ASH 2010 meeting report—Top 10 clinically oriented abstracts in sickle‐cell disease
Authors: Carlo Brugnara
Journal: American Journal of Hematology (2011)

At the American Society of Hematology 2010 meeting in Orlando, Florida more than 110 abstracts on sickle cell disease were selected for either oral or poster presentation in the “Hemoglobinopathies, excluding Thalassemia” and “Health Services and Outcome Research” categories. Here, I summarize and discuss the top 10 abstracts for sickle cell disease, all presenting relevant information, which may affect clinical practice. Abstracts are published in full in the November 19, 2010 issue of Blood (volume 116, No. 21) and are identified here by their abstract numbers. For the discussed topics, we particularly highlight references, which were recently published in the American Journal of Hematology. Chronic red cell transfusion is an established therapeutic modality for children with sickle cell disease at risk of developing acute cerebral vascular complications like stroke. The NIH-sponsored Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial had the objective of comparing 30 months of hydroxyurea therapy plus phlebotomy versus standard transfusion therapy and chelation to prevent secondary stroke and reduce transfusional iron overload in children with sickle cell disease. The primary end-point of the study was a composite one, which included both secondary strokes and iron overload, in an attempt to balance an expected possible increase in recurrent strokes with the benefit of a greater reduction of iron burden in the hydroxyurea plus phlebotomy arm. Between October 06 and April 09, 133 subjects were randomized into this study. An interim data analysis was scheduled and performed after one third of the subjects had completed the study, with ∼ 80% of the patient-treatment times completed. This interim data analysis resulted in premature termination of the study due to an unacceptable high incidence of recurrent strokes in the hydroxyurea plus phlebotomy arm (7 vs. 0 in the standard therapy arm). The data highlight the difficulties in identifying successful alternative therapies for children with sickle cell disease on chronic transfusion therapy due to prior stroke. At the present time, no validated alternative option is available to chronic transfusion therapy and to the associated risks of iron overload and RBC alloimmunization. Only a small fraction of these children is either eligible for or has access to curative stem cell transplantation. Transfusional strategies aimed at reducing iron overload (erythrocytopheresis or modified manual exchange transfusions) are used and available only for a limited number of patients [1, 2]. Thus, while European and US studies have shown clinical benefit for the early use of hydroxyurea in children, with possible prevention of primary strokes [3, 4], the clinical alternatives to chronic transfusion for patient already affected by stroke remain quite limited. Reference [5] provides an excellent review of hydroxyurea efficacy and toxicity in children. A 1-year treatment with the oral iron chelator desferasirox, has been shown to reduce iron burden in patients with sickle cell disease >2 years of age [6]. This work provides data of a long-term, 5-year follow-up of 52 of the patients originally enrolled in the study. No unexpected major drug toxicities were observed in this study, with most of the drug-related adverse events reported being mild, such as nausea, vomiting, diarrhea and increase in serum creatinine. Decreases in serum ferritin were minor, with larger decreases observed in patients treated at higher doses. Based on the well-known and demonstrated toxicity of iron overload associated with chronic transfusion therapy in thalassemias, attention has been focused on the growing number of patients with sickle cell disease on chronic transfusion therapy for either prevention of stroke, stroke recurrence, or other disease complications. It has been shown that the monitoring of iron overload and its possible complications is less intensive in sickle versus thal patients [7]. The usefulness of serum ferritin in monitoring iron overload is diminished in sickle cell disease due to the concomitant chronic inflammation, which also increases serum ferritin. Organ complications differ between thal and sickle patients on chronic transfusion and in particular cardiomyopathy seems to be less prominent in sickle patients [8-10]. Thus, it seems important that alternative methods of assessing the extent and the clinical impact of iron overload be developed for chronically transfused sickle cell disease patients. Acute splenic sequestration (ASpSq) is a major complication of sickle cell disease in young children [11]. The study aims to identify predictive factors for this complication with a retrospective survey of a cohort of 197 children who have been followed from birth and were older than 2 years of age at the last encounter. ASpSq was defined by the simultaneous presence of a >20% decrease in Hb and a spleen increase >2 cm. With a median follow-up of 7.9 years, 1820 patient years were examined. ASpSq occurred in 32% of the patients, at a median age of 2.0 yr (range 0.1–12.9). A 32% (95%CI: 25–39%) cumulative risk of ASpSq was determined at age 7. Multivariate analysis identified alpha thalassemia as a significant risk factor for ASpSq, in conjunction with low platelet count and reticulocytosis. Patients who had developed ASpSq were more likely to experience severe vaso-occlusive crises and hospitalization, but did not have greater incidence of acute chest episodes. The occurrence of ASpSq in children with sickle cell disease is associated with more severe vaso-occlusive manifestations requiring hospitalization. There are no unique combinations of clinical and laboratory criteria to allow specific identification