A. Clinical Aspects

1. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Medicine (Baltimore). 2005;84:363-76.

The authors report the findings from a prospective longitudinal study in a heavily populated region documenting the evolving clinical course of sickle cell anemia over more than 4 decades of observation. The report provides an overview of the mortality and morbidity and describes the risk of chronic life-threatening complications in sickle cell anemia in relation to age, sex, and hematologic status by calendar era and prior clinical events.

The study population consisted of 1,056 sickle cell anemia patients observed more than 4 decades for a total of 11,427 person-years.

Sickle cell crisis marked by acute painful events is the hallmark condition of sickle cell anemia and was associated with the majority of hospitalizations. The mean overall hospitalization rate was 79 per 100 person-years of observation. 739 patients (70%) had been hospitalized with a sickle crisis. Of these, 51% (n = 536) had episodes of hospitalized sickle crisis concurrent with a primary precipitating condition such as acute chest syndrome or avascular necrosis. There was an increase in the frequency of total hospitalizations for painful events in patients during the third and fourth decade of life. In adults, hospitalization for vaso-occlusive sickle crisis was a maker of the increased likelihood of the presence of irreversible organ damage.

Acute chest syndrome was reported in 48% of patients; hypersplenism, including acute splenic sequestration crisis in young children, was reported in 20% of patients; aplastic crisis, meningitis/septicemia, neurologic disorder and bone infarction were each reported in 12-15% of patients.

Eight forms of irreversible organ damage were evaluated: (1) CVA, (2) generalized osteonecrosis with localized avascular necrosis, (3) gallbladder disease, (4) chronic renal insufficiency, (5) recurrent leg ulcer, (6) tricorporal priapism in males ≥17 years of age, 7) retinopathy, grade III and IV, and (8) sickle chronic lung disease often with pulmonary hypertension. The diagnosis of clearly evident clinical conditions such as leg ulcer, osteonecrosis, and retinopathy predicted an increased likelihood of developing a more lethal form of organ damage and earlier death: 77% of patients with chronic lung disease, 75% of those with renal insufficiency, and 51% of those with stroke had a prior chronic condition. Of the 232 patients who died, 73% had 1 or more clinically recognized forms of irreversible organ damage. By the fifth decade, nearly one-half of the surviving patients (48%) had documented irreversible organ damage.

The median age of survival for female patients was 36.3 years and for males, 38.7 years. Overall, the majority of deaths (80%, n = 186) occurred in patients aged 20 years and older. After 20 years, the risk of death increased in frequency with each decade. 13% of the deaths occurred in children younger than 10 years of age.

Fifty percent of children born with sickle cell anemia during the 21st century can expect to survive into the fifth decade of life plagued by an assortment of debilitating medical conditions. Improvement in childhood morality has produced an increased overall median survival at the authors' institution. This longer life span is accompanied by a clinical course for adult patients characterized by an increasing number of complications that negatively impact their quality of life and are associated with premature mortality.

(Comment: The statistic that stands out among all of the others in this comprehensive report of the outcome of sickle cell anemia patients is that the median age of survival for females was 36.3 years and was 38.7 years for male patients (that is, more than 60% are dead before the age of 40). The authors state that their study underscores the need for preventive therapy to ameliorate the progression of the sickle vasculopathy. Hematopoietic cell transplantation is such a therapy and, considering the markedly shortened life span of these patients, should be utilized more frequently. With modern transplant therapy, it is highly unlikely that 60% of patients transplanted at a young age would be dead by the age of 40.)

2. Risk factors and prediction of outcomes in children and adolescents who have sickle cell anemia. Quinn CT, Miller ST. Hematol Oncol Clin North Am. 2004;18:1339-54, ix.

There are widely disparate therapeutic options for each patient with sickle cell disease (SCD) (supportive care, hydroxyurea, chronic RBC transfusion, and hematopoietic cell transplantation) and one must balance the risks of treatment with the severity of disease. Optimally, any treatment should be implemented before organ damage occurs. (For discussion of this point, see Interactive Forum for Medical Professionals, "What are the appropriate criteria for unrelated cord blood transplantation of children with sickle cell disease?")

The authors discuss predictors of global disease severity and mortality, including β-Globin genotype, fetal hemoglobin, β^sGlobin haplotype, α-thalassemia, and other predictors, and present results of predictive modeling. They then discuss predictors of specific complications and state that by 18 years of age, 11% of children who have SS will suffer a clinically overt stroke; in addition, nearly 20% will have a clinically "silent" stroke. (Note, these percentages seem significantly lower than the estimates provided by a recent presentation at the American Society of Hematology Meeting which indicated that nearly 50% of patients with sickle cell disease develop brain injury.

