Treatment Of Myelodysplastic Syndrome Patients Research Articles

Azacitidine Treatment in MDS: A Systematic Literature Review and Meta-Analysis Comparing the Efficacy of Real World Data with Randomized Controlled Trials

Background: Myelodysplastic Syndromes (MDS) are a group of myeloid malignancies affecting the hematopoietic stem and progenitor cells and occurring mainly in elderly individuals. Two hypomethylating agents (HMA), Azacitidine (AZA) and Decitabine (DAC), have shown efficacy in treatment of MDS patients and received approval based on randomized controlled trials (RCTs) more than a decade ago. Since then, many publications have reported real world experience on HMA treatment in MDS patients, which showed a reduced efficacy of HMA than the RCT. The reasons for this difference have been extensively discussed but a systematic review never performed. Aim: We performed a systematic literature review and meta-analysis to compare the efficacy of real world data with randomized controlled trials and to identify potential cofactors for different outcomes. Material and Methods: We performed a systematic literature search from observational studies (OBSTs) describing real world experience of AZA treatment in MDS patients using Embase, Ovid Medline, and Web of Science databases. Patient characteristics, IPSS/IPSS-R, and outcome (response rates, overall survival) were collected from OBSTs that were performed between 2003 and 2023. Kaplan-Meier curves with log-rank tests were used to assess differences in survival outcomes. An inverse variance weighted meta-analysis was performed by using restricted mean survival times or proportions (response rate outcome). The restricted mean survival time and the standard error at 12, 24 and 36 months was calculated by using the R package survival. The pooled effect and prediction intervals from random effect models were reported. Results: In our systematic literature search, data from OBSTs describing real world experience of AZA treatment in MDS patients could be extracted and compared to the only RCT published with AZA (Fenaux P et al., Lancet Oncology 2009). Patient and disease characteristics were similar for AZA-RCT and OBST (respect of gender ratio, median age, IPPS/IPSS-R). Restricted mean survival time and standard error of the OBSTs and AZA-RCT showed no significant difference for the time points at 12 months (10.0 [95%-CI: 9.6; 10.3] months (OBSTs) vs 10.0 [95%-CI: 9.5; 10.5] months (AZA-RCT); figure part A) and 24 months (15.5 [95%-CI: 14.6; 16.5] months (OBSTs) vs. 16.9 [95%-CI: 15.7; 18.2] months (AZA-RCT); figure part B). At 36 months, the restricted mean survival time of OBSTs was 18.7 [95%-CI: 17.3; 20.1] months compared to 22.3 [95%-CI: 20.2; 24.5] months of the AZA-RCT (figure part C), which was different in favor of the RCT. Using random effect models, the AZA treatment response rate was 0.51 [95%-CI: 0.47; 0.56] for the OBSTs and 0.49 [95%-CI: 0.42; 0.57] for the AZA-RCT (figure part D). Conclusion: Compared to AZA-RCT data, restricted mean survival time (for time points 12 months and 24 months) and response rate of OBSTs describing real world data of AZA treatment in MDS patients are comparable. Regarding the observation time point at 36 months, the lower restricted mean survival time of the OBSTs compared to AZA-RCT may be most likely explained by study patient selection bias.

Health-Related Quality of Life Assessment in Patients with Myelodysplastic Syndromes: Evidence from Randomized Clinical Trials

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and blood cytopenia with a variable risk of progression to acute myeloid leukemia. The main goal of therapy for the large majority of patients is to improve health-related quality of life (HRQoL). Its rigorous assessment is now recommended in international MDS guidelines. Our review provides an overview of HRQoL results from randomized controlled trials (RCTs) in MDS patients. The literature search undertaken in PubMed identified 10 RCTs with HRQoL endpoints (all secondary) published between August 2008 and September 2020. These RCTs have helped to better understand the impact of therapies from the patient perspective and have generated valuable information that can be used to further support clinical decisions. However, the number of RCTs in MDS patients, including HRQoL endpoints, is still low. Given the importance of symptom relief and HRQoL improvement in the treatment of MDS patients, the assessment of the patient perspective in future RCTs is highly recommended to keep expanding the knowledge of the impact of new MDS therapies.