of patients at risk of developing ASpSq. While leukocytosis and severe anemia do not seem to be specific risk factors for ASpSq, the role of dactylitis was not examined in this analysis. Concerns remain on the overall definition of ASpSq, since the increase in spleen size was not assessed with objective, independently validated criteria. Any recommendation for either splenectomy or stem cell transplantation based on these data seems quite premature and unwarranted. A novel stimulator of Hb F production, HQK-1001, which targets the fetal globin gene promoter, has shown acceptable safety and pharmacokinetic when administered orally to normal subjects in Phase 1 studies. This reports presents data on a Phase1/2 study in 24 patients with sickle cell disease (SS and S-Beta thal) who took part in a randomized, placebo-controlled, blinded study assessing three dose levels (10, 20, 30 mg/Kg) administered once daily for two 6 week cycles separated by a two-week break. There were no significant adverse events. Hb F increases were observed in all treated patients, with greater response at higher dosages. In the treated patients, this was accompanied by an increase in total Hb (mean 1.3 g/dL, range 0.9 to 2.4 g/dL). Fetal globin mRNA also increased considerably and did not seem to have reached peak levels by the end of the trial. Despite the remarkable successes of hydroxyurea therapy in SS disease [12], the lack of generalized use of this safe and effective drug has prompted a search for novel stimulators of Hb F production. In addition, concerns remain about hydroxyurea cytotoxicity and variability in the therapeutic response in adult. Even in hydroxyurea-responding patients, additional increments in Hb F levels induced by combination therapy could be beneficial. The present study shows promising effects in conjunction with a good safety profile. Recent new developments in our understanding of the regulation of Hb F production hold promise for additional pharmacological targets which may lead to increase Hb F production in patients with sickle cell disease [13]. In the absence of either motor or sensory clinical manifestations of neurologic disease, silent cerebral infarction (SCI) and acute silent cerebral ischemic events (ASCIEs) can be identified in children with sickle cell disease using MRI and MRI with diffusion-weighted imaging (DWI), respectively. ASCIEs were detected in 10 out of the 640 children enrolled in the study (1.2% of the 844 assessed MRI). Follow-up MRIs were available for two of these subjects, showing evolution to SCI in one and disappearance of the lesion in the other. A new SCI was detected in 8 out of the 220 children who had MRI-confirmed SCI at baseline, providing an estimated incidence of recurrence of 10.7/100 patient-years (95% CI: 4.6–21.0), which was four times lower than that of ASCIEs (43.3/100 patient-years; 95% CI: 20.7–79.6). Although ASCIEs were observed in only 10/640 children, while 220/640 had SCI, the arbitrary definition used by the authors of DWI-MRI providing an observation window for the prior 10 days, results in a much greater incidence of ASCIEs vs. SCI/100 patient years. This conclusion would benefit from additional independent methodological validation. The present study shows the promise of DWI-MRI and justifies additional studies and longitudinal observations in patients with sickle cell disease, especially those with a more pronounced inflammatory phenotype, who seem to have the greatest risk for strokes [14]. The clinical meaning of an elevated tricuspid regurgitation velocity (TRV) measured with echocardiography, its reliability and its association with pulmonary hypertension in patients with sickle cell disease are currently the subject of a heated debate [15, 16]. This observational sub-study, part of the Walk-PHaSST trial (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) examines various correlates of TRV in 453 subjects with homozygous sickle cell disease. Presence of a hemolytic component was defined by using % reticulocytes, serum LDH, AST and bilirubin. TRV elevations of 2.7–2.9 m/sec were observed in 22% and ≥3.0 m/sec in 17% of the subjects. When data were analyzed based on the age of the participants, left ventricular dysfunction with TRV elevation and hemolysis seem to progress in intensity with age. Older patients also had higher creatinine and lower Hb. The age-dependent progression in severity of TRV elevation as well as the association with worsening hemolysis, renal function, and anemia are of interest, although not unexpected. A strength of the study is the large number of subjects studied and its focus on Hb SS disease, without inclusion of other disease genotypes. A weakness of the study is the inevitable patient selection bias with inability of deriving conclusions truly applicable to all patients. Larger questions like relationships of these findings to pulmonary hypertension, and the rationale for specifically targeting TRV with therapeutic measures remain unanswered and require future specifically designed studies. This study is based on the notion that vascular occlusion by sickle erythrocytes is dependent upon WBC adhesion to the vascular endothelium [17] and that treatment of this process requires blocking of the adhesion molecule E-selectin on the vascular endothelium. The IC50s of GMI-1070, the drug tested in this study, indicates that this compound blocks E-selectin at approximately two orders of magnitude lower concentration (4.3 mM) than P-selectin (423 mM) and nearly that much lower concentration than L-selectin (337 mM) [18]. These authors previously have documented the dominance of P-selectin over the other selectins in mediating rolling adhesion of WBC [19], and others have shown that blocking P-selectin but not E-selectin prevents WBC adhesion to the endothelium in a sickle cell mouse [20]. The study