Long-term Transfusion Research Articles

Management of Sickle Cell Disease Summary of the 2014 Evidence-Based Report by Expert Panel Members

Yawn, Barbara P.*; Buchanan, George R.†; Afenyi-Annan, Araba N.‡; Ballas, Samir K.§; Hassell, Kathryn L.∥; James, Andra H.¶; Jordan, Lanetta#; Lanzkron, Sophie**; Lottenberg, Richard††; Savage, William J.‡‡; Tanabe, Paula J.§§; Ware, Russell E.∥∥; Murad, M. Hassan¶¶; Goldsmith, Jonathan C.##; Ortiz, Eduardo##; Fulwood, Robinson##; Horton, Ann***; John-Sowah, Joylene## Author Information

Paroxysmal nocturnal haemoglobinuria at Oslo University Hospital 2000-2010.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disease characterised by chronic haemolysis, pancytopenia and venous thrombosis. The condition is attributable to a lack of control of complement attack on erythrocytes, thrombocytes and leukocytes, and can be diagnosed by means of flow cytometry. In this quality assurance study, we have reviewed information from the medical records of all patients tested for PNH using flow cytometry at our laboratory over a ten-year period. In the period 2000-2010 a total of 28 patients were tested for PNH using flow cytometry at the Department of Immunology and Transfusion Medicine, Oslo University Hospital. We have reviewed the results of these examinations retrospectively together with information from medical records and transfusion data for the patients concerned. Flow cytometry identified 22 patients with PNH: four with classic disease and 18 with PNH secondary to another bone marrow disease. Five patients had atypical thrombosis. Seventeen patients received antithymocyte globulin or drug treatment; of these, six recovered from their bone marrow disease, while six died and five had a need for long-term transfusion. Five patients with life-threatening bone marrow disease underwent allogeneic stem cell transplantation, three of whom died. Six of 22 patients received eculizumab; the need for transfusion has been reduced or eliminated in three patients treated with eculizumab over a longer period. Flow cytometry identified PNH in a majority of patients from whom we obtained samples. Most patients had a PNH clone secondary to bone marrow failure. Atypical thrombosis should be borne in mind as an indication for the test. Treatment with eculizumab is relevant for selected patients with PNH.

Cerebral Arterial Velocities in SCA-Children with Abnormal Doppler Are Reduced and Normalized More Frequently after Transplantation Than after Transfusion Program (French National Trial “Drepagreffe” AP-HP N°: NCT 01340404)

Background: Evidence-based practices have shown that transfusion program (TP) is beneficial to SCA-patients with abnormally high velocities by Doppler; however, TP cannot be stopped safely, except following HSCT. No prospective trial has to date compared the extent of cerebral vasculopathy following TP or HSCT. The premise of the French National Trial “Drepagreffe” is that cerebral velocities will be reduced to a greater extent after HSCT than under TP.Patients and Methods: We present here preliminary results from this prospective trial with 2 arms (TP/HSCT), defined by the random-availability of a genoidentical donor. Inclusion criteria were SCA (SS/Sb0) children younger than 15 years with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec), placed on long-term transfusion programs, with at least one non-SCA sibling and parents accepting HLA-typing and HSCT if a genoidentical donor was available. Transplanted patients received as conditioning regimen Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin with CSA and short MTX or MMF for GVHD prophylaxis. In the TP arm, HbS% was maintained at < 30% with Hb 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, cerebral MRI/MRA were performed along with cognitive performance testing, the latter done in parallel in the control sibling. Primary endpoint was the significantly greater reduction of velocities in the HSCT than in the TP arm. Among the various secondary endpoints, Doppler normalization defined by velocities < 170 cm/s in all arteries was to occur more often after HSCT than on TP.Results: SCA-children (n=67; 36F-31M) from 10 French SCA-centers were enrolled between 12/2010 and 6/2013 at the mean (SD) age of 7.6 (3.1) years. History of stroke was present in 6 patients (4 in HSCT and 2 in TP) and 1 TIA in HSCT arm. At TP initiation, velocities≥200/cm/sec were found in middle (n=50), anterior (n=11) and internal carotid arteries (n=30) as abnormal velocities were observed in more than one artery in several patients. Mean (SD) maximum velocities were 219 (26) cm/s (range: 200-333). At enrollment all patients were on TP and paired analysis showed that mean(SD) maximum velocities had significantly decreased (p<0.001) under TP:169 (46) cm/s vs 219 (26) cm/s). Following HLA-typing, 35 without genoidentical donor were included in the transfusion arm and 32 with genoidentical donor were transplanted in 6 HSCT-centers. Mean (SD) maximum velocities were not significantly different in both arms at enrollment: 167 (41) in TP vs 170 (51) cm/s in HSCT. During the 12 months follow-up, no stroke was observed but one patient in the TP arm experienced a hyperammonemic reversible coma, without MRI/MRA alteration requiring transfer to intensive care. In the HSCT arm, all patients successfully engrafted, one grade II and two grade III acute GVHD, and no chronic GVHD were observed. Two patients required transfer to intensive care for seizures and pneumonia. Other complications were seizures (n=2), CMV (n=9) or EBV replications (n=1), hemorrhagic cystitis (n=3), aspergillosis (n=1), prolonged but reversible thrombopenia (n=2), transitory hemolytic anemia (n=1). At 12 months, data, available in 63/67 patients, showed that all patients were alive, mean (SD) Hb and HbS% in TP arm were 9.1 (0.9) and 27.5% (11.9), respectively, whereas in the HSCT arm, mean (SD) Hb and % donor chimerism were 12.0 (1.0) g/dL and 86.5% (12.2) respectively (range:60-100%). All transplanted patients had the same Hb electrophoresis than their donor. Mean (SD) maximum velocities were significantly lower post-HSCT (n=31) than under TP (n=32):128 (34) vs 174 (36) cm/s, respectively; (p<0.001), and were decreased more significantly following HSCT than on TP: mean(SD)Δ: -44 (24) vs +6 (3), respectively. The percentage of patients with normal velocities was significantly higher post-HSCT (27/31) than in the TP arm (16/32) (p=0.003).Conclusions: This prospective national trial comparing TP vs. HSCT in SCA-patients with a history of abnormal velocities shows for the first time that HSCT repeatedly and significantly results in a greater decrease in velocities than TP, and has very little toxicity. These preliminary results are encouraging and suggest that suppression of host SCA-erythropoiesis by HSCT is the treatment of choice for SCA-children with abnormal-TCD and genoidentical donor. [Display omitted] [Display omitted] DisclosuresBernaudin:Novartis: Research Funding.

