Intended for healthcare professionals in the Belux only

Myelodysplastic syndromes (MDS)

MDS can be grouped into two major categories: higher risk or lower risk.6 Patients with higher-risk MDS carry a major risk of progression to acute myeloid leukaemia and short survival.7 Lower-risk MDS account for the majority of patients with MDS with anaemia being the main clinical challenge.6,8

Typically, treatment goals for higher-risk MDS include modifying the natural course of disease and improving survival.9 Since survival rates are low for patients with higher-risk MDS, pharmacological treatments should be initiated quickly.10 Treatment options include haematopoietic stem cell transplant (for eligible patients), hypomethylating agents (azacitidine) and chemotherapy. Azacitidine is the first-line standard of care for patients that are not eligible to receive haematopoietic stem cell transplant.7,11

Treatment options for higher-risk MDS include HSCT, hypomethylating agents and chemotherapy.7,11

HSCT, haematopoietic stem cell transplant; MDS, myelodysplastic syndromes.

Treatment goals for lower-risk MDS include symptom management (of the disease and associated anaemia) and delaying progression.9,12 Initial management of asymptomatic patients may involve watchful waiting, with active or supportive treatment initiated when cytopenias, most often anaemia, become symptomatic.11 Treatment options for lower-risk MDS include active, disease-modifying agents (lenalidomide), immunosuppressive therapies (antithymocyte globulin [ATG]) and supportive care options to manage chronic anaemia (erythropoiesis-stimulating agents and red blood cell transfusions). Lenalidomide is indicated for the treatment of adult patients with transfusion-dependent anaemia due to lower-risk MDS associated with an isolated del(5q) cytogenetic abnormality when other therapeutic options are insufficient or inadequate. ESAs are the standard of care for symptomatic anaemia in patients with lower-risk MDS without a del(5q) cytogenetic abnormality.7,11

Treatment options for lower-risk MDS include ESAs, disease-modifying agents such as lenalidomide, immunosuppressive therapy such as antithymocyte globulin, RBC transfusions and other supportive measures such as ICT and platelet transfusions.7,11,13

ESA, erythropoiesis-stimulating agent; ICT, iron chelation therapy; MDS, myelodysplastic syndromes; RBC, red blood cell.

In lower-risk MDS, ESAs and red blood cell transfusions are often administered to improve haemoglobin levels and manage the symptoms of anaemia.5,14,15 Among patients treated with ESAs, response rates range between 30% and 60%, with a median duration of response of 20 to 24 months.16 The presence of specific prognostic factors is associated with worse response to ESAs, including high endogenous serum erythropoietin levels or high red blood cell transfusion burden.16 Primary ESA failure or relapse after an initial response can frequently occur and subsequent treatment options are scarce with patients often limited to red blood cell transfusions.7,16

Red blood cell transfusions provide temporary management of severe anaemia, as patients who receive transfusions may continue to experience fluctuations in haemoglobin.17 Patients receiving red blood cell transfusions may also experience complications, such as iron overload and alloimmunisation.18,19

β‑thalassaemia

In β‑thalassaemia, symptoms and treatment vary depending on the severity of the disease and the underlying mutations occurring in the β‑globin gene.20,21 The standard of care and mainstay treatment for β‑thalassaemia is red blood cell transfusions with iron chelation therapy (to prevent or treat iron overload).4 The goals of treatment in β‑thalassaemia vary according to the dependency on red blood cell transfusions. For transfusion-dependent patients, the aim of treatment is to change the natural course of the disease and improve survival by aiming to reduce transfusion burden and the need for iron chelation therapy. Treatment of non-transfusion-dependent β‑thalassaemia involves managing symptoms, such as anaemia and iron overload, and improving quality of life.22,23 The majority of patients with the most severe forms of β‑thalassaemia will receive life-long red blood cell transfusions and iron chelation therapy.4,21 Patient characteristics will determine eligibility for various other available treatments such as haematopoietic stem cell transplant, gene therapy and splenectomy.23,24 The only definitive cure for β‑thalassaemia is haematopoietic stem cell transplant. Recently approved gene therapy is potentially curative but eligibility is limited to a specific subset of patients.23-25

Treatment options for β‑thalassaemia include RBC transfusions with ICT, HSCT, gene therapy and splenectomy.23,24

HSCT, haematopoietic stem cell transplant; ICT, iron chelation therapy; RBC, red blood cell; TD, transfusion dependent.

