值均＜0.05],3组S+G2/M期细胞比例明显高于对照组(P＜0.01).CD34+CD38-细胞比例≤12.0%的MDS患者治疗有效率高于CD34+CD38-细胞比例＞12.0%的患者,但差异无统计学意义.结论 MDS患者原代骨髓CD34+细胞亚群分化异常,BMMNC存在G1期阻滞现象,提示CD34+细胞亚群和细胞周期测定可能有助于MDS患者的辅助诊断以及疗效和预后判断.     

Primary myelodysplastic syndrome in children--clinical, hematological and histomorphological profile from a tertiary care centre in India

We describe the clinical, hematological and histomorphological features in children of primary myelodysplastic syndrome (MDS) seen at the All India Institute of Medical Sciences over three years (Jan 2001-Jan 2004). Twenty-one patients of primary MDS aged 17 year or less were classified using the latest proposed WHO classification for Pediatric MDS. The median age was 9 years with male predominance (80%). Pallor was present in all the cases while fever and bleeding diathesis was present in more than 50% of the cases. Morphological assessment of the peripheral blood showed macrocytosis in 50%, pancytopenia in 15% and blast cells in 45% of cases. A complete analysis of clinical features in conjunction with the bone marrow profile revealed 8 cases of refractory cytopenia (RC), 3 cases of refractory anemia with excess blasts (RAEB), 5 cases of refractory anemia with excess blasts in transformation (RAEB-T), 4 cases of Juvenile myelomonocytic leukemia (JMML) and a solitary cases of acute myeloid leukemia (AML) in Downs syndrome.These children were followed up from 1-36 months (mean 15 months). Three patients of RAEB-T progressed to AML within 3-4 months. RC had the best prognosis and all are alive and under regular follow up. The solitary case of AML of Downs syndrome died 1.5 months after initial diagnosis. All 3 cases of RAEB are under regular follow-up and doing well. Three cases of RAEB-T died (all had progressed to AML); the remaining 2 cases were lost to follow up. Of the 4 cases of JMML 1 died within 6 months of diagnosis; the other 3 cases are under regular follow up of whom 1 has a progressively increasing blast count.We conclude that the latest proposed WHO classification for Pediatric MDS can be successfully applied to all cases of primary MDS.     

International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes

The International Prognostic Scoring System (IPSS) was created for evaluating clinical outcomes of patients with myelodysplastic syndromes (MDS). We evaluated the depth of cytopenias to determine whether this parameter could further refine the prognostic ability of the IPSS. Correlation was determined between the depth of cytopenias in 816 patients from the International MDS Risk Analysis Workshop database and patients' clinical features. Univariate analyses of hemoglobin (Hb), absolute neutrophil count, and platelet depth levels were assessed relative to the IPSS risk groups, refined French-American-British categories, cytogenetic groups, bone marrow blast percentage (%), age groups, overall survival (OS), and time to evolution of acute myeloid leukemia (AML). Multivariate analysis of different cytopenic levels was performed to determine whether depth of cytopenias was prognostically additive to the IPSS. All cytopenic categories had statistically significant rank correlations with IPSS, bone marrow blast %, and refined French-American-British categories. In multivariate analysis, Hb levels had additive prognostic value to the IPSS for evaluation of OS, but not time to AML, with greatest prognostic value in Intermediate-1 and Intermediate-2 categories. In contrast, platelet or absolute neutrophil count levels alone or in combination lacked additive prognostic value to the IPSS regarding OS or time to AML evolution. The depth of Hb level per se at the time of diagnosis has additive predictive value to the IPSS for OS in the intermediate-risk groups. This information should prove useful for aiding therapeutic decision-making, prognostic classification, and designing clinical trials for patients with MDS.     

Validation of cytogenetic risk groups according to International Prognostic Scoring Systems by peripheral blood CD34+FISH: results from a German diagnostic study in comparison with an international control group

International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%–20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34⁺) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34⁺ peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34⁺ blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913).     

Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution

This study evaluated whether the NCCSS truly improves the prognostic stratification of 630 consecutive de novo MDS patients and established which cytogenetic grouping [NCCSS or International Prognostic Scoring System (IPSS)], when combined with the WHO classification, best predicted the clinical outcome of myelodysplastic syndromes (MDS). The frequency of chromosomal defects was 53.8%. Clinical parameters, including number of cytopenias, WHO classification, IPSS cytogenetic categories and scores, NCCSS were all relevant for overall survival (OS) and leukemia‐free survival (LFS) and were included in six distinct multivariate models compared by the Akaike Information Criterion (AIC). The most effective model to predict OS included the number of cytopenias, the WHO classification and the NCCSS, whereas the model including the number of cytopenias, blast cell percentage and the NCCSS and the model including the number of cytopenias the WHO classification and the NCCSS were almost equally effective to predict LFS. In conclusion, the NCCS (i) improves the prognostic stratification of the good and poor IPSS cytogenetic categories by introducing the very good and the very poor categories; (ii) is still incomplete in establishing the prognostic relevance of rare/double defects, (ii) applied to patients who receive supportive treatment only identifies five different prognostic subgroups, but applied to patients treated with specific therapies reveals only a trend toward a significantly different OS and LFS when patients of the poor and intermediate cytogenetic categories are compared, (iii) combined with the WHO classification is much more effective than the IPSS in predicting MDS clinical outcome. Am. J. Hematol. 88:120–129, 2013. © 2012 Wiley Periodicals, Inc.     

Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome

Wnt signaling activates the canonical pathway and induces the accumulation of non-phosphorylated beta-catenin (NPBC) in the nucleus. Although this pathway plays an important role in the maintenance of haematopoietic stem cells as well as in oncogenesis, the significance of nuclear NPBC remains unclear in malignant haematopoiesis. This study examined the expression of nuclear NPBC in bone marrow specimens from 54 and 44 patients with de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), respectively. On immunohistochemistry with an anti-NPBC antibody, the nuclei were positively stained in 22 and 18 of AML and MDS specimens, respectively. Staining of nuclear NPBC was associated with AML subtypes (M6 and M7), low complete remission (CR) rate, and poor prognosis. Nuclear NPBC was also associated with a high score when using the International Prognostic Scoring System (IPSS) for MDS and with −7/−7q and complex karyotypes. These findings suggest that in situ detection of nuclear NPBC by immunohistochemistry could provide new insights into the pathogenesis and prognosis of AML and MDS.     

A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome

The granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for proliferation and differentiation of myeloid progenitor cells. Here we report on the identification of a rare single nucleotide polymorphism within its intracellular domain (G-CSF-R_Glu785Lys). Screening a cohort of 116 patients with primary myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML) (84 patients), as well as 232 age- and sex-matched controls revealed a highly significant association of the G-CSF-R_785Lys allele with the development of high-risk MDS as defined by more than 5% bone marrow blasts (9.7% versus 0.9% in controls; P = .001; odds ratio [OR], 12.5; 95% confidence interval [CI], 2.4-58.9) or an International Prognostic Scoring System score of intermediate-2 or high (13.0% versus 0.9%; P < .001; OR, 14.0; 95% CI, 3.4-85.0). Functional analysis by retroviral transfer of G-CSF-R_785Lys into myeloid progenitor cells of G-CSF-R-deficient mice showed a significantly diminished colony-formation capacity after G-CSF stimulation as compared with cells transduced with the wild-type receptor. These results suggest that lifelong altered G-CSF response by the G-CSF-R_785Lys may render individuals susceptible to development of high-risk MDS.