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Personalized management of MDS
being retrospective analyses or registry studies.113-117 Currently, the drugs used for iron chelation are deferasirox (oral), deferioxamine (intravenous via an infusion pump) and deferiprone (oral). A prospective randomized, double- blind study was performed, which assessed event-free sur- vival and safety of deferasirox compared with placebo.118 Although not demonstrating an improvement in overall survival, the median event-free survival was prolonged by approximately 1 year with deferasirox treatment. Clinical guidelines include recommendations for the use of iron chelation therapy in some populations of MDS patients. However, debate regarding the clinical utility of iron chela- tion therapy remains.9,82,119-122
Erythropoiesis-stimulating agents
Erythropoiesis-stimulating agents (ESA) constitute standard treatment for the anemia of lower-risk MDS.9,83 Both the EMA and FDA have evaluated numerous studies on the effects of ESA in the treatment of anemia in MDS, although both agencies formally approved erythropoietin and darbepoetin only recently, based on placebo-con- trolled trials.123,124 Erythropoietin α and β and later darbe- poetin have been extensively evaluated for MDS and were shown to improve hemoglobin levels and reduce transfusion needs in 40% to over 60% of patients with an overall duration of 18-24 months.125 Higher doses (60,000 to 80,000 U per week) may give a slightly better response rate in transfusion-dependent patients.126 Lower serum erythropoietin levels are associated with higher response rates. There is no evidence from any trial or registry that treatment with ESA is associated with an increased risk of disease progression or leukemic transformation.125
A study of a large cohort of patients included in the European Union MDS Registry recently added significant novel information. Patients with symptomatic anemia who did not require transfusions and were treated with ESA had a significantly better response rate and longer time to a permanent transfusion need than those treated after the onset of regular transfusions.127 This led to an important change in the European guidelines, which now recommend treatment at the onset of symptomatic ane- mia. Relapse of anemia is usually not associated with dis- ease progression and the biological reasons for treatment failure are yet to be explored. Several randomized phase II studies and epidemiological investigations also showed that the addition of low-dose G-CSF to erythropoeitin may improve the response rate to ESA, and improve over- all survival.128-130 The synergistic effect is seen particularly in MDS-RS and is related to the anti-apoptotic effects of G-CSF on mitochondria-mediated apoptosis.
Lenalidomide for del(5q)
An initial clinical trial showed that MDS patients with the del(5q31) chromosomal abnormality were particular- ly responsive to lenalidomide, demonstrating a major reduction in transfusion requirements and reversal of cytogenetic abnormalities.131 These effects were con- firmed and extended in a larger phase II trial and a subse- quent phase III, randomized, placebo-controlled trial which demonstrated erythroid response rates of ~50- 60%, including a transfusion independence rate of ~28% together with concomitant cytogenetic responses.132 A phase III randomized trial in lower-risk, ESA-refractory, non-del(5q) patients comparing lenalidomide alone with lenalidomide in conjunction with recombinant human
erythropoietin suggested that lenalidomide may restore sensitivity of MDS erythroid precursors to erythropoi- etin.133 These data led to the recommendation in the NCCN and MDS-Europe guidelines on the symptomatic treatment of anemic del(5q) MDS patients with lenalido- mide.9,83 The negative impact of TP53 mutations (present in ~30% of these patients) on responsiveness and out- come after lenalidomide is notable.134
Immunosuppressive treatment
Treatment with immunosuppressive agents such as antithymocyte globulin and cyclosporine A may improve cytopenias in certain patients with MDS.135-138 As recently described in a well-performed meta-analysis there are few large prospective studies, follow-up times in many studies are short, and each study has used different immunosuppressive regimens.139 In an analysis of 570 patients with a median age of 62 years, 80% of patients had low or intermediate-1 IPSS scores, the complete response and red cell transfusion independence rates were 12.5% and 33%, respectively, and the rate of pro- gression to AML was 8.6% per patient-year. Immunosuppressive therapy has not been confidently evaluated in relation to mutational profiles. Both European and USA guidelines identify a group of younger, lower-risk MDS patients with hypo- or normo- plastic bone marrow and normal karyotype, with the exception of trisomy 8, who may respond to immuno- suppressive therapy. Some responders may experience durable and possibly permanent responses, indicating that immunosuppressive therapy may be considered prior to SCT in patients with these features.
Hypomethylating agents
Azacitidine
Based on early phase I/II studies, two large randomized phase III studies were designed to evaluate the effects of azacitidine in MDS.140-142 The CALGB9221 trial included patients with all subtypes of MDS, and showed improved overall response rate and progression-free survival in the azacitidine arm. The second randomized study, AZA- 001, was designed to demonstrate a possible difference in overall survival.143 The median overall survival for the azacitidine-treated patients was 24.5 months vs. 15 months for patients assigned to the control arm. Both studies showed that responses are often delayed until the patient has received ≥3 treatment cycles.142,143 Azacitidine is approved in Europe for the treatment of higher-risk MDS and in the USA for the treatment of all MDS sub- groups.
Some phase II studies have also shown effects in lower- risk MDS although the clinical benefits and risks in this population are still unclear and no studies have provided evidence for prolonged survival in this group of patients.141,144-146 A large randomized study (NCT01566695) is assessing the effect of oral azacitidine in lower-risk MDS and will perhaps bring more clarity on its role in the treatment of these patients.
Much effort has been given to identifying factors that could predict response. Predictive models based on basic clinical data have not generated clinically meaningful tools.147-149 Neither have studies on mutational profiles resulted in robust response prediction. Better responses have been reported for patients with TET2, ASXL1 and EZH2 mutations but the data are conflicting.149-152
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