The Safety, Tolerability and Efficacy of Deferasirox in Older Patients with Transfusional Dependent Anemia

BackgroundThe majority of myelodysplastic syndrome (MDS), primary myelofibrosis (MPN) and aplastic anemia (AA) patients during the course of the disease develops a symptomatic anemia requiring transfusions of packed red blood cells (PRBC), each of them containing approximately 200 mg of elementary iron. Because of the fact that human beings are unable to actively eliminate iron from the body, secondary emosiderosis yet becomes evident when body iron content is above 7-14 grams, an amount easily reached after receiving as few as 15-30 PRCB units.From a pathophysiologic point of view, long-term transfusion therapy is certainly the most important cause of iron overload (IOL) in these patients; nevertheless, others mechanism account for this phenomenon, and in particular the role of the ineffective erythropoiesis.Deferasirox (DSX) is the principal option currently available for iron chelation therapy in the management of IOL due to transfusion dependent anemia. DSX is also a potent NF-kB inhibitor, and this effect may explain in part the phenomenon of hematological improvements reported in different clinical trials and in case reports.Materials and MethodsWe analyzed 21 patients,16 male and 5 female, with transfusion dependent anemia and with a transfusional history of almost 10 packed PRBC, treated with DSX from 1 February 2013 to 1 February 2014. Median age was 80 years (65-88). 20 patients (95%) have almost a comorbidity, 7 of them (30%) have more than 3 comorbidities. Heart disease was the most common comorbidity. At baseline median creatinine clearance was 76 ml/min; in 12 patients was < 60ml/min but >40 ml/min, according to NCCN Guidelines. All patients (16 MDS, 3 MPN, 1 AA, 1 hemolytic anemia) were evaluated for IOL by serum ferritin (SF), while only 7 with RM T2*.Median SF at baseline was 1750 μg/L and median PRBC was 32.The starting dose of DSX was 10 mg/kg/day; the dosage should be adjusted up to 20–30 mg/kg/daily according to the transfusional regimen, SF and IOL, if tolerated.ObjectivesTo observe safety, tolerability, and efficacy of iron chelation therapy with DSX in older patients with transfusion dependent anemia.ResultsThe SF decreased of 50% and 66% after 3 and 6 months respectively. The SF was normalized (SF<500 μg/L) in 5 patients (24%) after six months. The IOL occurred also in patients with a short transfusional history, inferior to 10 packed red blood cells, and SF <1000 μg/L. That was more evident in MDS patients especially in RARS. The median dose tolerated of DSX was 20 mg/kg/daily.The drug related adverse events (AE) was evaluated by the Common Terminology Criteria for Adverse Events (CTCAE versione 4.02). The severe adverse events (SAE) occurred in 10%.The most Common AE were diarrhea, nausea, upper abdominal pain, serum creatinine increase and rash. Hematologic response according to IWG criteria 2006 with DSX were observed in 17% of patients and was more frequent in MPN than MDS, independently from IOL.ConclusionDSX has shown high efficacy in a variety of iron overloaded patients with different anemias. Appropriate patient selection and regular clinical multidisciplinary evaluation of comorbidity and concomitant therapy remains a critical components of successful ther­apy, combined with carefull monitoring for both adverse effects and clinical efficacy, in order to derive the most benefit from a carefully imple­mented chelation strategy.In our cohort improvement of erythropoiesis was marginal. This might be due to the very small patient group analyzed. DisclosuresNo relevant conflicts of interest to declare.

