Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

BACKGROUND: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. RESULTS: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.

The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482144); BCL11A (rs1427407, rs4671393 and rs11886868); and HMIP-2 (rs9399137 and rs9402686) loci on baseline and HU-induced HbF levels in 111 HbSS patients. We found that both BCL11A and HMIP-2 were associated with increased endogenous levels of HbF. Interestingly, we also found that BCL11A was associated with higher induction of HbF with HU. This effect was independent of the effect of BCL11A on baseline HbF levels. Additional studies will be needed to validate these findings and explain the ample inter-individual variations in HbF levels at baseline and HU-induced in patients with SCA.

Length of treatment and dose as determinants of mutagenicity in sickle cell disease patients treated with hydroxyurea.

Hydroxyurea (HU) is an antineoplastic drug widely used in the clinical management of patients with sickle cell disease (SCD), and many questions related with its use remain unresolved. Given the severity of SCD, HU benefits, although not thoroughly confirmed, seem to outweigh its potential carcinogenicity. This study aimed to assess the genotoxicity associated with HU dose and treatment length by evaluating mutagenicity in patients with SCD treated with HU (SCHU) using the cytokinesis-block micronucleus assay (CBMN) in white cells. The study was conducted with 35 individuals in the SCHU group and 34 controls matched according to age, sex and smoking habit. CBMN results showed an increase (p=0.032) in the number of micronuclei (MN), but not of nucleoplasmic bridges (NPB) or nuclear buds (NBUD) in the SCHU group. The increased frequency of MN in the SCHU group was significantly correlated with treatment length and final HU dose, which confirms that patients with SCD treated with HU should be carefully monitored to reduce the risk of carcinogenicity.

DNA damage in blood leukocytes of individuals with sickle cell disease treated with hydroxyurea.

Hydroxyurea (HU) plays an important role in the treatment of patients with sickle cell disease (SCD). Although HU has been associated with an increased risk of leukemia in some patients with myeloproliferative disorders, the mutagenic and carcinogenic potential of HU has not been established. This study investigated levels of DNA damage using the alkaline (pH>13) comet assay to analyze peripheral blood leukocytes sampled from 28 patients with SCD treated with HU (SCHU) and from 28 normal individuals. The damage index (DI) in the SCHU group was significantly higher than in controls (p<0.05). Gender, smoking or age were not associated with DNA damage in controls or SCHU individuals. In the group of SCHU individuals, mean HU dose and DI were positively correlated, and individuals who received a mean dose of >20 mg/kg HU (DI=24.9+/-5.5) showed significantly more DNA damage than those who received < or =20 mg/kg HU (DI=14.6+/-1.8) (p<0.05). Individuals treated for > or =42 months (DI=23.1+/-4.2) showed significantly greater DNA damage than those treated for <42 months (13.6+/-1.9) (p<0.05). DI was inversely correlated with body mass index in the SCHU group.

Prophylactic Iron Supplementation in Pregnancy: A Controversial Issue.

In our world today, iron deficiency (ID) is the most frequent nutritional deficiency and it is being considered as an epidemic public health crisis. Women of reproductive age and infants are at particular risk of ID, especially in underdeveloped countries. During pregnancy, iron deficiency anemia is a specific risk factor associated with negative maternal and perinatal outcomes. Many countries have iron supplementation (IS) programs-as recommended by the World Health Organization-during pregnancy; however, IS clinical benefits and risks are unclear. This review aims to discuss the threats and benefits of routine IS on maternal and infant outcomes.

Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia.

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15mg/kg; maximum of 1000mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia.

High prevalence of anemia in children and adult women in an urban population in southern Brazil.

This population-based study was designed to detect the prevalence of anemia in a healthy population of children (18 months to 7 years) and women (14 to 30 years) tested in 2006-2007 in the state of Rio Grande do Sul, Brazil as part of an effort to tackle this massive problem that still affects so many people in the XXI century. Anemia was defined according to the WHO. Capillary blood was measured and socioeconomic status was determined according to the Brazilian Association of Market Research Agencies. The median prevalence of anemia in 2198 children was 45.4% and in 1999 women 36.4%. Anemia decreased with age during childhood; although significantly more prevalent in lower classes individuals, it was also high in the upper classes. There are indirect evidences that the lack of iron supplementation and/or iron fortified food may play a role in it. Professionals and society wise measures of education have to be implemented in order to address possible biologic factors involved in childhood psychosocial development in southern Brazil.

