Impact on survival of different treatments for myelodysplastic syndromes (MDS)

Therapies for myelodysplastic syndromes (MDS) often achieve hematological responses but their impact on overall survival has generally not been evaluated. The Duesseldorf MDS Registry allowed us to perform matched-pair analyses to assess a possible survival benefit of treatment with thalidomide, valproic acid, low-dose Ara-C, antithymocyte globulin (ATG), induction chemotherapy, or allogeneic stem cell transplantation (allo-SCT). For all treatment modalities, lengthening of survival was restricted to certain subgroups of patients. With the exception of allo-SCT, MDS treatment was generally palliative. Recently, epigenetic treatment with demethylating agents proved to be the first therapy that can significantly prolong survival in patients with higher-risk MDS.     

Refractory anaemia with excess of blasts (RAEB): analysis of reclassification according to the WHO proposals

The French-American-British (FAB) classification assigns patients with myelodysplastic syndromes to the category of refractory anaemia with excess blasts (RAEB) if they have a medullary blast count of 5-20%, and/or a peripheral blast count of 2-5%. The new World Health Organization (WHO) classification subdivides RAEB into RAEB I with a medullary blast count < or =10% and a peripheral blast count < or =5% and RAEB II with >10% medullary and/or >5% peripheral blasts. RAEB II is also diagnosed if Auer rods are present. In 558 patients, we analysed these subtypes of RAEB in terms of haematological characteristics, karyotype anomalies and prognosis. RAEB I was diagnosed in 256 and RAEB II in 302 patients. In the RAEB II group, 22% of patients had >5% peripheral blasts or the presence of Auer rods. The median survival was 16 months for RAEB I as compared with 9 months for RAEB II. Patients with Auer rods, regardless of their medullary and peripheral blast count, had no worse prognosis. No significant differences were identified between the RAEB subtypes with respect to clinical, morphological, haematological and cytogenetic parameters. The survival data support the WHO reclassification of RAEB based on peripheral and medullary blast counts and Auer rods. The WHO classification is useful for diagnosis and provides risk stratification, supported by cytogenetic data for clinical decision making, identifying those RAEB patients with an unfavourable prognosis who should be offered chemotherapy or stem cell transplantation.     

Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes

Low-risk myelodysplastic syndrome (MDS) with normal cytogenetics accounts for approximately 50% of MDS patients. There are no pathognomonic markers in these cases and the diagnosis rests on cytomorphologic abnormalities in bone marrow and/or peripheral blood. Affymetrix high-resolution single-nucleotide polymorphism (SNP) genotyping microarrays allow detection of cytogenetically cryptic genomic aberrations. We have studied 119 low-risk MDS patients (refractory anemia [RA] = 22; refractory cytopenia with multilineage dysplasia [RCMD] = 51; refractory anemia with ringed sideroblasts [RARS] = 12; refractory cytopenia with multilineage dysplasia with ringed sideroblasts [RCMD-RS] = 12; 5q- syndrome = 16; refractory anemia with excess blasts [RAEB] = 6) using SNP microarrays to seek chromosomal markers undetected by conventional cytogenetics. Loss of heterozygosity (LOH) detected by 50K arrays was verified using 250K and 500K arrays. We demonstrate the presence of uniparental disomy (UPD) in 46%, deletions in 10%, and amplifications in 8% of cases. Copy number (CN) changes were acquired, whereas UPDs were also detected in constitutional DNA. UPD on 4q was identified in 25% of RARS, 12% of RCMD with normal cytogenetics, 17% of RAEB, and 6% of 5q- syndrome cases. Univariate analysis showed deletions (P = .04) and International Prognostic Scoring System (IPSS; P < .001) scores correlated with overall survival; however, on multivariate analysis only IPSS scores retained prognostic significance (P < .001). We show, for the first time, that SNP microarray analysis in low-risk MDS patients reveals hitherto unrecognized UPD and CN changes that may allow stratification of these patients for early therapeutic interventions.     

Meeting report: Vienna 2008 Workshop of the German–Austrian Working Group for Studying Prognostic Factors in Myelodysplastic Syndromes

Criteria, scoring systems, and treatment algorithms for myelodysplastic syndromes (MDS) have been updated repeatedly in recent years. This apparently results from increased awareness and early recognition of the disease, an increasing number of new diagnostic and prognostic markers and tools, and new therapeutic options that may change the course and thus prognosis in MDS. To address these challenges and to create useful new diagnostic and prognostic parameters and scores, the German–Austrian Working Group for Studying Prognostic Factors in MDS was established in 2003 and later was extended to centers in Switzerland (D-A-CH group). In addition, the group cooperates with the European LeukemiaNet, the MDS Foundation, and other national and international working groups in order to improve diagnosis and prognostication. The current article represents a meeting report from the latest workshop organized by the group in Vienna in October 2008.     

Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroup

The survival of patients with myelodysplastic syndromes is strongly affected by chromosomal abnormalities. Patients with an isolated del(5q31) have a favourable prognosis that worsens with the addition of another chromosomal abnormality. It has been reported that both patients with isolated del(5q31) and those with one single additional chromosomal abnormality achieve hematological and cytogenetic remissions with lenalidomide therapy. Whether this translates into improved overall survival of the patient population is unclear. We analysed data of 25 patients with myelodysplastic syndrome and complex chromosomal abnormalities including del(5q31) and show that their median survival is between 7 and 8 months, irrespective of the medullary blast count. Furthermore, we present data of a patient with complex karyotypic anomalies inclusive of del(5q31) treated with lenalidomide who achieved complete cytogenetic remission. This cytogenetic remission was diagnosed after 6 months, and the hematological response is ongoing at 9 months of therapy at a dose of 5 mg p.o. daily. We conclude that lenalidomide has the potential to induce sustained hematological and cytogenetic remissions in the poor prognosis MDS subgroup of del(5q31) patients with complex chromosomal anomalies and that this is likely to improve overall survival.     

Evaluating the prognosis of patients with myelodysplastic syndromes

One of the hallmarks of myelodysplastic syndromes (MDS) is their prognostic heterogeneity which complicates decision making regarding treatment for individual patients. The French-American-British (FAB) classification provides significant prognostic information, but carries the disadvantage of arbitrary demarcation of subgroups and overemphasis of morphological findings. In addition, there is considerable variation in survival and risk of acute myeloblastic leukemia (AML) development even within defined FAB subgroups, particularly in patients with refractory anemia with ring sideroblasts (RARS) and chronic myelomonocytic leukemia (CMML). Over the last 2 decades, several research groups have tried to identify additional clinical, hematological, and cell biological parameters in order to more accurately predict the natural course of MDS. These investigations have clarified that the number and extent of peripheral blood cytopenias, the bone marrow blast count, and the cytogenetic pattern are the most powerful prognostic indicators in MDS. Recent efforts have been directed at constructing prognostic scoring systems. These scoring systems try to enhance the predictive power by combining several features of the disease, which have proved their independent prognostic weight on multivariate analysis. The International MDS Risk Analysis Workshop substantially advanced the prognostic categorization of MDS patients by proposing a new scoring system (International Prognosis Scoring System, IPSS) that can be successfully applied to risk assessment of newly diagnosed patients and will likely prove useful for the design and analysis of therapeutic trials in MDS.