Pathy's Principles and Practice of Geriatric Medicine. Группа авторов
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Platelet growth factors have been an area of active research and investigation. Thrombopoietin is the endogenous hormone responsible for maintaining normal platelet counts. A pegylated derivative, megakaryocyte growth and development factor (MGDF), has been tested as an adjunct to supportive care in patients with AML induction therapy.90,91 Its use did not decrease bleeding complications or reduce platelet transfusions in AML. Furthermore, when tested in healthy volunteers, it resulted in antiplatelet antibodies and thrombocytopenia, halting further development of this compound. Low doses of recombinant human interleukin‐11, a thrombopoietic cytokine, have been tested in patients with MDS and bone marrow failure.92 Five of 11 evaluable patients with MDS had an increase of platelet counts with a median duration of 12–30 weeks. Side effects even at low doses included fluid retention, peripheral oedema, conjunctival injection, and myalgias. Romiplostin, a peptibody found to increase platelet production through the thrombopoietin (TPO) receptor c‐Mpl, has been tested in clinical studies involving healthy volunteers and patients with chronic immune thrombocytopenia and found to increase the platelet count.93 In a phase 1 study using this agent as part of supportive care in patients with lower‐risk MDS, with baseline platelet counts of ≤50 × 109 l−1,94 durable platelet responses were achieved in 19 of 44 patients (46%). Bleeding events and platelet transfusions were reduced in those patients who had sustained responses. One thrombotic event was noted, and reticulin grade in the marrow was increased in 7 patients, unchanged in 10 patients, and decreased in 7 patients. Non‐neutralizing antibodies to either romiplostim or endogenous TPO were found. Of concern was that two patients progressed to AML in the study, and four cases of transiently increased blast counts were noted. No changes in cytogenetics were noted for patients with baseline and end‐of‐study cytogenetics available. Romiplostim has been tested in patients with low‐ or intermediate‐risk MDS receiving azacitidine therapy as an adjunct to supportive care.95 There was no statistically significant difference seen in the groups receiving romiplostim 500 or 750 μg or placebo in terms of clinically significant thrombocytopenic events or platelet transfusions. However, romiplostim 750 μg significantly raised the median platelet count during cycle 3 on day 1 and at the nadir compared with the placebo.
Eltrombopag is an oral small‐molecule non‐peptide agonist of the thrombopoietin receptor. In a phase 1 placebo‐controlled clinical trial of 73 healthy male subjects, eltrombopag given once daily in doses ranging from 5 to 75 mg resulted in a dose‐dependent increase in the platelet count. There were no adverse events in the subjects receiving drug or placebo.96 Eltrombopag is currently being studied in patients with high‐risk MDS.
Pyridoxine, androgens, and vitamins
The rationale for the use of pyridoxine in MDS is the potential improvement in ineffective erythropoiesis. Pyridoxine is a non‐toxic cofactor required for haem biosynthesis and is usually given for three months in patients with anaemia from MDS, but responses are rare. There is no clear role for androgens, danazole, or vitamins in the therapy of MDS.
Disease‐modifying agents for high‐risk disease
The goal of treatment for patients with high‐risk MDS is to limit disease progression and improve survival rates. In general, feasibility of allo‐HSCT should be considered even in older adults and at least for young‐older adults (65–75 years old) in good clinical condition. CGA can be extremely useful in selecting candidates for transplantation.
For those not suitable for allo‐HSCT, hypomethylating agents are a good alternative. Given the limited impact on the disease course in high‐risk groups and the possible significant effects on quality of life, CGA is highly recommended when planning treatment. Best supportive care still remains the most reasonable option for very frail patients with severe multimorbidity, overt disability, and limited life expectancy.
Hypomethylating agents
Azacitidine (5‐azacytidine, 5‐aza, Vidaza) is a pyrimidine nucleoside analogue of cytidine whose mechanism of action is thought to be DNA hypomethylation in addition to a direct cytotoxic effect on the haematopoietic elements of the bone marrow. Another hypomethylating agent, decitabine (5‐aza−2–deocytidine), has also demonstrated promise as an agent for MDS. Chemically it is closely related to azacitidine. Both compounds are approved for use in MDS in the US; only azacytidine has been approved by EMA.
Two phase 3 clinical trials comparing azacitidine with best supportive care demonstrated this drug's clinical efficacy in treating MDS.97,98 Azacitidine treatment (75 mg/m2 per day for seven days, then once a week by subcutaneous injection) was continued in the absence of progression or unacceptable toxicity, and the median number of cycles administered was nine. Complete and partial remission rates for the azacitidine arm were superior to conventional care, at 29 versus 21%, respectively. With a median follow‐up of 21.1 months, the median overall survival was 24.5 months for the azacitidine arm compared with 15 months for the conventional care arm (p = 0.0001).
A phase 3 randomized trial of decitabine versus best supportive care in high‐risk MDS showed similar results, although a survival benefit was not demonstrated, probably due to a higher‐risk study population.99 Even though no prospective comparative analysis has been carried out between the two drugs, a retrospective analysis suggests equivalent efficacy between azacitidine and decitabine.100
Hypomethylating agents offer limited response: complete response/partial response/hematologic improvement is achieved in 40–50% of high‐risk patients. This benefit could be even smaller in real‐world experience. In general, response is slow, so both agents should be given for four to six cycles before the treatment is considered a failure. Generally, these treatments are well tolerated, with the most relevant side effects being worsening of cytopenias (which usually improve during treatment), nausea, and fatigue. Patients who respond are recommended to continue therapy indefinitely until progression, as response is quickly lost after treatment discontinuation, and outcome after stopping the drug is dismal.101
It has been suggested the hypomethylating agents offer a benefit in quality of life, as they improve fatigue, dyspnoea, physical function, and psychological well‐being. However, these data have not been replicated by other studies. It should also be considered that patients require intensive monitoring and frequent attendance to an outpatient clinic.
Haematopoietic stem cell transplantation
The only possible definitive cure for MDS is represented by allogeneic HSCT.81‐83 For many years, older age was considered per se a contraindication to transplant, mainly because of the intensive, myeloablative conditioning chemotherapeutic regimens used. The development of reduced‐intensity conditioning approaches has made HSCT an option even for fit older adults. This treatment modality seeks to maximize the immune effect of graft versus leukaemia while minimizing the toxicity associated with ablative conditioning regimens. Non‐myeloablative transplantation has a low short‐term mortality rate in patients with MDS up to age 70–75 with overall survival rates comparable to those for ablative transplantation, mainly due to the higher risk of relapse.84
In a large retrospective study conducted in the US, 1106 patients ≥70 underwent HSCT. The proportion of allogenic HSCT increased over time (from 0.1% in 2000 to 3.85% in 2013; total number: 298). Acute myeloid leukaemia and myelodysplastic syndromes represented the most common disease indications. Two‐year OS and PFS significantly improved over time (OS: 26% in 2000–2007 to 39% in 2008–2013; PFS: 22% in 2000–2007 to 32% in 2008–2013, P = .003). Two‐year treatment‐related mortality ranged remained unchanged over time (33–35%). Higher comorbidity and myeloablative conditioning were associated with higher mortality rates.102