Outcomes with venetoclax in myelodysplastic syndromes: A systematic review.

e19035 Background: Myelodysplastic syndromes (MDS) are clonal hemopoietic disorders causing cytopenia(s) and increased risk of transformation to acute myeloid leukemia (AML). Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells. The FDA has approved venetoclax for the treatment of newly diagnosed adult AML patients unfit for intensive chemotherapy and its utility in MDS is being explored. We present a systematic review aimed to evaluate outcomes with venetoclax in MDS patients. Methods: We performed a literature search on 3 databases (Pubmed, Cochrane, and Clinicaltrials.gov) following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We screened 62 studies using the Mesh terms ‘myelodysplastic syndrome’ and ‘venetoclax’. After excluding review, duplicate and non-relevant articles, 8 studies were included in the analysis. Quality evaluation was done using the NIH quality assessment tool. Pooled analysis was done using the ‘meta’ package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed. The Inter-study heterogeneity among the studies was assessed using the Q statistic proposed by Cochrane and the I2 index introduced by Higgins and Thompson. Results: We identified 313 patients from 8 studies (1 prospective, 3 retrospective, 2 ex-vivo, 2 clinical trials). Venetoclax was used in combination with hypomethylating agents (HMA) in 6 studies and with other agents in 2 studies. Most patients were pre-treated. Complete response (CR) with or without hematological recovery (CRi) was reported in 45% of patients (95% CI 0.26-0.66, I2= 90%, n = 292). Stable disease (SD) was seen in 18% patients (95% CI 0.08-0.37, I2= 85%, n = 223). Overall response rate (ORR) was 51% (95% CI 0.31-0.70, I2= 89%, n = 122). Hematopoietic stem cell transplant (HCT) was performed in 22% patients (95% CI 0.09-0.44, I2= 75%, n = 122). Twenty percent patients (95% CI 0.15-0.28, I2= 0%, n = 149) died. Common adverse events seen with venetoclax were cytopenias, gastrointestinal side effects and infections, often requiring drug interruption or dose. Conclusions: Despite heterogeneity of available literature, venetoclax seems to be a promising agent in treatment of MDS patients. Prospective clinical trial data is needed to ascertain safety and efficacy of venetoclax in MDS and impact on overall survival, in particular, in patients proceeding to HCT.[Table: see text]

Development and Exploitation of a Fully Human and Modular Organotypic Bone Marrow Niche Model to Study the Role of Stroma-Produced Factors in Human MDS

Background: Myelodysplastic syndromes (MDS) are a heterogenous group of stem cell driven disorders primarily affecting the elderly and characterized by inefficient production of mature blood cells and a high risk (30%) of evolution to secondary acute myeloid leukemia. Despite tremendous progress in the past decade, treatment options for MDS patients remain limited, and primarily address disease symptoms, rather than altering disease course. This points to the urgent need to better understand the pathogenesis of this heterogenous group of syndromes to develop new therapies that address disease vulnerabilities. However, this effort has been largely hampered by the limited availability of model systems that allow the exploration of MDS biology in a fully humanized setting. In recent years, studies from our lab and others, have highlighted the crucial role niche cells play in human MDS, hence reinforcing the notion that MDS is a disease of a tissue rather than hematopoietic cells alone. Therefore, exploration of MDS biology requires the further development of fully human MDS models in which both constituents of the disease, namely hematopoietic and niche cells, are present. Methods: To address this issue we successfully isolated endothelial cells (ECs) and mesenchymal stromal cells (MSC) from bone marrow biopsies obtained from MDS patients or healthy age matched controls, and subsequently utilized them to develop fully human 2D and 3D organotypic niche models, which were successfully used to support normal and MDS HSPCs expansion ex-vivo. The 3D system makes use of a collagen scaffold, as this protein makes up for 90% of the matrix proteins in the bone. Importantly, MSC and EC cultures could be successfully established from several independent donors and immortalized to generate primary cell lines that can be used to reproducibly establish these ex-vivo systems in a robust manner. Moreover, we could show that these niche cells were easily amenable to genetic editing using CRISPR-Cas9 technology as well as modified to carry fluorescent reporter proteins for tracking cellular interactions using live cell imaging and confocal microscopy. Results: In this work, we successfully isolated human mesenchymal and endothelial cells, from primary bone marrow biopsies (MDS and healthy) and established fully human 2D and 3D organotypic co-cultures ex-vivo. Of note, although bone marrow ECs represent an essential component of the hematopoietic niche, they have so far been omitted in previously described human bone marrow niche models, owing to the notorious difficulties in isolating and expanding this cell type from primary bone marrow biopsies. Therefore, we established immortalized EC lines (iECs) that faithfully recapitulate the morphological, phenotypic and functional features of primary bone marrow ECs. When cultured at defined ratios and under defined conditions, MSCs instructed ECs and iECs to form of vessel-like structures that mimic the meshwork observed in vivo and are typically escheated by aSMA positive cells that stabilize the structures. Genetic manipulation of the cellular components of the niche also allowed to explore the functional relevance of a specific ECM protein, which we previously identified to be significantly upregulated in MSCs isolated from MDS patients, namely the Secreted Protein Acidic and Rich in Cysteine (SPARC). SPARC ablation triggered enhanced proliferation of MDS derived HSPCs and sensitized them treatment with 5-Azacytidine, a standard of care hypomethylating agent used for the treatment of MDS patients. Additional studies are underway to further understand the underlying molecular mechanisms and define a potential druggable target that could sensitize MDS cells to standard of care treatment. Besides gene targeting studies, these organotypic models are also being used to evaluate the relative fitness of MDS and healthy stem/progenitor cells in healthy versus patient derived niches, to explore the contribution of niche components to the establishment of the progressive clonal dominance observed in MDS. Disclosures Bönig: Terumo BCT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiadis: Honoraria; Bayer: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fresenius: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Uniqure: Research Funding; medac: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Healthineers: Current equity holder in publicly-traded company; Chugai: Honoraria, Research Funding; Erydel: Research Funding; Miltenyi: Honoraria, Research Funding; Polyphor: Research Funding; Sandor-Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stage: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Götze:Celgene: Research Funding. Medyouf:Bergenbio: Consultancy, Research Funding.

