1.
Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders
Malouf R, Ashraf A, Hadjinicolaou A V, Doree C, Hopewell S, Estcourt L J
The Cochrane Database of Systematic Reviews. 2018;5:CD012342.
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Abstract
BACKGROUND Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. OBJECTIVES To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. SEARCH METHODS We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. SELECTION CRITERIA We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. MAIN RESULTS We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. AUTHORS' CONCLUSIONS We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.
Clinical Commentary
Xiangrong He, MD, PhD & Claudia S. Cohn, MD, PhD, both of University of Minnesota, Department of Laboratory Medicine and Pathology.
What is known?
Thrombocytopenia represents a common problem for patients withchronic bone marrow failure disorders, the most common of which are myelodysplastic syndrome (MDS) and anaplastic anemia (AA). In addition to thrombocytopenia, both morphologic and functional platelet abnormalities may be seen in these patients as well. Platelet transfusion support is the primary management option for thrombocytopenia and active bleeding in these patients. Platelets are usually transfused prophylactically at counts less than 10 x 109/L and with higher counts in patients with hemorrhage. As compared with no prophylaxis, prophylactic platelet transfusions have been shown to be superior in reducing moderate to severe bleeding, primarily in people with leukemia. However, the evidence of prophylactic use for platelet transfusions in people with chronic bone marrow failure is lacking. Meanwhile, platelets are a precious resource and platelet transfusion carries many risks. Thus, avoiding unnecessary prophylactic platelet transfusions will have significant financial and safety implications for health services.
What did this paper set out to examine?
The authors set out to to review in thrombocytopenic patients with chronic bone marrow failure, whether prophylactic transfusions are really necessary or whether these patients can be effectively supported with only therapeutic platelet transfusions given with the onset of bleeding. In particular, they wanted to show that a therapeutic-only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant bleeding in thrombocytopenic patients with primary bone marrow failure disorders.
What did they show?
The review included all patients with MDS, acquired AA, or congenital bone marrow failure disorders that were not being actively treated with a stem cell transplant or intensive chemotherapy. To maximize the number of studies eligible for inclusion, not only randomized controlled trials (RCTs), but good quality non-RCTs, and controlled before-after studies were included. Only one trial met the inclusion criteria for this review. Unfortunately, the trial was incomplete due to an unexpected slow recruiting rate. Therefore, no results were provided by the trial authors. Although the review was unable to make any recommendations on prophylactic platelet transfusion policies for this patient population, it did identify an urgent need for good quality studies in this area.
What are the implications for practice and for future work?
Thrombocytopenia (platelet counts < 10 x 109/L) is one of the most common complications in patients with chronic bone marrow failure. For example, 40% to 65% of MDS patients have thrombocytopenia. Meanwhile, in some Western countries, bone marrow failure is one of the most common underlying reasons for receiving a prophylactic platelet transfusion. However, guidelines on a therapeutic platelet transfusion strategy versus a prophylactic platelet transfusion strategy in this population are still lacking. Due to the absence of relevant data, the current review was not able to reach any conclusions on the safety and efficacy of prophylactic platelet transfusion compared with therapeutic platelet transfusion for patients with chronic bone marrow failure. Nontheless, this review identified a major gap in the literature and underscored the urgency of prioritizing research in this area. In the meantime, platelet transfusions for people with bone marrow disorders should still be managed according to national transfusion guidelines.
2.
A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA)
Pennell DJ, Porter JB, Piga A, Lai Y, El-Beshlawy A, Belhoul KM, Elalfy M, Yesilipek A, Kilinc Y, Lawniczek T, et al
Blood. 2014;123((10):):1447-54.
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Abstract
Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 beta-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.
Clinical Commentary
Prof David Roberts, NHS Blood & Transplant, Oxford, UK
What is known?
Patients with transfusion- dependent thalassaemia accumulate considerable amounts of iron in their tissues, which causes oxidative stress, cell damage and significant functional impairment in the liver, heart and endocrine organs. Chelating agents such as the standard treatment of subcutaneous deferoxamine or the newer oral drug deferasirox can remove iron. The efficacy of iron removal for any given tissue Is different for each iron chelators. The relative effectiveness of each chelator over many months or years will inform the choice of chelation regime for individual patients with different absolute and relative levels of tissue iron loading.
What did this paper set out to examine?
The authors set out to compare efficacy and safety of deferasirox for myocardial iron removal as part of a randomised control trial of and deferasirox and subcutaneous deferoxamine in nearly 200 patients with beta-thalassemia major patients with significant myocardial iron loading as measured by magnetic resonance imaging where the T2* parameter is < 20 milliseconds (T2* 6-20 milliseconds) but with no signs of cardiac dysfunction. In particular, they wanted to show that deferasirox was no worse than deferoxamine in removing iron from the heart.
What did they show?
They showed that both oral deferasirox and subcutaneous deferoxamine removed iron from the heart and so the T2* parameter increased. There was no significant difference between the groups, although there was trend for greater removal of iron from the heart with deferasirox. The precise degree of iron removal depends on the dose of iron chelator that is given. The important finding is that both drugs can remove iron from the heart in transfusion- dependent thalassaemia. There was a high but similar frequency of overall adverse events in both groups.
What are the implications for practice and for future work?
It is now clear that the widely available iron chelator drugs all remove iron from the liver, heart and endocrine organs in a dose-dependent manner but efficacy and side effect profile differs between patients. The key for optimal treatment of patients is to decide a regime that suits each patient and to monitor tissue specific iron loading carefully and to adjust doses and/or treatment according to individual response. Within this framework, future RCTs that define the efficacy of individual iron chelators are very valuable, even essential to understand what iron chelators can be used, to define differences in side-effect profiles and in long term outcomes.