An extremely strong risk factor for stroke is a previous stroke; recurrence rates range from 49% to 90%. Chronic RBC transfusions can reduce the risk to between 10 and 20%; however, once started, transfusions should not be discontinued according to the NHLBI STOP II Trial. The authors point out that chronic transfusions are limited by inconvenience, alloimmunization, the risk of infection, and the long-term morbidity and mortality of iron overload.

The authors state that families and physicians must continue to collaborate to choose the best course of management using incomplete data and suboptimal prognostic tools. They point out that the choices of parents may be discordant from those of their children's physicians. (One is left to wonder how often the choice of cord blood transplantation is offered for consideration.)

3. Survival of Children with Sickle Cell Disease Charles T Quinn, Zora R Rogers, and George R Buchanan. Blood 2004; 103:4023-4027.

Although this article does not deal with transplantation, an understanding of the natural history of sickle cell anemia is critical to developing appropriate indications for hematopietic cell transplantation. The authors point out that a NIH-sponsored cooperative study of sickle cell disease in 1994 estimated that the median survival for individuals with the disorder was 42 years for men and 48 years for women, and that sickle cell disease related mortality in childhood contributed significantly to this shortened survival.

The authors defined an inception cohort of newborns in the State of Texas with sickle cell anemia (SS), sickle-βo-thalassemia (Sβo), sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were identified by newborn screening and followed for up to 18 years. The 711 subjects provided 5,648 patients-years of observation. The incidence of death and stroke were calculated (other morbid outcomes were not studied). Thirty had at least one stroke, all of which occurred in sickle cell subjects. The first clinical stroke occurred most frequently between 2 and 8 years of age, and the authors estimated that 11.5% of individuals with SS will have a stroke by 18 years of age. Twenty-five subjects died. The mean age of death was 5.6 years. No sickle cell disease related deaths or stokes occurred in SC or Sβ+ subjects (N=263). The authors indicate that their study of survival of children with SS reveals that mortality has decreased, the mean age at death has increased, and that fewer die of infection. They go on to state that there is an urgent need for new therapies to decrease the morbidity of SS.

4.Predicting clinical severity in sickle cell anaemia. Steinberg MH. Br J Haematol. 2005;129:465-81 .

This is an extensive article that reviews available information about the relationship of disease severity to a variety of clinical and genetic characteristics of sickle cell disease patients. The author points out that the ability to predict the phenotype of an individual with sickle cell anemia would allow a reliable prognosis and could guide therapeutic decision making. Among factors considered are fetal hemoglobin, beta-globin haplotypes, genetic regulation of HbF, predictors of the response to hydroxyurea, α-thalassemia, interactions of α-thalassemia and HbF, polymorphism in genes that could modify the phenotyhpe of sickle cell disease, painful episodes, stroke, priapism, osteonecrosis, pulmonary hypertension, acute chest syndrome, gallstones, leucocytosis and compound phenotypes.

The conclusion reaches is that some risk factors for individual disease complications are known but are insufficiently precise to use for prognostic purposes; predicting the global disease severity is not yet possible.

(Comment: The lack of good prognostic indicators is considered a barrier to the use of hematopoetic cell transplantation, since some sickle cell patients are said to do well. However, recent reports indicate that silent cerebral infarcts are increasingly recognized as a major cause of school problems, performance on tests measuring intelligence quotients, and other neurological defects. Further, nearly half of all patients with sickle cell anemia suffer brain injury. This complication of sickle cell disease is so frequent and so clinically significant as to suggest that hematopoietic cell transplantation should be utilized more frequently at an age prior to development of serious adverse outcomes of the disorder.)

5. Circumstances of death in adult sickle cell disease patients. Darbari DSf, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Am J Hematol. 2006; 81:858-63.

The purpose of the study was to analyze clinical and/or autopsy findings at the time of death among adults with sickle cell disease (SCD) at Howard University in Washington, DC over a 25-year period. A single physician recorded circumstances of death among 141 adult SCD patients he treated and knew well from 1976 to 2001. These findings were determined by autopsy report and/or clinical assessment.

The mean +/- SD age at death was 36 +/- 11 years. Leading circumstances of death included pulmonary hypertension (PHT) (26.2%), sudden death (23.4%), renal failure (22.6%), infection (18.4%), thromboembolism (14.9%), cardiac diagnoses (12.0%), cirrhosis (11.3%), pneumonia or acute chest syndrome (9.9%), bleeding (7.8%), and iron overload (7.0%). When circumstances of deaths that occurred after 1991 (n = 69) were compared to those that occurred in 1991 or earlier (n = 72), PHT (36.2% vs. 16.6%; P < 0.01) was significantly more common in 1992 or later. Significant associations were found between PHT and thromboembolism and between cirrhosis and iron overload. In this proportional mortality study of adults with SCD, PHT was the leading finding at the time of death. Thromboembolism was associated with PHT, and iron overload was associated with cirrhosis.

6. Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea. Lanzkron S, Haywood C Jr, Segal B, Dover GJ. Am J Hematol. 2006; 81:927-32.

The multicenter study of hydroxyurea (MSH) in sickle-cell anemia (SCA) demonstrated that patients treated with hydroxyurea (HU) had a 44% decrease in hospitalizations when compared with those taking placebo. A subsequent study looking at the cost-effectiveness of HU showed that decreased hospitalizations for painful crisis accounted for the majority of cost savings in those taking HU.

The purpose of this study was to examine whether the expected decrease in hospital utilization occurred after the approval of HU in Maryland. The authors used data collected by the Maryland Health Services Cost Review Commission to obtain SCA discharge data for Maryland from FY1995 through FY2003. They also reviewed the inpatient and outpatient charts of all adults with SCA admitted to a large university hospital during 2003.

Hospitalization rates for adults with SCA in Maryland have increased significantly since approval of HU. While the total costs of inpatient care in Maryland are estimated to have increased by 31% above inflation from 1995 to 2003, the costs of inpatient care for adult SCA patients has increased by almost 60% above inflation. By comparison, there has been no significant increase in the pediatric hospitalization rate. 70% of patients in one hospital who were appropriate candidates for HU were not taking the medication.

Hospital utilization among adults with SCA has increased significantly. There are likely many factors that have played a role in this increase. One factor that appears to be involved is the underutilization of HU.

7. Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience. Gulbis B, Haberman D, Dufour D, Christophe C, Vermylen C, Kagambega F, Corazza F, Devalck C, Dresse MF, Hunninck K, Klein A, Le PQ, Loop M, Maes P, Philippet P, Sariban E, Van Geet C, Ferster A. Blood. 2005;105:2685-90.

The authors studied 127 sickle cell disease (SCD) patients treated with hydroxyurea (HU) with no attempt to reach maximal tolerated doses. There were 8 patients at risk of secondary stroke. They were followed for a median of 6 years (range 3-9 years), with 44 cumulative patient-years of follow-up. At entry, 3 patients were no longer transfused because of poor compliance, parents' refusal, or alloimmunization, while 5 patients were still under a chronic transfusion program. Recurrent stroke occurred in one patient after 6 years of follow-up despite evidence of good compliance with therapy as assessed by hematologic response to HU. This rate of recurrent stroke (1/8) is comparable to reported rates of 13-22% in transfused patients.

Thirty-four patients were considered at risk of primary stroke on the basis of abnormal transcranial Doppler studies, and 7 of the 21 explored by MRI/MRA had moderate/severe arterial stenosis. Only 1 of these 34 patients presented a cerebrovascular event (seizures) after an evaluation of 96 patient-years. The authors indicated that they did not perform neuropsychologic evaluation in this cohort.

In the cohort of 32 patients treated for 6 years, clinical improvement persisted throughout this period with significant reduction of the number of hospitalizations and duration compared with baseline data. Nevertheless, more events were reported during years 4 to 6 than 1 to 3. There was a lower than expected incidence of acute chest syndrome, as has previously been reported by these authors.

The authors concluded that their results confirm the benefit of HU, even in very young children, and its possible role in primary stroke prevention. They also suggested the possible equivalence between HU and a conventional transfusion program for primary and secondary stroke prevention, but indicated that this should be assessed by a prospective randomized study.

8. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Zimmerman SA, Schultz WH, Davis JS, et al. Blood. 2004;103:2039-45.

The authors point out that hydroxyurea improves hematologic parameters for children with sickle cell disease (SCD), but its long-term efficacy at maximum tolerated dose (MTD) has not been determined. Between 1995 and 2002, hydroxyurea therapy was initiated for 122 pediatric patients with SCD including 106 with homozygous sickle cell anemia and 16 with variant sickle cell disease genotypes. Median age at initiation of therapy was 11.1 years. Hydroxyurea was escalated to MTD, with an average dose of 25.4 +/- 5.4 mg/kg per day; the average duration of hydroxyurea therapy has been 45 +/- 24 months (range, 6-101 months). Hydroxyurea was discontinued for 15 (12%) children with poor compliance. Mild transient neutropenia occurred, but no hepatic or renal toxicity was noted. Hydroxyurea therapy led to significant increases in hemoglobin level, mean corpuscular volume, and fetal hemoglobin (HbF) level, whereas significant decreases occurred in reticulocyte, white blood cell, and platelet counts and serum bilirubin levels. Children with variant SCD genotypes also had hematologic responses to hydroxyurea. HbF induction has been sustained for up to 8 years without adverse effects on growth or increased numbers of acquired DNA mutations. Long-term hydroxyurea therapy at MTD is well tolerated by pediatric patients with SCD and has sustained hematologic efficacy with apparent long-term safety.

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