Duffy and kidd genotyping facilitates pretransfusion testing in patients undergoing long-term transfusion therapy.

Objective: Conventional serologic typing of red blood cell systems other than ABO and RhD can be inaccurate and difficult to interpret in patients who have recently undergone blood transfusion. While molecular-based assays are not used routinely, the usefulness of genotyping was investigated in order to determine patients who may benefit from this procedure. Materials and Methods: Blood samples were taken from 101 patients with haemato-oncological, chronic renal, or gastroenterological diseases and from 50 donor controls; the samples were tested for Fya and Fyb by applying serologic and genetic methods. All patients had received 3 or more units of RBCs during the last 3 months. An average of 6.1 RBC units were transfused per patient. The average length of time from transfusion until blood sampling was 24.4 days. The haemagglutination test was applied for serological analysis, and the restriction length polymorphism assay was used for genotyping.Results: In total, 33 (32.7%) patients showed positive reactions with anti-Fya or anti-Fyb while being negative genetically. False-positive Fya results were found in 23 samples, and false-positive Fyb in 10 specimens. During the last 3 months, significantly more RBC units were transfused to patients with discrepant results than to those with accurate phenotyping/genotyping results: median of 5 (mean ± SE: 6.85±0.69) versus median of 4 (mean: 5.71±0.51), respectively (p=0.025). The median length of time after the last transfusion was 25 days (mean: 28.72±2.23 days) in the group with accurate phenotyping/genotyping results versus a median of 14 days (mean: 15.52±1.95 days) in the group with discrepant results (p=0.001). Phenotypes and genotypes coincided in all donor samples.Conclusion: Genotyping assays for the Duffy system should be considered if the patient underwent blood transfusion less than 3 or 4 weeks before the sample collection. If the time frame from RBC transfusion exceeds 6 weeks, Duffy phenotyping can provide accurate results.

Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.

Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. To support and expand the number of health professionals able and willing to provide care for persons with SCD. Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

Deferasirox for managing transfusional iron overload in people with sickle cell disease.

Sickle cell disease (SCD) is a group of genetic haemoglobin disorders, that occurs in about 2.2 per 1000 births worldwide. Increasingly, some people with SCD develop secondary iron overload due to occasional red blood cell transfusions or are on long-term transfusion programmes for e.g. secondary stroke prevention. Iron chelation therapy can prevent long-term complications.Deferoxamine and deferiprone have been found to be efficacious. However, questions exist about the effectiveness and safety of the newer oral chelator deferasirox. To assess the effectiveness and safety of oral deferasirox in people with SCD and secondary iron overload. We searched the Cystic Fibrosis &amp; Genetic Disorders Group's Haemoglobinopathies Trials Register: date of most recent search:13 March 2014.We searched MEDLINE, Embase, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE, EBMR and The Cochrane Library, respectively; date of most recent searches: 02 August 2013.We searched four trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/; www.drks.de; date of most recent searches: 03 June 2013. Randomised controlled trials comparing deferasirox with no therapy or placebo or with another iron chelating treatment schedule. Two authors independently assessed risk of bias and extracted data. We contacted the corresponding study authors for additional information. Two studies (with 203 and 212 people) comparing the efficacy and safety of deferasirox and deferoxamine after 12 months and 24 weeks, respectively, were included. The overall quality, according to GRADE, for the main outcomes was moderate to low. Only limited data were available on mortality and end-organ damage, although one study did assess mortality, relative risk 1.26 (95% confidence interval 0.05 to 30.41), the 24-week follow up was too short to allow us to draw firm conclusions. One study reported a relative risk of 1.26 for the incidence of type 2 diabetes mellitus (95% confidence interval 0.05 to 30.41). Serum ferritin reduction was significantly greater with deferoxamine, mean difference of change of 440.69 µg/l (95% confidence interval 11.73 to 869.64). Liver iron concentration (reported in one study) measured by superconduction quantum interference device showed no significant difference for the overall group of patients adjusted for transfusion category, mean difference -0.20 mg Fe/g dry weight (95% confidence interval -3.15 to 2.75).The occurrence of serious adverse events did not differ between drugs. Nausea, diarrhoea and rash occurred significantly more often in people treated with deferasirox, while adverse events of any kind were more often reported for patients treated with deferoxamine (one study). The mean increase of creatinine was also significantly higher with deferasirox, mean difference 3.24 (95% confidence interval 0.45 to 6.03). Long-term adverse events could not be measured in the included studies (follow up 52 weeks and 24 weeks). Patient satisfaction and the likelihood of continuing treatment, were significantly better with deferasirox. Deferasirox appears to be of similar efficacy to deferoxamine depending on depending on the appropriate ratio of doses of deferoxamine and deferasirox being compared. However, only limited evidence is available assessing the efficacy regarding patient-important outcomes. The short-term safety of deferasirox seems to be acceptable, however, follow up in the available studies was too short to assess long-term side effects. Long-term safety and efficacy data are available from a non-controlled extension phase not included in our review; however, no valid comparative conclusions can be drawn and future studies should assess comparatively long-term outcomes both for safety and efficacy.

