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The myelodysplastic syndromes (MDS) share their origin in the hematopoietic stem cell but have otherwise very heterogeneous biological and genetic characteristics. Clinical features are dominated by cytopenia and a substantial risk for progression to acute myeloid leukemia. According to the World Health Organization, MDS is defined by cytopenia, bone marrow dysplasia and certain karyotypic abnormalities. The understanding of disease pathogenesis has undergone major development with the implementation of next-generation sequencing and a closer integration of morphology, cytogenetics and molecular genetics is currently paving the way for improved classification and prognostication. True precision medicine is still in the future for MDS and the development of novel therapeutic compounds with a propensity to markedly change patients' outcome lags behind that for many other blood cancers. Treatment of higher-risk MDS is dominated by monotherapy with hypomethylating agents but novel combinations are currently being evaluated in clinical trials. Agents that stimulate erythropoiesis continue to be first-line treatment for the anemia of lower-risk MDS but luspatercept has shown promise as second-line therapy for sideroblastic MDS and lenalidomide is an established second-line treatment for del(5q) lower-risk MDS. The only potentially curative option for MDS is hematopoietic stem cell transplantation, until recently associated with a relatively high risk of transplant-related mortality and relapse. However, recent studies show increased cure rates due to better tools to target the malignant clone with less toxicity. This review provides a comprehensive overview of the current status of the clinical evaluation, biology and therapeutic interventions for this spectrum of disorders., (Copyright© 2020 Ferrata Storti Foundation.)

Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS ( P <1×10 -4 ): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860., (Copyright© 2020 Ferrata Storti Foundation.)

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at clinicaltrials.gov identifier: 00600860., (Copyright© 2020 Ferrata Storti Foundation.)

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860., (Copyright© 2018 Ferrata Storti Foundation.)

A high proportion of patients with lower-risk del(5q) myelodysplastic syndromes will respond to treatment with lenalidomide. The median duration of transfusion-independence is 2 years with some long-lasting responses, but almost 40% of patients progress to acute leukemia by 5 years after starting treatment. The mechanisms underlying disease progression other than the well-established finding of small TP53 -mutated subclones at diagnosis remain unclear. We studied a longitudinal cohort of 35 low- and intermediate-1-risk del(5q) patients treated with lenalidomide (n=22) or not (n=13) by flow cytometric surveillance of hematopoietic stem and progenitor cell subsets, targeted sequencing of mutational patterns, and changes in the bone marrow microenvironment. All 13 patients with disease progression were identified by a limited number of mutations in TP53 , RUNX1 , and TET2 , respectively, with PTPN11 and SF3B1 occurring in one patient each. TP53 mutations were found in seven of nine patients who developed acute leukemia, and were documented to be present in the earliest sample (n=1) and acquired during lenalidomide treatment (n=6). By contrast, analysis of the microenvironment, and of hematopoietic stem and progenitor cells by flow cytometry was of limited prognostic value. Based on our data, we advocate conducting a prospective study aimed at investigating, in a larger number of cases of del(5q) myelodysplastic syndromes, whether the detection of such mutations before and after lenalidomide treatment can guide clinical decision-making., (Copyright© Ferrata Storti Foundation.)

Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥ 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621)., (Copyright© Ferrata Storti Foundation.)

The phase III AZA-001 study established that azacitidine significantly improves overall survival compared with conventional care regimens (hazard ratio 0.58 [95% confidence interval 0.43-0.77], P<0.001). This analysis was conducted to investigate the relationship between treatment response and overall survival. AZA-001 data were analyzed in a multivariate Cox regression analysis with response as a time-varying covariate. Response categories were "Overall Response" (defined as complete remission, partial remission, or any hematologic improvement) and "Stable Disease" (no complete or partial remission, hematologic improvement, or progression) or "Other" (e.g. disease progression). Achieving an Overall Response with azacitidine reduced risk of death by 95% compared with achieving an Overall Response with the conventional care regimens (hazard ratio 0.05 [95%CI: 0.01-0.43], P=0.006). Sensitivity analyses indicated that significantly improved overall survival remained manifest for patients with a hematologic improvement who had never achieved complete or partial remission (hazard ratio 0.19 [95%CI: 0.08-0.46], P<0.001). Stable Disease in both azacitidine-treated and conventional care-treated patients was also associated with a significantly reduced risk of death (hazard ratio 0.09, [95%CI: 0.06-0.15]; P<0.001). These results demonstrate azacitidine benefit on overall survival compared with conventional care regimens in patients with higher-risk myelodysplastic syndromes who achieve hematologic response but never attain complete or partial remission, in addition to the survival advantage conferred by achievement of complete or partial remission.