Brazilian Guidelines for transcranial doppler in children and adolescents with sickle cell disease.

BACKGROUND: Sickle cell disease is the most common monogenic hereditary disease in Brazil. Although strokes are one of the main causes of morbidity and mortality in these patients, the use of transcranial Doppler to identify children at risk is not universally used. OBJECTIVE: To develop Brazilian guidelines for the use of transcranial Doppler in sickle cell disease children and adolescents, so that related health policies can be expanded, and thus contribute to reduce morbidity and mortality. METHODS: The guidelines were formulated in a consensus meeting of experts in transcranial Doppler and sickle cell disease. The issues discussed were previously formulated and scientific articles in databases (MEDLINE, SciELO and Cochrane) were carefully analyzed. The consensus for each question was obtained by a vote of experts on the specific theme. RESULTS: Recommendations were made, including indications for the use of transcranial Doppler according to the sickle cell disease genotype and patients age; the necessary conditions to perform the exam and its periodicity depending on exam results; the criteria for the indication of blood transfusions and iron chelation therapy; the indication of hydroxyurea; and the therapeutic approach in cases of conditional transcranial Doppler. CONCLUSION: The Brazilian guidelines on the use of transcranial doppler in sickle cell disease patients may reduce the risk of strokes, and thus reduce the morbidity and mortality and improve the quality of life of sickle cell disease patients.

Intranenous ferric carboxymaltose for the treatment of iron deficiency anemia

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non- dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia.

Brazilian Guidelines for transcranial doppler in children and adolescents with sickle cell disease

BACKGROUND: Sickle cell disease is the most common monogenic hereditary disease in Brazil. Although strokes are one of the main causes of morbidity and mortality in these patients, the use of transcranial Doppler to identify children at risk is not universally used. OBJECTIVE: To develop Brazilian guidelines for the use of transcranial Doppler in sickle cell disease children and adolescents, so that related health policies can be expanded, and thus contribute to reduce morbidity and mortality. METHODS: The guidelines were formulated in a consensus meeting of experts in transcranial Doppler and sickle cell disease. The issues discussed were previously formulated and scientific articles in databases (MEDLINE, SciELO and Cochrane) were carefully analyzed. The consensus for each question was obtained by a vote of experts on the specific theme. RESULTS: Recommendations were made, including indications for the use of transcranial Doppler according to the sickle cell disease genotype and patients age; the necessary conditions to perform the exam and its periodicity depending on exam results; the criteria for the indication of blood transfusions and iron chelation therapy; the indication of hydroxyurea; and the therapeutic approach in cases of conditional transcranial Doppler. CONCLUSION: The Brazilian guidelines on the use of transcranial doppler in sickle cell disease patients may reduce the risk of strokes, and thus reduce the morbidity and mortality and improve the quality of life of sickle cell disease patients.

Cirurgia e anestesia na doença falciforme / Anesthesia and surgery in sickle cell disease

Pacientes com doença falciforme (DF) que serão submetidos a procedimentos anestésicos e cirúrgicos demandam cuidados específicos. Condições comumente associadas a estes procedimentos, como hipóxia, acidose, hipotermia, infecção e hipovolemia, podem ter conseqüências deletérias especialmente graves no paciente com DF. Há uma tendência ao aumento da eritrofalciformação e dos fenômenos vaso-oclusivos, o que pode levar à síndrome torácica aguda, episódio álgico agudo, priapismo, acidente vascular cerebral dentre outras complicações diretamente relacionadas à DF. Para minimizar o risco destas complicações, recomenda-se que pacientes com DF tenham avaliação pré-operatória multidisciplinar, atenção especial à hidratação e oxigenação, escolha de procedimentos cirúrgicos menos invasivos e cuidados pós-operatórios intensivos. Mesmo com a adoção destes cuidados, a incidência de complicações cirúrgicas em pacientes com DF é especialmente alta, estimada em 25 por cento a 30 por cento. O objetivo desta revisão é abordar as principais condições cirúrgicas associadas à DF e os cuidados perioperatórios que devem ser tomados neste grupo de pacientes.