Rechallenge with intravenous recombinant human erythropoietin can be successful following the treatment of anti-recombinant erythropoietin associated pure red cell aplasia

Anti recombinant human erythropoietin (r-HuEpo) associated pure red cell aplasia (PRCA) is an immunologic adverse effect of using subcutaneous r-HuEpo. Immunosuppressive agents have been suggested as treatment of this serious complication. After the reversal of anti-r-HuEpo antibody, the patients continue to have renal anemia and require long-term blood transfusion, albeit less frequently than when the antibody is positive. It is controversial whether re-challenging the patients with r-HuEpo is appropriate because re-challenging may cause the reappearance of the antibody. To balance the risk of antir-HuEpo antibody reappearance and longterm blood transfusion complications, we re-challenged r-HuEpo in five anti-r-HuEpo associated PRCA cases after a successful reversal of antibody using prednisolone in combination with cyclophosphamide. The rechallenge was performed intravenously since there were no reports of anti-r-HuEpo associated PRCA cases using this administration route. The duration after the reversal of antibody was 2.4 months before the re-challenge. Two patients were immediately re-challenged as soon as the antibodies reversed. After rechallenge with intravenous r-HuEpo, all patients responded to r-HuEpo: target level of Hb was maintained, blood transfusion was not required, and anti-r-HuEpo was consistently negative. All patients were followed for at least 6 months after re-challenge. Our data suggest that re-challenge with intravenous r-HuEpo can successfully treat anti- r-HuEpo associated PRCA.

The abandoned controversy surrounding universal white blood cell reduction.

The abandoned controversy surrounding universal white blood cell reduction.

Effect of long-term transfusion therapy on the glycometabolic status and pancreatic beta cell function in patients with beta Thalassemia major

Background:Diabetes mellitus is a major complication of iron overload in patients with beta thalassemia major.Design:This is a descriptive study conducted in a Tertiary Care Teaching Hospital to analyze beta cell function and insulin resistance, and their relation to iron overload status in beta thalassemia major. Fasting glucose, two-hour post load glucose, fasting insulin, alanine amino transaminase (ALT), and ferritin were used as outcome measures. The homeostatic model assessment (HOMA model) was used to calculate the beta cell function and insulin resistance index.Results:Of the 30 cases, 20% had impaired fasting glucose, 3.3% had impaired glucose tolerance, and none had diabetes. Fasting glucose was not significant between the cases and controls (P = 0.113). Fasting insulin (P = 0.001), ferritin (P = 0.001), and ALT (P = 0.001) levels were significantly high in the cases. Insulin resistance index was significantly higher in the cases (P = 0.001) as also the beta cell function (P = 0.001). With increase in age and the number of units transfused there is a decline in beta cell function, fasting insulin, and insulin resistance after attaining the maximum level. This suggests that initial insulin resistance is followed by insulin depletion due to loss of beta cell function, leading to diabetes mellitus.Conclusion:Impaired glucose tolerance (IGT) and insulin resistance precede the onset of insulin-dependent diabetes and adequate chelation therapy is essential for delaying the onset or for prevention of diabetes.

