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Treatment Options in Elderly MDS Patients

Chapter 11 - Myelodysplastic Syndromes in the Senior Patient

Transfusion Therapy, Growth Factors and Iron Chelation

An essential goal in the treatment of senior patients is to manage and to counteract the consequences of cytopenias and to maintain and increase the quality of life (QoL).

Treatment options in Senior Lower-risk MDS

  • Anaemia is present in the vast majority (80-90%) of MDS patients and results in an impaired HR-QoL. In addition, a high red blood cell (RBC) transfusion frequency represents an unfavourable risk factor for survival. Transfusion therapy using RBC aims to reach a range of 80-100 G/L in cardio-respiratory healthy persons and >100-120 G/L in elderly and in persons displaying co-morbidities. RBC-transfusions should be kept to a minimum. Erythropoiesis-stimulating agents (ESAs) with or without granulocyte-colony stimulating factor (G-CSF) represent the standard of treatment for transfusion-dependent anaemia in lower-risk MDS (Figure 1).
  • ESAs represent an effective treatment of anaemia in MDS to improve haemoglobin levels, to reduce transfusion need and to increase QoL. As low endogenous erythropoietin (EPO) levels as well as a low transfusion need result in an increased response rate, predictive models for ESA treatment have been developed.The Nordic Score identifies patients with low, intermediate and high probability of response (Table 5). Moreover, G-CSF is administered in combination with ESAs in low/intermediate risk patients to augment the erythroid response, which is particularly effective in patients with an increase of ring sideroblasts (RARS). ESAs have been used safely in larger numbers of MDS patients with no evidence for negative impact on survival or AML evolution. Moreover, ESAs even seem to improve survival in treated patients. Despite their widespread use in MDS, ESAs are so far not registered in this indication. Prospective, randomised clinical studies are ongoing. When applying ESAs the increased risk of thromboembolic complications should be considered. Whereas the majority of MDS-patients suffer from iron-overload, iron deficiency should be assessed at the start and during the course of an ESA-therapy by analysing serum ferritin levels, transferrin saturation and corrected by iron supplementation orally or i.v.
  • In neutropenic infections in MDS the interventional use of G-CSF is recommended.
  • In thrombopenic patients platelet transfusions are given to prevent bleeding. However, due to immunisation, frequent transfusions might cause a poor response. Thrombopoietic agents like romiplostim or eltrombopag, which are approved for the treatment of immune thrombocytopenic purpura (ITP), have been introduced in MDS and are currently evaluated in clinical trials. First reports promising results show that romiplostim results in a decrease in the number of bleeding events and platelet transfusions. Although the study drug was discontinued because of an initial concern of AML risk, survival and AML rates were similar with romiplostim and placebo.
  • Frequent RBC transfusions result in iron overload and may cause transfusion-related hemochromatosis, which primarily affects the heart and the liver. As the risk of events becomes apparent when RBC transfusions exceed 20 andserum ferritin levels exceed 1500-2000 ng/mL, treatment with iron-chelating agents such as desferoxamine (applied either subcutaneously or intravenously) or deferasirox (orally), should be considered. In most guidelines a reasonable expected survival (at least more than one year) is anticipated. Renal function has to be monitored carefully in elderly patients treated with deferasirox.

Immunomodulating Agents

  • Lenalidomide represents an immunomodulating drug (IMiD) which is highly active in MDS with 5q-. Lenalidomide produces major clinical and even cytogenetic responses that formed the basis for EMA and FDA approval. Lenalidomide also reveals activity in non-del5q- lower risk MDS (phase III studies to evaluate the relevance of lenalidomide in non-del5q- lower-risk MDS are ongoing). Relevant side effects of Lenalidomide are neutropenias and thrombocytopenias.
  • Immunosuppressive strategies using combinations of anti-thymocyte globulin (ATG) and Cyclosporin-A (CyA) are effective in subgroups of younger patients in hypoplastic MDS and with a HLADR15 Phenotype. As ATG is poorly tolerated in elderly patients, a CyA monotherapy is generally preferred. Due to nephrotoxicity renal function has to be monitored closely.

Epigenetic Therapies

Treatment options in Senior Higher-risk MDS

The hypomethylating agents 5-azacitidine and decitabine have shown encouraging results in higher-risk MDS patients. 5-azacitidine (AZA) is already considered to be the standard of therapy in elderly higher-risk MDS, who are not eligible for intensive therapies such as AML-induction or haematopoietic stem cell transplantation (HSCT) (Figure 2). AZA has received EMA approval in MDS for this indication. In low risk patients, these drugs are analysed in clinical studies and might so far only be considered when signs of progression occur. AZA was demonstrated in a phase III study to significantly extend overall survival in higher-risk MDS in comparison with a conventional care regimen. Effectiveness of AZA in response and survival prolongation was demonstrated in a subgroup analysis even in elderly MDS patients (75 years). As patients respond often after several courses, at least six cycles of AZA are recommended. In the absence of unacceptable toxicity or disease progression, continued AZA treatment might further improve responses in MDS. Besides induction of a complete remission (Cr) or a partial remission (PR), haematologic improvement of anaemia or thrombocytopaenia including stable disease, might be clinically relevant as they have shown to be associated with prolonged survival. Actually studies are ongoing to improve the effectiveness of AZA by addition of lenalidomide or histone deacetylase inhibitors.

  • Decitabine and azacitidine show similar response rates and toxicities, azacitidine significantly improved overall survival and time to acute myeloid leukaemia Transformation. These benefits were not found with decitabine (Xie M et al. 2014). Therefore, azacitidine is recommended as the first-line hypomethylating agent for MDS, especially in elderly patients or those with high risk.
  • Valproic acid (VPA) was used as an anticonvulsant for decades and might be effective in myeloid neoplasms by the inhibition of histone deacetylase. As VPA causes an erythroid response in about 50% of patients in low-risk MDS, treatment with valproic acid might represent a useful alternative in low-risk MDS patients with a low probability of erythropoiesis-stimulating factors (ESF) response (Figure 1). In senior patients monitoring of VPA serum concentrations is essential.

Intensive Therapies in elderly MDS: Current Standards

Allogeneic HSCT represents so far the only curative treatment approach in MDS. As this therapy is associated with a relatively high risk of transplant-related morbidity and mortality, a HSCT with reduced intensity conditioning (RIC-HSCT) can only be offered to a small cohort of elderly patients, who are characterised by an excellent performance status and the lack of relevant co-morbidities. Similarly to HSCT, intensive AML-like polychemotherapy can restore normal polyclonal haematopoiesis in subgroups of patients, but induces long-term disease-free survival only in a minority of patients. In a given elderly patient, the final decision to apply intensive therapies must be based on multiple parameters including Karyotype, functional capacities, co-morbidities and patient preference (Figure 2).

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