Rodolfo Delfini Cançado

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.)

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 (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.

Guidelines on neonatal screening and painful vaso-occlusive crisis in sickle cell disease: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular: Project guidelines: Associação Médica Brasileira - 2016

Josefina Aparecida Pellegrini Braga, Monica Pinheiro de Almeida Verissimo, Sara Teresinha Olalla Saad, Rodolfo Delfini Cancado, Sandra Regina Loggetto a Escola Paulista de Medicina, Universidade Federal de Sao Paulo (Unifesp), Sao Paulo, SP, Brazil b Centro Infantil Boldrini, Campinas, SP, Brazil c Faculdade de Ciencias Medicas, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil d Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo (FCMSCSP), Sao Paulo, SP, Brazil e Hospital Samaritano, Sao Paulo, SP, Brazil f Centro de Hematologia de Sao Paulo (CHSP), Sao Paulo, SP, Brazil

Assessment of liver and cardiac iron overload using MRI in patients with chronic anemias in Latin American countries: results from ASIMILA study

ABSTRACT Objectives: A multicenter, noninterventional, observational study was conducted in the Latin American countries including Argentina, Brazil, Colombia, Mexico, and Venezuela to assess the prevalence of liver and cardiac iron overload using magnetic resonance imaging (MRI) in patients with chronic anemias except thalassemia. Methods: Patients aged >10 years with transfusion-dependent anemias, except thalassemia, either with <20 units of red blood cell (RBC) transfusions with serum ferritin (SF) levels >2000u2005ng/mL or with ≥20 units of RBC transfusions regardless of SF level in their lifetime, were enrolled. Iron overload was assessed using MRI. Results: Among 175 patients included, the majority had sickle cell disease (SCD; 52%), followed by aplastic anemia (AA; 17.7%), myelodysplastic syndrome (MDS; 8.6%), Diamond-Blackfan anemia (DBA; 4%), pure red cell aplasia (1.1%), and others (16.6%). Liver iron overload was observed in 76.4% of patients, while cardiac iron overload was seen in 19.2% when assessed by MRI. The prevalence of iron overload was 80.2% in patients with SCD, 73.3% in MDS, 77.4% in AA, 100% in pure red cell aplasia, 71.4% in DBA, and 68.9% in other transfusion-related disorders. A moderate correlation between liver iron concentration (LIC) and SF was observed in patients with SCD and MDS (ru2009=u20090.47 and ru2009=u20090.61, respectively). All adverse events reported were consistent with the published data for deferasirox or underlying disease. Conclusion: A high prevalence of iron overload in this patient population in Latin American countries indicates that a better diagnosis and management of iron overload is required in these countries.

Quality of life scores differs between genotypic groups of patients with suspected hereditary hemochromatosis

BackgroundHereditary hemochromatosis (HH) encompasses a group of autosomal recessive disorders mainly characterized by enhanced intestinal absorption of iron and its accumulation in parenchymal organs. HH diagnosis is based on iron biochemical and magnetic resonance imaging (MRI) assessment, and genetic testing. Questionnaires, such as SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient’s quality of life (QL). In addition, different genotypes are identified as results of genetic tests in patients with suspected primary iron overload. In the present study, our aim was to evaluate whether domains of QL are different according to genotypic groups in patients suspected of HH.MethodsSeventy-nine patients with primary iron overload were included and two genotypic groups were formed (group 1: homozygous genotype for the HFE p.Cys282Tyr mutation; group 2: other genotypes).ResultsGroup 1 had higher means of plasma transferrin saturation (86u2009±u200919%) and serum ferritin (1669u2009±u20091209xa0ng/mL) compared to group 2 (71u2009±u200912%, 1252u2009±u2009750xa0ng/mL, respectively; pu2009=u20090.001). Four domains were significantly different among groups 1 and 2: physical functioning (pu2009=u20090.03), bodily pain (pu2009=u20090.03), vitality (pu2009=u20090.02) and social functioning (pu2009=u20090.01).ConclusionsOur main finding was that patients with p.Cys282Tyr homozygosity had a worse QL scenario assessed by SF-36, compared with patients with iron overload without the same genotype. Being aware of this relationship between genotypes and QL might be helpful in the overall management of patients suspected of hereditary hemochromatosis.

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 5u2009mg/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.

Pyruvate kinase deficiency: novel mutations and a better understanding of the genotype-to-phenotype correlation in Brazilian patients

Over the past few years, the inherited disorders of erythrocyte metabolism have been the object of intensive research resulting in a better understanding of their molecular basis.1 Pyruvate kinase (PK) deficiency is the most common cause of congenital non-spherocytic chronic hemolytic anemia and is the result of an erythrocyte enzyme defect. It is an autosomal recessive condition caused by a deficiency of erythrocytic PK. Although the gene frequency for PK deficiency is far lower than that for glucose-6-phosphate dehydrogenase (G6PD) deficiency, the vast majority of patients inheriting G6PD deficiency never suffer acute or chronic hemolysis, whereas chronic hemolysis of variable severity is common in those with PK deficiency.1,2 PK deficiency is an extremely rare disorder; the prevalence of this deficiency is unknown. The PK-catalyzed reaction is the second ATP-generating step of the glycolytic pathway and is of particular importance in energy production, yielding nearly 50% of the total ATP. PK enzymes consist of several isoforms. They are products of two distinct genes: the M (muscle) gene is expressed in muscles, the brain, white blood cells, and platelets; it is located on chromosome 15q22 and the M1 and M2 isoforms are the result of a differential processing of this single gene transcript; and the LR gene on chromosome

Guidelines on the treatment of anemia of chronic renal failure using recombinant human erythropoietin: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associação Médica Brasileira – 2014

pecial article uidelines on the treatment of anemia of chronic enal failure using recombinant human rythropoietin: Associacao Brasileira de ematologia, Hemoterapia e Terapia Celular uidelines Project: Associacao Medica Brasileira – 014 derson da Silva Araujoa, Clarisse Lopes de Castro Lobob, Dimas Tadeu Covasc, ernando Ferreira Costad, Leticia Medeirose, Rodolfo Delfini Cancadof,∗, andra Fatima Menosi Gualandrog, Sara Teresinha Olalla Saadd Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO), Rio de Janeiro, RJ, Brazil Faculdade de Medicina de Ribeirao Preto (FMRP), Universidade de Sao Paulo (USP), Ribeirao Preto, SP, Brazil Universidade de Campinas (Unicamp), Campinas, SP, Brazil Associacao Medica Brasileira (AMB), Sao Paulo, SP, Brazil Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo (FCMSCSP), Sao Paulo, SP, Brazil Universidade de Sao Paulo (USP), Sao Paulo, SP, Brazil