Below are two videoclips of experts discussing MDS and β-thalassaemia with the treatment options available

Treatment of
β‑thalassaemia

Professor Maria Domenica Cappellini, Professor of Internal Medicine, University of Milan

In this video, Professor Cappellini discusses the classification and treatment of transfusion-dependent and non-transfusion-dependent β‑thalassaemia.

7-minute video

Differences and similarities of MDS and β‑thalassaemia

Doctor Esther Natalie Oliva, Haematologist, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli

In this video, Doctor Oliva introduces MDS and β‑thalassaemia and the differences between the diseases. Doctor Oliva also discusses the differences and similarities in the treatment of both diseases.

5-minute video

Other haematological diseases

Aplastic anaemia

The goals of treatment for aplastic anaemia are to restore haematopoietic stem cells and ameliorate cytopenia-related complications.26 Treatment options may include stem cell transplant (the only treatment to offer a potential cure), immunosuppressive therapy (such as ATG in combination with cyclosporin), and stem cell stimulation therapy (such as the synthetic mimetic of thrombopoietin, eltrombopag) may be an option for patients refractory to or relapsing after immunosuppressive therapy and androgens.26-28 Blood transfusions (of platelets or red blood cells) and other supportive care measures are often utilised.26

Myelofibrosis

The current treatment goals for myelofibrosis are to reduce the burden of symptoms and reduce the risk of leukaemic transformation.29,30 For high-risk patients, treatment options may include stem cell transplant (the only treatment capable of extending survival or offering a potential cure) or an investigational agent within a clinical trial.29,30 For low-risk patients, observation alone may be an option and for intermediate-risk patients, and low-risk patients requiring treatment, options include investigational agents in the setting of a clinical trial.29 Other treatment options include ruxolitinib, an inhibitor of Janus Kinase 1 and 2 (JAK1, JAK2) for the treatment of constitutional symptoms and hydroxyurea for the treatment of symptomatic splenomegaly.29,30 For patients not eligible for stem cell transplant or clinical trial enrolment, symptom-directed therapeutic options include conventional treatments for anaemia (red blood cell transfusions, ESAs, androgens, steroids), splenomegaly, constitutional symptoms, localised bone pain, or symptomatic extramedullary haematopoiesis.29,30

Sickle cell anaemia

Treatment for sickle cell anaemia usually aims to relieve symptoms and prevent complications.31 Treatment may include red blood cell transfusions, antibiotics (including penicillin) to treat infections, antibiotics as prophylaxis to prevent infections in infants, pain relieving medications and hydroxyurea to reduce the frequency of painful crises.31,32 Stem cell transplant is an option to provide a potential cure but is usually only offered to younger patients.31

Congenital dyserythropoietic anaemias

Congenital dyserythropoietic anaemias are generally managed using red blood cell transfusions and iron chelation therapy. Interferon-α treatment and splenectomy have both been used successfully to reduce the dependency on red blood cell transfusions.3 As with β‑thalassaemia, the only definitive cure for patients with congenital dyserythropoietic anaemias is stem cell transplant, however, this is limited to patients with very severe anaemias.3,33

Inherited sideroblastic anaemias

For mild inherited sideroblastic anaemias a watch and wait approach may be adopted whilst patients with mild-to-severe anaemia may be treated with ESAs or regular red blood cell transfusions.2 Hypomethylating agents and stem cell transplant may be considered for the most severe cases.2

The limitations of red blood cell transfusions for chronic anaemia

Red blood cell transfusions for chronic anaemia in patients with haematological diseases can improve the symptoms of anaemia. However, red blood cell transfusions can also impact quality of life and are associated with significant complications, such as alloimmunisation, allergic reactions, infections, autoimmune reactions and iron overload, which can cause significant morbidity and mortality.4,19,22,23,34-38 Treatment of chronic anaemia places a considerable additional strain on the finite blood supply with blood service organisations facing pressure to maintain sufficient blood supplies and meet demands.39

The impact of transfusions and iron overload in MDS patients

Doctor David Valcárcel, University Hospital Vall d’Hebron

In this video, Dr Valcárcel outlines the risks associated with red blood cell transfusions in patients with MDS. Dr Valcárcel also describes the subsequent effect of iron overload and the impact of iron chelation therapy.