Background: Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31)., Design and Methods: Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only., Results: Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations., Conclusions: Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449).

In patients with low and intermediate risk myelodysplastic syndrome and deletion 5q (del(5q)) treated with lenalidomide, monitoring of cytogenetic response is mandatory, since patients without cytogenetic response have a significantly increased risk of progression. Therefore, we have reviewed cytogenetic data of 302 patients. Patients were analyzed by karyotyping and fluorescence in situ hybridization. In 85 patients, del(5q) was only detected by karyotyping. In 8 patients undergoing karyotypic evolution, the del(5q) and additional chromosomal aberrations were only detected by karyotyping. In 3 patients, del(5q) was only detected by fluorescence in situ hybridization, but not by karyotyping due to a low number of metaphases. Karyotyping was significantly more sensitive than fluorescence in situ hybridization in detecting the del(5q) clone. In conclusion, to optimize therapy control of myelodysplastic syndrome patients with del(5q) treated with lenalidomide and to identify cytogenetic non-response or progression as early as possible, fluorescence in situ hybridization alone is inadequate for evaluation. Karyotyping must be performed to optimally evaluate response.

Background: Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old., Design and Methods: We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine., Results: The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49-1.35) for survival and of 0.67 (95% CI, 0.42-1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22-1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22-1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40-3.42) and that for disease-free survival was 1.02 (99% CI, 0.40-2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65-2.27) for survival and 1.02 (95% CI, 0.56-1.85) for disease-free survival., Conclusions: Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy.

Clonal heterogeneity has not been described in patients with myelodysplastic syndrome with isolated del(5q), for which lenalidomide has emerged as a highly potent treatment. However, transformation to acute myeloid leukemia is occasionally observed, particularly in patients without a cytogenetic response to lenalidomide. We performed molecular studies in a patient with classical 5q- syndrome with complete erythroid and partial cytogenetic response to lenalidomide, who evolved to high-risk myelodysplastic syndrome with complex karyotype. Immunohistochemistry of pre-treatment marrow biopsies revealed a small fraction of progenitors with overexpression of p53 and sequencing confirmed a TP53 mutation. TP53 mutated subclones have not previously been described in myelodysplastic syndrome with isolated del(5q) and indicates a previously unknown heterogeneity of this disease. The aberrant subclone remained stable during the treatment with lenalidomide and expanded at transformation, suggesting that this pre-existing cell population had molecular features which made it insensitive to lenalidomide and prone to disease progression.

The classification of myelodysplastic syndromes is based on the morphological criteria proposed by the French-American-British (FAB) and World Health Organization (WHO) groups. Accurate enumeration of blast cells, although essential for diagnosis of myelodysplastic syndrome and for assignment to prognostic groups, is often difficult, due to imprecise criteria for the morphological definition of blasts and promyelocytes. An International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) of hematopathologists and hematologists expert in the field of myelodysplastic syndrome reviewed the morphological features of bone marrows from all subtypes of myelodysplastic syndrome and agreed on a set of recommendations, including recommendations for the definition and enumeration of blast cells and ring sideroblasts. It is recommended that (1) agranular or granular blast cells be defined (replacing the previous type I, II and III blasts), (2) dysplastic promyelocytes be distinguished from cytologically normal promyelocytes and from granular blast cells, (3) sufficient cells be counted to give a precise blast percentage, particularly at thresholds that are important for diagnosis or prognosis and (4) ring sideroblasts be defined as erythroblasts in which there are a minimum of 5 siderotic granules covering at least a third of the nuclear circumference. Clear definitions and a differential count of a sufficient number of cells is likely to improve precision in the diagnosis and classification of myelodysplastic syndrome. Recommendations should be applied in the context of the WHO classification.