Inadequate Long-Term Control Of Transfusion Iron Overload In Children With Sickle Cell Disease Chelated With Deferasirox

Background and objectivesEvidence-based indications for regular transfusions in children with SCD are increasing, and there is now a large population of children on long-term transfusion who require effective control of iron stores to prevent toxicity from transfusion iron overload. The oral iron chelating agent deferasirox (DFX) has been evaluated extensively in thalassemia major, but long-term data on efficacy and safety in children with SCD is relatively sparse. A Phase II trial by Vichinsky et al (2006) compared DFX with deferrioxamine (DFO) in 185 patients (50% paediatric) over one year. The extension study up to 5 years indicated a gradual improvement in serum ferritin associated with increased dose reaching a mean of 25 mg/kg/day. Responses were noted to be poorer in children. The extension study included only 33.5% of the original cohort and is not representative of the full population of children with SCD requiring long-term chelation. Furthermore, the study did not include sequential monitoring of liver iron concentration (LIC), which is considered a better measure of body iron and of chelation efficacy in SCD. In this study, we have evaluated the long-term efficacy and safety of DFX in a clinical care setting and addressed some of the deficiencies of the above study. MethodsThis was a multicentre retrospective, observational study of regularly transfused children in the East London and Essex Clinical Haemoglobinopathy Network. A standard protocol for dosing and monitoring was initiated after licensing of DFX in the EU in 2006. Initial dose was 20mg/kg, and increased in increments of 5mg/kg up to 35 mg/kg/day. Dose was interrupted for creatinine above the normal range for age, or for ALT elevations over 2 times the upper limit of normal when other aetiologies had been excluded. Monitoring of body iron was with monthly serum ferritin (SF) and annual R2 MRI-estimated LIC (in children aged >8 years). Adherence was assessed at monthly transfusion episodes. Support and encouragement with adherence to therapy was provided by dedicated nurse specialists in the hospital and community and a clinical psychologist. Adherence and acceptability were assessed by a questionnaire adapted from Alvarez et al (2009). For this study, data was censored at 36 months from treatment initiation. ResultsSixty-two patients were included, the mean age at initiation of DFX was 9.2 years and mean chelation duration 2.5 ±1.4 years. There were 120.7 years of patient exposure up to 36 months of treatment. The initial mean (± SD) daily dose was 19.8 ± 3.1 mg/kg and at 36 months was 24.6 ± 9.7 mg/kg. Mean SF increased significantly from 2542 ± 964ng/ml at baseline to 4691 ± 2255ng/ml at 36 months; the mean change was 1548ng/ml (95% confidence intervals; -26, 3122ng/ml, p=0.053). There was no significant change in LIC from first to second MRI scan (mean 10.3 mg/g dw on initial and 11.4 mg/g dw on second scan, p=0.35). We observed a statistically significant correlation (R2 =0.66, p <0.001) between the relative change in LIC and in SF. Serum creatinine and estimated Glomerular Filtration Rate (Schwartz formula) remained stable and within normal range. Fifty-two episodes of ALT elevation were recorded in 33 patients, with 14 having recurrent episodes (mean number of episodes per year 2.1± 0.8). In the questionnaire responses, adherence for at least 80% of doses was reported by 75% of respondents. However, more than 50% indicated problems when taking DFX, the most frequent complaint being unpleasant taste. ConclusionsOur experience in a large cohort of children with SCD indicate that iron stores, assessed by combined modalities of SF and LIC, are not adequately controlled with current recommended dosing regimes for DFX. This may be due to inadequate adherence, less favorable pharmacokinetics in children compared to adults, frequent elevations of ALT necessitating interruptions of dosing, or insufficient efficacy of DFX in this population. Changes in SF appear to have a useful role in assessing efficacy and show a reasonable correlation with changes in LIC. Alternative dosing regimes, combinations with other chelators, and more use of exchange transfusion in children may be needed to optimize iron stores in chronically transfused children with SCD. Studies that include a larger number of children and longer follow up periods are required in order to further validate these observations, and explore the role of alternative management strategies. Disclosures:No relevant conflicts of interest to declare.