Improving Treatment for Myelodysplastic Syndromes Patients.

Aging is the most potent of carcinogens, especially for the bone marrow stem cell clonal disorders called myelodysplastic syndromes (MDS). Age-associated changes in the microenvironment or the soil of the bone marrow (BM) as well as in the cell or the seed provide a growth advantage for clonal myeloid cells. Slowly accumulating senescent cells which can no longer divide because they have reached the end of their proliferative life cycle, but which continue to produce metabolic debris, overwhelm the natural autophagy mechanisms resulting in pro-inflammatory changes in the BM soil. In addition, the seed or stem cells acquire passenger mutations with each round of proliferation resulting from DNA copying errors. Some mutations commonly associated with MDS can be found in older, otherwise healthy individuals; however, when combined with other passenger mutations or in the setting of a noxious soil, the result could be a proliferative advantage for one stem cell over others, leading to its clonal expansion and development of the clinical syndrome. When considering therapeutic options for MDS patients, the important considerations are related to both the common co-morbidities of an elderly population along with the heterogeneous passenger mutations and the inflammatory changes in the soil. At present, allogeneic stem cell transplant is the only potentially curative option in MDS. Palliative strategies are directed at improving the quality of life and prolonging survival. Only three drugs are FDA approved, two being the hypomethylating agents azacytidine and decitabine while the third is lenalidomide which is restricted to lower risk MDS patients with deletion 5q. Promising future therapies are directed at reversing the pro-inflammatory changes in the microenvironment (luspatercept) or targeting specific mutations isocitrate dehydrogenase (IDH)1, IDH2, p53, EZH2. More durable responses are to be expected when the seed and soil are targeted simultaneously through a combination of drugs.

Expression and Significance of HOXA9 in Patients with Myelodysplastic Syndromes

To investigate the expression pattern of HOXA9 in myelodysplastic syndrome (MDS) patients and its relation with clinical characteristics and treatment response. The mRNA and protein expression levels of HOXA9 in bone marrow cells from 33 cases of MDS, 12 cases of AML, 20 cases of ITP and 18 normal controls were detected by real-time guautitative PCR(RT-PCR) and flow cytometry, respectively. The percentage of HOXA9(+)/CD34(+) and HOXA9(+)/CD34(+)CD38(-) in MDS patients were significantly higher than that in control group (P<0.05), and the mRNA and protein expression of HOXA9 in MDS patients had a similar trend. The percentages of HOXA9(+)/CD34(+) and HOXA9(+)/CD34(+)CD38(-) before decitabine treatment were (50.64±27.59)% and (55.67±28.57)% respectively, which were both higher than those in control group (P<0.05). After decitabine treatment, expression of HOXA9 significantly decreased (P<0.05). HOXA9 is overexpressed in MDS patients and associated with several clinical characteristics. The detection of HOXA9 expression may have guide roles for diagnosis and treatment of MDS patients.