4-minute video

Treating iron overload

Iron overload occurs when iron accumulates in the body and can lead to the production of reactive oxygen species, fibrosis and end organ damage.40,41 Although red blood cell transfusions are the primary cause of iron overload, patients with haematological diseases associated with ineffective erythropoiesis can experience iron overload even in the absence of red blood cell transfusions.20,40,42 Ineffective erythropoiesis can lead to iron overload by reducing hepcidin production, the hormone responsible for regulating iron absorption, which results in increased intestinal iron absorption and increased release of recycled iron from cells into the bloodstream.24,40,43 Iron is usually transported in the bloodstream bound to transferrin, however, in cases of iron overload resulting from regular red blood cell transfusions and/or ineffective erythropoiesis, transferrin becomes saturated leading to an increase in free, non-transferrin-bound iron.44 This excess free iron, which is toxic, accumulates in the body as there is no physiological pathway to excrete it. As the levels of free, non-transferrin-bound iron in the blood increase, iron deposits in various organs leading to clinical complications and organ damage.24,45-47

Iron overload occurs when iron accumulates in the body. Additional to the accumulation of iron caused by red blood cell transfusions, ineffective erythropoiesis can lead to iron overload by decreasing hepcidin production in the liver.23,24,40,45-47

NTBI, non-transferrin-bound iron.

Please see Normal and ineffective erythropoiesis for further details

Iron chelation therapy is used to treat iron overload in patients with haematological diseases; iron chelator molecules bind to the free, non-transferrin-bound iron in the bloodstream and allow subsequent excretion via the urine or faeces.23 Iron chelation therapy can balance iron accumulation with iron excretion and prevent increased free, non-transferrin-bound iron concentrations and end organ damage.23 Iron chelation therapy has been shown to be effective in improving survival and decreasing risk of heart failure and morbidities from iron overload. Although iron chelation therapy has markedly improved outcomes in patients, issues still remain, including patient adherence to therapy, cost, potential toxicities and patient burden.48

Treatment of iron overload in patients with
β-thalassaemia

Professor Antonis Kattamis, Professor of Pediatric Hematology Oncology, Aghia Sophia Children’s Hospital

In this video, Professor Kattamis describes the complications associated with iron overload in patients with β-thalassaemia and provides a summary of the iron chelation therapies currently available.

3-minute video

Iron overload

Professor Maria Domenica Cappellini, Professor of Internal Medicine, University of Milan

In this video, Professor Capellini describes the impact of iron overload on patient morbidity and explains how iron overload can be managed.

5-minute video

Iron chelation therapy

Professor Maria Domenica Cappellini, Professor of Internal Medicine, University of Milan

In this video, Professor Capellini discusses how the treatment of iron overload has evolved over the years and highlights the side effects of iron chelation therapy.

6-minute video

The unmet need in the treatment of chronic anaemia

For many haematological diseases, the only potential definitive cure is stem cell transplant, which is limited to a small number of eligible patients. Gene therapy may be potentially curative for patients with β-thalassaemia, but as with stem cell transplant, gene therapy is only appropriate for a specific subset of patients.3,7,23,31 Other treatments, such as ESAs and red blood cell transfusions with iron chelation therapy have limitations due to their own complications.1,4,19 ESAs can be effective in patients without adverse prognostic factors, however, many patients with lower-risk MDS receiving ESAs either relapse after an initial response or have primary resistance to these agents; for these patients there are limited effective treatment options available after the failure of ESAs. 16 Red blood cell transfusions may result in iron overload and other complications, whilst iron chelation therapy poses certain challenges such as poor adherence and regular monitoring.22,41,45,48 Therefore, in haematological diseases there is a significant unmet need for therapies targeting alternative pathways involved in the development of chronic anaemia, such as those implicated in ineffective erythropoiesis caused by an erythroid maturation defect, with the goal of reducing patient reliance on red blood cell transfusions and iron chelation therapy.

Please see Erythroid maturation defect (EMD) for further details

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