Audiologic and vestibular assessment in patients with β-thalassemia major receiving long-term transfusion therapy

Life-long transfusion therapy with chelators is a treatment choice for patients with β-thalassemia major. Some investigators have proposed auditory impairment related to the use of deferoxamine, but the mechanisms remain unclear and whether or not deferiprone has similar side effects needs to be evaluated. Thirty-seven patients with β-thalassemia major who received regular transfusion in our hospital were enrolled. Chelation agents, including deferoxamine and deferiprone, were used. To assess audiologic function, otoscopy, pure tone audiometry (PTA), tympanometry, transient evoked oto-acoustic emission (TEOAE), and auditory brainstem response (ABR) were conducted. Bithermal caloric test was performed to evaluate vestibular function. All of the 37 patients had normal findings on otoscopic evaluation and their tympanograms were type A. Thirteen patients (35.1%) had hearing impairment at one or more frequencies as detected by PTA. Compared to those without hearing impairment, patients with hearing impairment had lower serum ferritin levels (P = 0.01). Seven of 21 patients (33.3%) failed to pass the TEOAE, while 13 (61.9%) had abnormal ABR findings. Sixteen patients (80%) had canal paresis in the caloric test. The incidence of auditory impairment and vestibular dysfunction was high in patients with β-thalassemia major receiving long-term transfusion therapy. Potential lesions of auditory impairment may exist anywhere along the auditory pathway, from the inner ear to the brainstem. Lower serum ferritin levels may be associated with hearing impairment. Therefore, regular check-ups of serum ferritin levels and periodic audiologic assessment are mandatory.

How we treat lower-risk myelodysplastic syndromes

AbstractLower-risk myelodysplastic syndromes (MDSs) are defined as having low or intermediate 1 risk by the International Prognostic Scoring System and are characterized mainly by anemia in most cases. Supportive care—primarily red blood cell transfusions—remains an important component of their treatment, but exposes patients to insufficient correction of anemia, alloimmunization, and organ iron overload (for which the role of iron chelation remains debated). Treatment aimed at preventing anemia recurrence should therefore be used whenever possible. Erythropoiesis stimulating agents remain the first-line treatment of anemia in most lower-risk MDS without del(5q), whereas anemia of low-risk MDS with del 5q responds to lenalidomide in two-thirds of the cases, but this drug should be used cautiously because profound cytopenias may occur initially. Treatment after failure of those first-line therapies are disappointing overall, with many patients eventually requiring long-term transfusions, but encouraging results have been reported with hypomethylating agents and lenalidomide. Selected patients respond to antithymocyte globulins, and thrombopoietin receptor agonists are under investigation in lower-risk MDS with thrombocytopenia. Some patients, while remaining at a “lower risk” MDS level, have severe cytopenias and/or poor prognostic factors, found using newer prognostic parameters, or resistance to treatment, making them urgent candidates for more intensive approaches, including allogeneic stem cell transplantation.

Deferasirox, an oral chelator in the treatment of iron overload

BACKGROUND Deferasirox is a once-daily oral iron chelator developed for treating iron overload complicating long-term transfusion therapy in patients with diseases such as beta-thalassemia and myelodysplastic syndromes. Iron overload can damage the liver, pancreas and the heart. Deferoxamine, the only other drug approved for iron chelation, can prevent these effects but requires parenteral administration. Deferasirox has been approved after a one-year, open-label trial in patients ≥ 2 years old with beta-thalassemia and transfusional emosiderosis randomized to once-daily oral 5, 10, 20, 30 mg/kg/day in comparison of subcutaneous deferoxamine 20-60 mg/mg/kg/day x 5/week. CONCLUSIONS Deferasirox 20-30 mg/kg/day produced reductions in liver iron concentration (LIC) similar to those with deferoxamine. Adverse effect of deferasirox (increases of serum creatinine and aminotransferases), including the gastrointestinal ones, are similar but more frequent than those occurring with deferoxamine. Information is lacking on the effects of deferasirox on cardiac iron and cardiac dysfunction which is the most serious complication of transfusional iron overload.

The severity of illness and inflammatory markers cannot predict red blood cell alloimmunization in cancer patients