Research progress of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in treatment of myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is likely to be the optimum method to cure international prognostic scoring system (IPSS) intermediate and high-risk patients with myelodysplastic syndrome(MDS). However, patients suffered with MDS are usually too old to undergo myeloablative conditioning allogeneic stem cell transplantation(MAC-HSCT). On account of its advantages of higher efficiency and lower toxicity, reduced intensity conditioning allogeneic stem cell transplantation(RIC-HSCT) is widely applied in the treatment of MDS patients. Currently, fludarabine plus alkylating regimens are widely applied, but the clinical outcomes are different from each regimen. Although RIC-HSCT has unique advantages in treating intermediate and high-risk elder MDS compared with MAC-HSCT and non-HSCT therapy, whether the outcome is influenced by factors such as tumor burden, recipient age, IPSS risk stratification, type of allo-HSCT, and comorbidity before transplantation is still unclear. In this article, we review literatures on RIC-HSCT in treatment of MDS. Key words: Myelodysplastic syndrome; Transplantation conditioning; Hematopoietic stem cell transplantation

Abstract 5304: A serum protein test for improved prognostic stratification of patients with myelodysplastic syndrome (MDS)

Abstract While existing scoring systems provide physicians with methods of assessing prognosis of patients with MDS and help with the choice of appropriate treatment regimens, some patients defined as lower risk still have poor outcomes and tests which can refine current stratifications are of clinical interest. Serum samples, clinical and survival data were available from 106 MDS patients with refractory anemia (RA) (n = 46), RA with excess blasts (n = 29), RA with ring sideroblasts (n = 14), and chronic myelomonocytic leukemia (n = 17). The international prognostic scoring system (IPSS) score distribution 0/0.5/1/&amp;gt;1 was n = 36/23/24/12. Matrix assisted laser desorption/ionization (MALDI) mass spectra were acquired from the samples using the deep MALDI method1, allowing a deep probing of the proteome. The spectra were preprocessed and spectral features defined. The integrated intensities of these features were combined with the survival data using deep learning based machine learning techniques to create classifiers able to stratify patients into groups with better and worse survival. Patients in the good prognosis group had median survival of 52 months, compared with 23 months in the poor prognosis group (hazard ratio = 0.37, p &amp;lt; 0.001). Within the subgroup of patients with refractory anemia (n = 46) it was possible to identify a group of patients with no death events before 30 months, while median survival in the other patients was only 25 months. Multivariate analysis stratified by MDS subtype found that the mass spectral (MS) classification was a significant independent predictor of survival even when adjusted for international prognostic scoring system (IPSS) score and cytogenetic status. MS classification was able to separate low to intermediate risk (IPSS 0-1) and good karyotype subgroups into groups with significantly better and worse survival. If validated in an independent dataset, this serum test would provide complementary information for physicians to consider in addition to existing scoring systems to aid in planning treatment for MDS patients. 1. M Duncan et al, Proceedings of the 61st ASMS Conference on Mass Spectrometry and Allied Topics. Minneapolis, MN June 8-9, 2013 MP 181. Citation Format: Joanna Roder, Judith Löffler-Ragg, Reinhard Stauder, Ulrich Germing, Wolfgang R. Sperr, Peter Valent, Heinrich Roder, Arni Steingrimsson, Heinz Zwierzina. A serum protein test for improved prognostic stratification of patients with myelodysplastic syndrome (MDS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5304. doi:10.1158/1538-7445.AM2015-5304

How Recent Advances in High-risk Myelodysplastic Syndrome Physiopathology May Impact Future Treatments

Myelodysplastic Syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis that often develop into acute myeloid leukemia (AML). MDSs are predominant in the elderly with an incidence of 20/100000 at 70 years of age. To date, the only curative treatment is allogeneic stem cell transplantation; however, a majority of patients are not eligible for this therapy. Azacitidine (AZA), a hypomethylating agent, remains the primary treatment for MDS patients, which leads to a significant increase in overall survival (OS), although it is not curative. Although it is well known that the impairment of apoptosis and differentiation are important features of this complex disease, the implication of autophagy in the pathogenesis of MDS is an emerging concept. Another significant advance in MDS pathogenesis research is the recent identification of mutations in genes encoding transcription factors implicated in hematopoiesis and proteins involved in splicing (SF3B1), methylation (DNMT3A), regulation of methylation (TET2 and IDH), DNA conformation (EZH2 and ASXL1) and differentiation (N- and K-RAS). Additionally, BCL2 family member expression and regulation may also affect the physiopathology of this disease. We have recently reported that targeting autophagy may be an interesting option for the treatment of AZA-resistant patients. Thus, targeting the products of the above-mentioned genes or the signaling pathways affected by the corresponding proteins may be of great interest for the development of a new arsenal of molecules to fight MDS. In this review, we discuss the new aspects of MDS physiopathology and how recent advances in MDS pathogenesis research may impact future treatments to improve the outcome of MDS patients.