Individuals with sickle cell disease (SCD) have special perioperative concerns that must be considered before their anesthesia and surgery. During the perioperative period, these individuals are at risk for vaso-occlusive events, including acute chest syndrome, pain crises, priapism and stroke because they are exposed to hypoxia, acidosis, hypothermia, infections and hypovolemia. Several suggestions to reduce risk have been made, including a structural multidisciplinary approach, paying special attention to hydration and oxygenation, postoperative respiratory care and selection of less aggressive or extensive surgical procedures. Even with meticulous care, approximately 25 percent to 30 percent of individuals with SCD will have a postoperative complication. This article provides readers with information about the role of surgery in SCD and the measures that should be taken to ensure patients are well cared for in the perioperative period.

Prevalência de talassemias e hemoglobinas variantes em pacientes com anemia não ferropênica / Prevalence of thalassemias and variant hemoglobins in patients with non-ferropenic anemia

Para estabelecer a freqüência de hemoglobinopatias e talassemias em pacientes com anemia não ferropênica foram estudados 58 casos de pacientes comprovadamente com anemia não ferropênica e 235 controles obtidos de pessoas sem anemia. Todas as amostras foram obtidas do Hospital de Clínicas de Porto Alegre (HCPA), RS, Brasil. As técnicas realizadas foram eletroforese em acetato de celulose, pH alcalino, pesquisa citológica de Hb H, HPLC, hemograma e ferritina. A análise dos dados realizada no grupo de pacientes com anemia não ferropênica demonstrou que 63,8 por cento eram portadores de alguma forma de anemia hereditária: 25,9 por cento de talassemia alfa heterozigota, 32,8 por cento de talassemia beta heterozigota, 3,4 por cento de heterozigose para hemoglobina S (Hb AS) e 1,7 por cento de homozigose para hemoglobina C (Hb CC). No grupo dos controles, foram identificados 14,1 por cento de anemias hereditárias, sendo destas 11,5 por cento de talassemia alfa, 0,9 por cento de talassemia beta, 1,3 por cento de heterozigose para hemoglobina S (Hb AS) e 0,4 por cento de heterozigose para hemoglobina C (Hb AC). Os resultados obtidos permitem concluir que a prevalência de talassemias e hemoglobinas variantes no grupo controle é coincidente com a descrita na literatura. Entretanto, a excepcional prevalência dessas hemopatias hereditárias em pessoas com anemia não ferropênica deve ser divulgada entre médicos e serviços de saúde dada a sua importância no diagnóstico definitivo de anemia e dos corretos procedimentos terapêuticos.

Long-term follow-up of kidney allografts in patients with sickle cell hemoglobinopathy

Although sickle cell anemia and sickle cell disease produce a variety of functional renal abnormalities they uncommonly cause end stage renal failure. Renal transplantation has been a successful alternative for the treatment of the rare terminal chronic renal failure with outcomes comparable with non-sickle recipients. This approach, however, has not been often described on patients with renal failure associated with SC hemoglobinopathy. Here we report the outcomes of two patients with chronic renal failure due to SC hemoglobinopathies who underwent renal transplantation. At the time of the transplantation they were both severely anemic and had frequent vasoocclosive pain crises. Both patients evolved with good allograft function, near normal hematological parameters, and very rare pain crisis, thirteen and eight years after transplant. These cases illustrate that terminal renal failure due to SC hemoglobinopathy can be successfully managed by renal transplantation and satisfactory long-term results are achievable not only in terms of renal allograft function but also of their hematological condition

Genetic aspects of Schistosoma mansoni infection severity

A variabilidade genética em 13 sistemas proteicos foi investigada em uma amostra de 61 pacientes com hepatosplenomegalia (H) esquistossomótica e 61 com a forma intrestinal (I) doença, provenientes de uma regiäo endêmica (Catolandia, estado da Bahia). Foi verificada apenas uma diferença significante nas distribuiçöes genotípicas de pacientes H e I. Os homozigotos GLO*1/GLO*11 têm uma incidência relativa da forma hepatosplênica 4 vezes maior e os heterozigotos GLO*1/GLO*2 3 vbezes maior do que os homozigotos GLO*2/GLO*2