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E. Hellström-Lindberg et al.
and survival and did not point towards a common genetic basis.94 The term clonal cytopenia of unknown signifi- cance defines individuals with myeloid mutations and some degree of cytopenia, but without fulfilling criteria for MDS or other hematologic diagnoses. The type and number of mutations, and variant allele frequencies are potential predictors of risk of progression and are current- ly being evaluated and reviewed in large cohorts.95,96 Single mutations in TET2 or DNMT3A with limited variant allele frequencies are observed in a relatively large fraction of individuals above 60 years and could thus be considered normal, while the presence of more than one mutation and any splice factor mutation may predict a high risk of developing MDS. Patients with clonal cytopenia of unknown significance, in particular if they are potential candidates for curative treatment, should be followed up, but results are presently too divergent to allow for precise recommendations.
Risk-based therapeutic decision-making
In addition to disease-specific variables, patient-related factors are also essential for risk estimation. Age and comorbidities, naturally, influence the spectrum of avail- able therapies. A number of comorbidity and so-called frailty scores have been developed both for MDS and blood cancers in general and, accounting for both disease- and patient-related factors, considerably improve risk stratification. Several comorbidity scores have been tested in the general MDS patient population, including the MDS-Specific Comorbidity Index and the Charlson comorbidity index.97,98
Therapeutic options
Therapeutic options for patients with MDS vary from supportive care to allogeneic SCT, depending on disease- and patient-related risk factors. Table 6 provides an overview of therapeutic options and is divided into treat- ments which either are formally approved by the FDA and/or EMA or are part of long-standing routine treatment used for MDS, albeit having been approved for other diag- nosis, or are in the process of being approved. As the MDS-Europe and NCCN guidelines are relatively specific about indications and dosing, these will not be detailed in the present review.
Supportive care
Supportive care is a cornerstone of the management of all MDS and MDS/MPN patients.91 Recent studies show reduced progression-free survival and quality of life in patients with a higher density of transfusions.15,19,99 A Nordic study showed that quality of life improved in patients responding to growth factors, but also in non- responders transfused to a target hemoglobin of >12 g/dL.100 A British study showed that higher transfusion tar- gets were associated with improved quality of life.101 Indeed, increasing evidence suggests that transfusion ther- apy should be tailored according to the patient’s subjective symptoms and not to specific hemoglobin trigger levels.83
Severe thrombocytopenia with the need for transfu- sions becomes increasingly frequent with time.14 Consensus-based guidelines agree that platelet transfu-
sions should be governed by trigger platelet count levels during active treatment with chemotherapy and hypomethylating agents (HMA), but mainly based on bleeding symptoms during untreated chronic thrombocy- topenia. Eltrombopag and romiplostim are licensed (the latter only in the USA) for the treatment of severe chronic immune thrombocytopenia. The results from the pivotal studies in lower-risk and higher-risk MDS did not generate licensing in any region, even though some positive responses were observed.102,103 Eltrombopag did not improve the outcome of patients treated with azacytidine in a randomized phase III study.103 These compounds may relieve bleeding symptoms in patients with lower-risk hypoplastic MDS with severe thrombocytopenia, and are sometimes used for such individuals. Granulocyte colony- stimulating factor (G-CSF) is not indicated for low neu- trophil counts, but can be used as supportive care in the case of neutropenia caused by HMA treatment, in partic- ular after recurrent infectious events.9,83
Iron chelation
Close to 50% of MDS patients need red blood cell trans- fusions as supportive care.21,30,50 Transfusion dependence leading to iron overload has a negative impact on organ function as well as infectious complications in some analy- ses.104-106 In cases of iron overload, the transferrin binding of iron is overwhelmed and free non-transferrin bound iron, a redox active component in the plasma, appears to be an important mediator of tissue damage.107-110
Prior observational studies have indicated that iron over- load may contribute to poorer clinical outcomes in patients with low/intermediate-1-risk MDS.111,112 Although studies have shown that iron chelation therapy may improve patients’ outcomes, most studies had limitations, such as
Table 6. Therapeutic options for myelodysplastic syndrome. Approved by EMA or FDA or part of standard care
- Transfusiontherapy
- Ironchelation1
- Erythropoiesis-stimulatingfactors
- Immunosuppressivetreatment
- Lenalidomideforlower-riskdel(5q)MDS - Azacytidine2
- Decitabine3
- Inductionchemotherapy
- Stemcelltransplantation
Available therapeutic options, but not approved for MDS by EMA or FDA
- Venetoclax(+HMAhypomethylatingagentsorlow-dosecytarabine)4 - Luspatercept5
- Eltrombopag,romiplostim6
- Ivosidenib(IDH1)andenasidenib(IDH2)7
1Desferrioxamine, deferasirox and deferiprone available in Europe. 1Desferrioxamine and deferasirox available in the USA. 2Approved for International Prognostic Scoring System (IPSS) intermediate-2 and high-risk myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) with 20-29% myeloblasts by the European Medicines Agency (EMA). Approved for all MDS and AML with 20-29% myeloblasts by the Food and Drug Administration (FDA). 3Approved for IPSS intermediate-2 and high-risk MDS by the FDA.Approved for AML by the FDA and EMA 4Approved for AML (in combina- tion with hypomethylating agents, low-dose ara-C) by the FDA. Approved for chronic
5
lymphocytic leukemia by the EMA. Expected FDA approval in April 2020.
6Eltrombopag and romiplostim approved for immune thrombocytopenic purpura, thrombocytopenia associated with hepatitis C, and aplastic anemia by the FDA. Only eltrombopag approved by the EMA. 7Approved for AML by the FDA. Not approved by the EMA.
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haematologica | 2020; 105(7)