Abstract A159: Epigenetic silencing of the M-type phospholipase A2 receptor gene in leukemic cells.

Abstract Background: The M-type phospholipase A2 receptor (PLA2R) plays a crucial role in a number of different signaling pathways and may act as tumor-suppressor. In the current study the expression and methylation of the PLA2R gene in the myeloid U937 cell line and blood leukocytes of patients with leukemia were analyzed. Methods. Expression of PLA2R in U937 cells was studied using RT-quantitative PCR. To determine methylation levels of the PLA2R locus, bisulfite-modified DNA fragments were sequenced. Identification of different 5′-CpG methylation sites in normal and leukemic patients was followed by methylation specific-high resolution melting (MS-HRM) analysis to quantify PLA2R methylations. Results: Our data establish that expression of PLA2R is completely down-regulated in U937 cells. Simultaneously, a 100% methylation of PLA2R promoter and down-stream regions was found in this cell line; after exposure of the cells to 5-aza-2 -deoxycytidine, PLA2R was re-expressed. MS-HRM analyzes in 34 patients with different types of leukemia indicated an average PLA2R methylation of 30%±18%, whereas in 52 normal subjects methylation levels were below 10%. In a preliminary study of high-risk myelodysplastic syndrome patients (MDS), three patients had increased PLA2R methylations. In the course of treatment with azacitidine (Vidaza) as methyltransferase inhibitor, two of these patients were responders in contrast to one patient who was a non-responder with increased methylation levels in blood leukocytes during treatment. Another patient with minimal residual disease after treatment of AML underwent preemptive treatment with azacitidine to avoid hematological relapse (HR). After two azacitidine cycles a minor cell fraction with 100% methylated PLA2R was completely diminished. However, three weeks later methylation of the PLA2R promoter increased to 50%, with 9% blasts detectable in blood samples. After further azacitidine treatment cycle, blasts diminished in blood samples but the methylation of PLA2R in blood leukocytes remained at 35%. During the following seven weeks with no further azacitidine treatment blasts increased up to 44% suggesting that the treatment with azacitidine was effective but not efficient enough to prevent a HR in this patient. Conclusions: The study shows for the first time that the PLA2R promoter and down-stream regions in leukemic cells are hypermethylated and that the determination of PLA2R methylation by MS-HRM may be useful as a biomarker in the diagnosis and therapeutic treatment of high-risk MDS and AML patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A159.

Clofarabine for myelodysplastic syndromes

Introduction: Treatment options in myelodysplastic syndromes (MDS) remain limited. The introduction of novel therapies that can improve response rates and survival outcomes in MDS remains a challenge. Clofarabine is a purine nucleoside analog that works primarily via inhibition of DNA biosynthesis and the ribonucleotide reductase enzyme with recent evidence suggesting that at low doses it may affect DNA methylation. It has been successfully used in the treatment of acute myeloid leukemia (AML) and is under investigation in MDS.Areas covered: A PubMed search for articles pertaining to clofarabine was conducted and streamlined to only include data on MDS or AML that evolved from MDS. Also included were clofarabine-related response and safety data from presentations at the 52nd Annual American Society of Hematology Meeting in Orlando, Florida, USA.Expert opinion: Clinical trials using clofarabine in MDS and MDS/myeloproliferative neoplasms have produced overall response rates of 31 – 43% including complete responders. Although myelosuppression is an important side effect, clofarabine is generally well tolerated in MDS. Clofarabine is currently available in an intravenous form with an oral formulation presently under investigation, either as a single agent or in combination therapy in MDS. Larger studies may help clarify the viability of clofarabine in the treatment of MDS patients.