examines the effects of IV administration of a 20 g/kg loading dose followed by a 10 mg/kg dose 10 hrs later in 13 Hb SS and 2 Hb S/beta 0 thalassemia patients. Significant neutrophilia was observed at 24 and 48 hours after administration of GMI0-1070, presumably as the result of inhibition of margination, but no blocking of WBC adhesion was documented in the ex vivo experiments. The lack of significant increase in blood flow velocity using computer-assisted intravital microscopy, a powerful method that has the capacity to detect meaningful changes in sickle RBC flow in vivo seems problematic [21, 22]. Two questions derive from analysis of this study: If selectin blocking with GMI-1070 is sufficient to recommend it for further development as therapy, why does it have so little effect on sickle cell blood flow?; and Does the lack of blood flow improvement concomitant with significant effects of GMI-1070 on WBC indicate that WBC adhesion is unimportant to sickle cell blood flow? Asthma is an important contributor to increased morbidity and mortality in sickle cell disease [23]. This observational study compares the clinical features of the diseases and its complications in patients with and without a physician-diagnosed asthma, among patients receiving care in the Washington University/Barnes Jewish Hospital system. The 34 patients with a diagnosis of asthma did not show any significant increase in the rates of acute chest syndrome (ACS), pain or lung function when compared with 80 patients with no diagnosis of asthma. However, patients reporting >2 episodes of wheezing progressing to shortness of breath, had a much greater incidence of ACS, pain, decreased lung function and possibly death. Additionally, among the 80 patients with no asthma diagnosis, 30 reported asthma-like symptoms at least one a month. Asthma has emerged in the last few years as a significant risk factor for severe sickle cell complications and death among patients [23]. In this study, patient-reported wheezing was more powerful as predictor of disease complications that asthma diagnosis by a physician. Since wheezing is an essential symptom of asthma, one could conclude that many of the patients diagnosed with asthma by a physician did not actually have such a condition. This study highlights the challenges of properly identifying patients at risk for this condition, even in a highly specialized Sickle Cell Center. It also shows how a carefully conducted patient history may be more informative that a diagnosis, which may at times be erroneous. Malaria infection is a major cause of both morbidity and mortality for African patients with sickle cell disease. This risk is particularly elevated in Senegal following the rainy seasons (July-October). Thus, a strategy based on malaria chemoprophylaxis for patients with sickle cell disease during periods at high risk for disease transmission is worth exploring. In this double-blind, placebo controlled, pilot study, 60 patients with sickle cell disease were randomly assigned to either placebo or monthly chemoprophylaxis with sulfadoxine 25 mg/kg and pyrimethamine 1.25 mg/kg given once from September to November. Study endpoints were the incidence of malaria infection and sickle-cell disease related morbidities. While no malaria cases were observed in the treatment arm, four cases were confirmed in the placebo arm. Vaso-occlusive crises and hospitalizations showed no changes while treated patients experienced fewer transfusions and disease-related complaints. This pilot study suggests feasibility for a strategy based on malaria chemoprophylaxis during periods at high risk of transmission for patients with sickle cell disease. A more intensive clinical/laboratory monitoring of these patients should be considered, to detect non-clinically apparent malaria infections that may still promote clinical complications. Novel flow-cytometry assays may be particularly useful for this approach [24]. Presence of concomitant diseases, such as HIV poses an additional challenge in response to therapy and disease severity [25, 26]. The impact of chemoprophylaxis on promoting drug-resistance should also be considered. Larger clinical studies both in adults and children with sickle cell disease are needed to assess both benefits and potential downfalls of this therapeutic approach. To assess the value of previously reported candidate modifiers associated with stroke in pediatric sickle cell disease, two cohorts of patients with either diagnosed stroke (n = 134) or nominally stroke-free (n = 104) were investigated. Of the 38 SNPs, which had been reported as being associated with stroke in previous studies, only five were found to perform satisfactorily in these cohorts. In addition, the association of alpha thalassemia trait with lower stroke risk was also confirmed. No association was found with any of the classical beta globin haplotypes, while a new association was reported with a novel sub-type of the Benin haplotype (BEN-Memphis). Stroke is a devastating complication of sickle cell disease [27]. Several studies have identified potential diseases modifier genetic polymorphisms in sickle cell disease [28-30]. Inflated false positivity due to multiple testing, population stratification and technical errors are well known problem of association studies [29]. Replicative studies are important to confirm the strengths of these associations in independent study populations. The lack of replication, as shown in this study, is not necessarily an indication of false positivity: the genetic background of the studied population may not be the same, and the phenotypic definitions may be different. This study however highlights the complexities associated with linking genotype and phenotype, especially in a complex disease such as sickle cell anemia and for a not easily defined clinical complication as stroke.