Hydroxyurea and Sickle Cell Anemia Clinical Utility of a Myelosuppressive “Switching” Agent

Abstract

Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises. It might also be expected to decrease the severity of anemia, although the pathogenesis of anemia in sickle cell anemia (SS disease) is not clearly understood. Reversion to production of fetal rather than adult hemoglobin became practical with the discovery that HU was an orally effective and relatively safe "switching agent." Preliminary dose-ranging studies led to a double-blind randomized controlled clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), designed to test whether patients treated with HU would have fewer crises than patients treated with placebo. The MSH was not designed to assess the mechanism(s) by which a beneficial effect might be achieved, but it was hoped that observations made during the study might illuminate that question. The 2 MSH treatment groups were similar to each other and were representative of African-American patients with relatively severe disease. The trial was closed earlier than expected, after demonstration that median crisis rate was reduced by almost 50% (2.5 versus 4.5 crises per year) in patients assigned to HU therapy. Hospitalizations, episodes of chest syndrome, and numbers of transfusions were also lower in patients treated with HU. Eight patients died during the trial, and treatment was stopped in 53. There were no instances of alarming toxicity. Patients varied widely in their maximum tolerated doses, but it was not clear that all were taking their prescribed treatments. When crisis frequency was compared with various clinical and laboratory measurements, pretreatment crisis rate and treatment with HU were clearly related to crisis rate during treatment. Pretreatment laboratory measurements were not associated with crisis rates during the study in either treatment group. It was not clear that clinical improvement was associated with an increase in Hb F. Crisis rates of the 2 treatment groups became different within 3 months. Mean corpuscular volumes (MCVs) and the proportion of Hb F containing red cells (F cells) rose, and neutrophil and reticulocyte counts fell, within 7 weeks. When patients were compared on the basis of 2-year crisis rates, those with lower crisis rates had higher F-cell counts and MCVs and lower neutrophil counts. Neutrophil, monocyte, reticulocyte, and platelet counts were directly associated, and F cells and MCV were inversely associated, with crisis rates in 3-month periods. In multivariable analyses, there was strong evidence of independent association of lower neutr...

Hydroxyurea treatment for sickle cell disease: impact on haematopoietic stem cell transplantation's outcome

“…Before HSCT, the severity of SCD was similar in the three groups except for the lower number of blood transfusions in group 3, probably as a result of chronic HU treatment that was proven to reduce the need of transfusion in children and adults 14,15 (Table 1). Group 3 patients had significant lower preconditioning absolute neutrophil count (ANC) than groups 1 and 2 (Po0.05), which again could result from chronic HU treatment.…”

“…Up to now, only a limited number of series of HSCT in SCD patients have been published, [6][7][8] and new transplantation approaches are currently being developed such as non-myeloablative conditioning [9][10][11][12] or cord blood transplantation. 13 Although hydroxyurea (HU) treatment for SCD children and young adults gives overall encouraging results [14][15][16][17][18][19][20][21][22][23] and reduces mortality in adults with frequent painful episodes, 24 we have pursued our HSCT programme for selected patients with a suitable family donor. We review here the outcome of 24 consecutive HSCT for SCD carried out in our unit (the Haemato-Oncology Unit of the Hoˆpital Universitaire des Enfants, Brussels) since 1988.…”

Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients

“…Treatment of SCA individuals with HC decreases white blood cell counts, myeloperoxidase activity (Steinberg et al, 1997;Kinney et al, 1999;Saleh et al, 1999) and cell-adhesive properties (Charache et al, 1996;Canalli et al, 2007). HC therapy also decreases the production of some inflammatory mediators and upregulates protective mechanisms (Lanaro et al, 2009).…”

Hydroxyurea therapy for sickle cell disease in community‐based practices: A survey of Florida and North Carolina hematologists/oncologists

“…In addition to increasing Hb F levels, other apparent beneficial effects of HU include an increase in hydration of erythrocytes, and a decrease in adhesion of erythrocytes to the vascular endothelium [3]. A decrease in the neutrophil count is associated with HU and correlates with clinical responses [4].…”