Red Blood Cell (RBC) alloimmunization remains a major complication for transfusion-dependent patients but factors governing risk for alloimmunization are little known. Antibody production is a serious complication in patients on long-term transfusion therapy; it may cause potentially life-threatening delayed hemolytic transfusion reactions (DHTRs), autoantibody formation as well as logistic problems, for example, to obtain timely and properly matched transfusion blood for patients in which new alloantibodies are detected. Even non-chronically transfused patients who become alloimmunized are 20 times more likely to form additional antibodies after one or more repeat transfusion events(1-3). This is not an ideal scenario for a patient population in which the benefit is proportional to the longevity of transfused RBCs and this may result in an extensive laboratory workup that consumes significant time and resources. In an effort to reduce alloimmunization, some programs have been designed and implemented to provide Rh and K antigen-matched RBC transfusions to patients who are in need of chronic transfusion support but some patients still become alloimmunized despite this antigen matching(4,5). In contrast to prophylactic antigen matching, some institutions argue that the data supporting a reduction in DHTRs are insufficient to offset the cost of labor and resources required to perform extended matching for polytransfused patients. Characterization of patients and clinical conditions with high alloimmunization risk could help in the selection of patients who need to be extensively matched. By identifying such risks, it may be possible to predict responders and non-responders, thereby avoiding the use of costly antigen-matched units for non-responders, and only selecting phenotyped/genotyped-matched units for responders to reduce alloimmunization-associated morbidity and mortality. Several factors are predicted to influence the reaction of the recipient's immune system to alloantigens including the dose and the immunogenicity of the antigen as well as genetic, and acquired patient-related factors and clinical conditions(6,7). It has also been shown that the number of transfusions plays an important role in RBC alloimmunization and that immune-compromised patients have a lower risk to develop red cell antibodies. However, other patient-related risks are little known. Although unexpected risk factors were found, such as solid tumors because of their chronic inflammatory state, there are few and limited studies showing that the inflammatory status of human transfusion recipients may regulate the immunogenicity of transfused RBCs(8). In this issue of the Revista Brasileira de Hematologia e Hemoterapia, there is an important retrospective case-control study on a small group of alloimmunized and nonalloimmunized patients with solid cancer, regarding the risk of RBC alloimmunization(9). The authors evaluated clinical factors related to the severity of the disease (ECOG performance scale, Karnofsky scale, presence of metastasis and body mass index) and inflammatory background (C-reactive protein) and concluded that these factors cannot be used to predict the risk of RBC alloimmunization in such patients. Although the relatively small number of patients is a limitation of the study, this paper represents an additional contribution in the field of RBC alloimmunization in patients with solid tumors. The results of the studies of Dinardo et al. do not ratify the thesis that the inflammatory status regulates the immunogenicity of transfused RBCs(9). This finding supports the concept that there are combinations of factors influencing the immune response to RBC antigens. We will have to look to future studies by this group and others to better understand the risk factors of RBC alloimmunization in cancer patients in order to provide or not antigen-matched RBC transfusions.

Red blood cell alloimmunisation among Chinese patients with β-thalassaemia major in Taiwan.

The development of red blood cell (RBC) antibodies can significantly complicate transfusion therapy in transfusion-dependent patients with thalassaemia. However, few data are available on the frequency of RBC alloimmunisation in the Chinese population with β-thalassaemia major. In this retrospective study, we investigated the development of RBC antibodies among Chinese patients with β-thalassaemia major who had received long-term transfusion therapy with leucodepleted blood in our hospital over a period of 20 years. Of the 64 patients studied, six (9.4%) developed RBC alloantibodies, including four anti-E, one anti-C and one anti-"Mi(a)". All of the six alloimmunised patients had experienced previous transfusion reactions, while only 12 of the 58 non-immunised patients had had previous transfusion reactions (100% vs 15.5%; p <0.001). After subsequent transfusions with RBC which were negative for the antigens for the corresponding alloantibodies, all the RBC alloantibodies became undetectable within 1 year without additional interventions to eliminate them. RBC alloantibodies in Chinese patients with β-thalassaemia major in Taiwan were different from those in other populations. The development of RBC alloantibodies was associated with previous transfusion reactions. Additional treatment may not be necessary for patients with alloantibodies.

An update on iron chelation therapy.

Iron overload is a common clinical problem, arising from disorders of increased iron absorption such as hereditary haemochromatosis or thalassaemia intermedia syndromes or as a consequence of chronic blood transfusions for various blood disorders. Regular red blood cell (RBC) transfusions are the principal supportive therapy for many rare anaemias involving a decrease in RBC production, an increase in cell destruction, or chronic blood loss1. Anaemias such as beta-thalassaemia and sickle cell disease are examples of chronic diseases that require long-term transfusion therapy to improve life expectancy. Although transfusion requirements may vary according to the diagnosis, chronic blood transfusion therapy inevitably leads to secondary iron overload that can cause significant damage to many organs, such as the liver and heart, and to the endocrine system2,3. Iron overload is associated with the production of free radicals that can damage tissues, resulting in cardiac toxicity, endocrine dysfunction, and liver toxicity. The effects of iron overload are visible after damage has been done, when patients already have liver dysfunction, cirrhosis, cardiomyopathy or diabetes1,4. Iron is an essential element within the body and its quantity is tightly regulated physiologically; however, the body has no mechanism to excrete excess iron and it deposits iron into end organs leading to severe dysfunction. Each unit of RBC transfused contains 180 to 200 mg of iron. Chronic packed RBC transfusion therapy increases liver iron by approximately 1 mg/mL (by dry weight) for every 15 mL/kg delivered5. Labile plasma iron (LPI) is a toxic and chelatable form of iron that is produced continually during conditions of iron overload, and has been linked to the development of co-morbidities6. It is very important to remove excess iron and suppress LPI to avoid the serious clinical sequelae associated with iron overload. In this specific context phlebotomy cannot be used because patients are usually anaemic and other means must be used to mobilise the excess iron. The gold standard is iron chelation therapy.