Background and Objectives: The anemia of low-risk myelodysplastic syndromes (MDS), refractory anemia (RA) and RA with ringed sideroblasts (RARS), may respond to treatment with hematopoietic growth factors (GF)); erythropoietin (Epo) +/- granulocyte colony-stimulating factor (G-CSF). The present study was designed to assess whether functional iron deficiency may develop in MDS patients receiving these treatments., Design and Methods: Erythrocyte scattergrams from 34 patients with RA and RARS (untreated, transfused, or GF-treated with partial or complete erythroid response) were analyzed with Bayer-Advia equipment., Results: In untreated RARS, the proportion of hypochromic erythrocytes (Hypo-e, median 6.2%, range 1.1-8%) and hypochromic reticulocytes (Hypo-r, median 45%, range 22-48%), as well as mean corpuscular volume (MCV, median 101 fL) were significantly elevated compared to corresponding values in controls. These values increased further after GF-treatment (median 11%, 57%, and 105 fL, respectively), in spite of improved hemoglobin values and adequate body iron stores. The values observed in untreated RA patients largely fell within the normal range, and there was no significant influence of GF treatment. Notably, the hemoglobin content of reticulocytes (MCHr) did not differ between MDS and controls, and was not influenced by GF treatment., Interpretation and Conclusions: The red cell population in RARS shows morphological abnormalities in terms of varying but overall increased size, and reduced hemoglobin concentration. The proportion of abnormal cells increases after successful pro-erythroid GF treatment, indicating that GF promote erythroblast survival, and maturation into erythrocytes. Hence, the finding of hypochromic red cells should not routinely be interpreted as a marker for Epo-induced functional iron deficiency in MDS.

Background and Objective: There are several therapeutic options for patients with myeiodysplastic syndrome (MDS) but most of them are poorly effective and the potentially curative ones are available only for a minority of individuals. The aim of this article is to define a rational basis for a patient-oriented approach to treatment of MDS., Evidence and Information Sources: All four authors have done clinical studies of treatment of MDS, including stem cell transplantation, intensive and low-dose chemotherapy, and use of hematopoietic growth factors. They also participated in the Fourth international Symposium on MDS (Barcelona, 24-27 April 1997). In addition, the present review critically examines relevant articles and abstracts published in journals covered by the Science Citation Index and Medline., State of the Art and Perspectives: At present, the only two treatments that can prolong survival are allogeneic stem cell transplantation (SCT) and intensive chemotherapy, but only a minority of MDS patients can really benefit from them. The heterogeneity of MDS patients, the wide variety of patient inclusion criteria and transplant procedures used, and relatively small numbers of patients in the individual reports of allogeneic SCT make it difficult to draw many definitive conclusions. However, approximately 40% of patients with MDS who are eligible for allogeneic SCT are likely to be cured by this treatment. Intensive chemotherapy with a combination of cytosine arabinoside and an anthracycline should be offered to all patients with an increase in bone marrow blasts who are not eligible for allogeneic SCT, especially those patients up to 65 years of age. Complete remission rates are similar to those obtained in patients with acute myelogenous leukemia, but probability of long-term survival is low. The remaining treatments validated in clinical trials (erythropoietin and/or granulocyte colony-stimulating factor, low-dose cytosine arabinoside) can improve the efficiency of hematopoiesis in subsets of patients. Responsive individuals might experience an improvement in quality of life but very few studies have addressed this question so far. The majority of MDS patients still rely upon supportive therapy. A clinical decision path based on findings of clinical trials and the patient's expectations can help physicians in decision making. Because of the inadequacies of all current treatment modalities, participation in clinical trials should always be encouraged.