Myelodysplastic Syndromes in the Elderly — A Prominent Medical Concern with Significant Effects on Healthcare Systems

Myelodysplastic syndromes (MDS) represent one of the most challenging health-related problems in the elderly. As the population continues to age, MDS will become a more prominent medical problem with a significant effect on healthcare systems. MDS are characterised by dysplastic morphology in the bone marrow in association with ineffective haematopoiesis; there are various pathophysiological causes of these diseases, including genetic abnormalities within myeloid progenitors, altered epigenetics and changes in the bone marrow microenvironment. There is uncertainty about how to diagnose patients who may benefit from a specific treatment; in fact, MDS probably constitute several molecularly distinct entities that share common changes in blood and bone marrow. The International Prognostic Scoring System (IPSS) is a useful tool to guide treatment decisions, but revisions of the original IPSS are under way as it fails to consider many aspects of the treatment of MDS patients, especially in elderly patients. This article examines treatment goals, options and directions when treating elderly MDS patients. Furthermore, it explores how treatment has evolved according to new survival data and how various therapies are contributing to improve the survival rate.

Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996)

AbstractThis phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

Myelodysplastic syndromes with del(5q): indications and strategies for cytogenetic testing

Cytogenetics is a major predictor of disease behavior and treatment outcome in myelodysplastic syndromes (MDS). Deletion of the long arm of chromosome 5, del(5q), is the most common chromosomal abnormality found in patients with MDS. The development of lenalidomide (Revlimid; Celgene, Summit, NJ) as an effective targeted therapy for low/intermediate-risk MDS with a del(5q) has increased the importance of karyotyping in disease management. In the present review, the importance of an accurate cytogenetic diagnosis in del(5q) MDS, its impact on prognosis, and the effect it can have on the choice of treatment was discussed. In addition, the strengths and limitations of conventional and novel cytogenetic testing techniques currently available for patients with del(5q) MDS were evaluated. A practical diagnostic algorithm was provided to help facilitate the early detection and optimal treatment of MDS patients with a del(5q) abnormality. While the gold standard for genetic testing remains metaphase karyotyping, emerging novel molecular techniques such as fluorescence in situ hybridization may provide clinically valuable complementary and supplemental data.

Continuous infusion of low-dose 5-Aza-2'-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome.

There is no standard therapy for elderly patients with high-risk myelodysplastic syndrome (MDS). The treatment options of low-dose Ara-C and haematopoietic growth factors are disappointing in regard to response rate or response duration. We tested the treatment with a 72-h continuous infusion of low-dose 5-Aza-2'-deoxycytidine (DAC) in a group of 29 elderly patients with high-risk MDS. In 15 patients (54%) we observed a response. Eight complete responses were reached, even among patients with bad prognostic cytogenetic findings. The actuarial median survival from the start of the therapy was 46 weeks. The only (and major) toxicity was myelosuppression, leading to a prolonged cytopenic period and thus leading to five toxic deaths (17%) in this high-risk patient group. We conclude that DAC is an effective drug in the treatment of MDS patients and that it probably works via its cytotoxic activity. Myelotoxicity is its major adverse effect.

Clinical and biological effects of erythropoietin treatment of myelodysplastic syndrome.

To evaluate its clinical efficacy as well as its biologic safety, human recombinant Erythropoietin (rh-Epo) was given to 19 patients with myelodysplastic syndromes (MDS) in an open non-randomized study. Among the seventeen evaluable patients only two showed an apparent hematologic response to rh-Epo treatment. In these patients hemoglobin levels increased from a mean pretreatment value of 8.5 and 8.4 g/dl up to 11.7 and 11.3 g/dl respectively and remained relatively stable for several weeks. In one of these patients the transfusion requirement decreased from 4 to 1.5 units per month whereas the other had no transfusion requirement during the whole period of rh-Epo treatment. Interestingly, when the responding patients, after a "wash-out" period of at least ten weeks, received an additional course of rh-Epo results were less impressive. Before treatment the serum level of endogenous Epo was 18 and 110 mU/ml in the two responding patients, whereas a mean value of 532 mU/ml (range 17-2797 mU/ml) was observed in non responders. The treatment of MDS patients with rh-Epo was clinically well tolerated since no relevant side effects were registered. Moreover, no evidence of harmful cytogenetic changes nor activation of myeloid growth factor genes, as determined by Northern blot analysis of GM-CSF and G-CSF gene expression, could be related to rh-Epo treatment. Overall, it appears that administration of rh-Epo is well tolerated but the therapeutic effects appear to be restricted to a minority of patients and a limited period of time.