Ventricular Structure and Function in Children With Sickle Cell Disease Using Conventional and Tissue Doppler Echocardiography

Conventional 2-dimensional, M-mode, and spectral Doppler echocardiographic techniques have documented abnormal ventricular function in adults with sickle cell disease (SCD), but assessments in children are conflicting. Tissue Doppler echocardiography (TDE) provides additional information about myocardial function. Two-dimensional, M-mode, tricuspid regurgitation jet velocity (TRJV) data, and tissue Doppler echocardiographically derived myocardial velocity measurements of left ventricular (LV) and right ventricular function were taken from children with SCD compared to those of similar healthy historical controls and correlated with clinical characteristics and hemoglobin levels. Compared to 55 controls, 54 children with SCD (mean age 14.2 years, range 6 to 21) had a larger left ventricle, greater LV mass, and higher LV fractional shortening; 30% had increased pulmonary artery pressure (TRJV ≥2.5 m/s). Conventional echocardiographic measurements of LV systolic function and spectral Doppler measurements of LV and right ventricular diastolic function were essentially normal, but TDE indicated that 31% of SCD children had evidence of LV diastolic dysfunction (peak early diastolic velocity of LV inflow Doppler/peak early diastolic velocity at lateral mitral valve annulus >8), a finding that correlated with lower hemoglobin levels. Although decreasing hemoglobin levels in children with SCD correlated with LV hypertrophy, LV dilation, and LV diastolic dysfunction, long-term transfusion or hydroxyurea therapy did not affect these measurements. In conclusion, 1/3 of children with SCD had tissue Doppler echocardiographic evidence of LV diastolic dysfunction, which was correlated with hemoglobin levels. Adding serial assessments of ventricular function with TDE to conventional echocardiography may detect early cardiac changes, especially in children with severe anemia.

Anti‐AnWj causing acute hemolytic transfusion reactions in a patient with aplastic anemia

AnWj is a high-prevalence red blood cell (RBC) antigen in the ISBT 901 series. Only nine reports of anti-AnWj have been published since it was first documented in 1972; two of these cases involved transfusion reactions. We present a case of a patient with aplastic anemia who developed anti-AnWj with clinically significant hemolysis after transfusion of AnWj-positive RBCs. A 56-year-old woman with aplastic anemia developed a pan-reactive antibody with clinically significant hemolysis after transfusion of RBCs. Investigations included antibody identification by serologic methods at the national immunohematology reference laboratory and the in vitro monocyte-monolayer assay (MMA) to predict clinical significance. The antibody was identified as having specificity for the AnWj antigen. The posttransfusion MMA indicated that the antibody had complement-fixing capability highly likely to cause clinically significant acute hemolytic transfusion reactions. The patient required long-term transfusion support with AnWj-negative RBCs and Lu(a-b-) RBCs of the In(Lu) type which have reduced AnWj expression. Cross-Canada and international collaboration was required to obtain rare units for transfusion. A case of acute hemolytic transfusion reaction caused by anti-AnWj is reported in a patient with aplastic anemia requiring allogeneic stem cell transplantation. This is the second documented case of anti-AnWj to cause a hemolytic transfusion reaction. The case demonstrates the complexity of managing patients with rare antibodies and the importance of international collaboration in the management of these difficult cases.

Long-term transfusion independence in del(5q) MDS patients after short term therapy with lenalidomide: 2 new cases

The introduction of the immunomodulatory drug lenalidomide as revolutionized the treatment of patients with myelodysplastic yndromes and interstitial deletion of the long arm of chromosome [del5(q) MDS]. Treatment with lenalidomide results in transfuion independence in the vast majority of patients [1]. Despite these mpressive results some questions remain unresolved, among them he duration of treatment. Adding to this discussion has been the bservation of a number of unexpected long term remissions in atients who stopped lenalidomide for various reasons. Here we eport two additional such cases that add some new information o this interesting phenomenon.