Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease.

Children with sickle cell disease (SCD) and stroke receive chronic transfusions to prevent stroke recurrence. Transfusion risks including infection, erythrocyte allosensitization, and iron overload suggest a need for alternative therapies. We previously used hydroxyurea (HU) and phlebotomy in two young adults with SCD and stroke as an alternative to transfusions. We have now prospectively discontinued transfusions in 16 pediatric patients with SCD and stroke. Reasons to discontinue transfusions included erythrocyte alloantibodies or autoantibodies, recurrent stroke on transfusions, iron overload, noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d based on hematologic toxicity. Patients with iron overload underwent phlebotomy. The children have been off transfusions 22 months, (range, 3 to 52 months). Their average HU dose is 24.9 +/- 4.2 mg/kg/d, hemoglobin concentration is 9.4 +/- 1.3 g/dL, and mean corpuscular volume (MCV) is 112 +/- 9 fL. Maximum percentage fetal hemoglobin (%HbF) is 20.6% +/- 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% +/- 14.7%. Fourteen patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg) removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had neurological events considered recurrent stroke, each 3 to 4 months after discontinuing transfusions, but before maximal HU effects. These preliminary data suggest some children with SCD and stroke may discontinue chronic transfusions and use HU therapy to prevent stroke recurrence. Phlebotomy is well-tolerated and significantly reduces iron overload. Modifications in HU therapy to raise HbF more rapidly might increase protection against stroke recurrence.     

Comparison of psychological symptoms in post-cryptogenic cerebral-vascular accident (CVA) and/or transient ischemic attack (TIA) patients who have undergone foramen ovale closure, and in post-CVA patients

The patent foramen ovale (PFO) is a controversial risk factor for CVA or TIA. In our center, adult PFO patients diagnosed with post cryptogenic CVA/TIA undergo trans-catheter closure of the PFO to decrease the risk of recurrent stroke. The aim of the study was to compare levels of functioning, depression and anxiety in post PFO closure patients following cryptogenic CVA/TIA and in other patients post CVA/TIA without PFO. Eighty-nine patients who had undergone trans-catheter PFO closure and 56 non-PFO post-CVA patients completed demographic, functioning, anxiety and depression questionnaires. Additional medical data were recorded from the medical files. Patients who had undergone trans-catheter PFO closure post CVA or TIA reported better level of functioning and substantially lower levels of depression and anxiety. The 70% of depression and 55% of anxiety variances were explained by female gender, older age, lower education, lower functioning level and additional health problems. Functioning level was the strongest contributor to the explained variance of psychological symptoms. We conclude that patients who have undergone trans-catheter PFO closure following cryptogenic CVA/TIA, which may prevent stroke recurrence, show good functioning and low levels of psychological symptoms. The procedure helps to keep these patients in a good physical and psychological health.     

Stroke recurrence in children with sickle cell disease treated with hydroxyurea following first clinical stroke

Chronic transfusion therapy is the treatment of choice for preventing stroke recurrence in children with sickle cell disease (SCD). The majority of children affected by this devastating complication live in the developing world where access to regular blood transfusions may be impractical. Since 2000, in the absence of regular blood supplies, all children at the Sickle Cell Unit who had experienced a first clinical stroke were offered hydroxyurea (HU) as the only intervention to prevent stroke recurrence. Forty-four children were identified as having experienced a first clinical stroke between January 1, 2000 and September 30, 2009; one died at that presentation. Forty-three children were therefore followed for 111 person-years, of whom 10 (23.3%) agreed to start HU. Only one child in the HU group, incidence rate 2/100 person-years, had clinical stroke recurrence, compared to 20/33 in the non-HU group, incidence rate 29/100 person-years (Hazard ratio (HR) 9.4 [95% Confidence interval (CI): 1.3-70.6]; P = 0.03). When the groups were compared, in the non-HU group, four died (vs. zero), 13 (53% vs. 10%) had moderate-severe physical disability (P = 0.017), and 12 (44% vs. 20%) required special education or were too disabled to attend school. Our data support the role of HU as a useful intervention for prevention of stroke recurrence in SCD when transfusion programs are not available or practical.     

Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial)

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence‐based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non‐imaging TCD measurements (≥200 cm/s) received moderate fixed‐dose hydroxyurea therapy (～20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient‐years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.     

Long-term results using hydroxyurea/phlebotomy for reducing secondary stroke risk in children with sickle cell anemia and iron overload

Children with sickle cell anemia (SCA) and a primary overt stroke are at high risk of recurrent (secondary) stroke. Chronic transfusion therapy dramatically reduces but does not eliminate this high risk, and inevitably results in transfusion-related hemosiderosis. We previously reported the use of hydroxyurea/phlebotomy as an alternative to transfusions to reduce the risk of secondary stroke and improve management of iron overload in 35 children with SCA. To report long-term results, we retrospectively reviewed clinical and laboratory data through October 2008. With a median of 5.6 years and total of 219 patient-years of follow-up, 10 of 35 patients (29%) had recurrent stroke after switching to hydroxyurea; seven were previously reported and three new strokes occurred during extended follow-up. The overall secondary stroke event rate was 4.6 per 100 patient-years. Children on hydroxyurea received serial phlebotomy and had lower mean serum ferritin values than children on transfusions (591 ng/mL vs. 3410 ng/mL, P = 0.02). In this cohort, long-term hydroxyurea treatment reduced but did not eliminate the risk of stroke recurrence and, uniquely, allowed phlebotomy to reduce iron overload. Long-term assessments of this therapy should evaluate risk factors for secondary stroke and assessments of hemosiderosis, neurocognitive outcome, and health-related quality of life.     

Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload.     

Clinical and laboratory effects of hydroxyurea in children and adolescents with sickle cell anemia: a Portuguese hospital study

Our aim was to assess the efficacy and safety of hydroxyurea (HU) in children with severe forms of sickle cell anemia followed in a Portuguese hospital. We carried out an open-label uncontrolled prospective study, which included children with severe forms of sickle cell anemia. Hydroxyurea was started at 15 mg/kg/day and increased to a maximum dose of 25 mg/kg/day. Patients were monitored to assess compliance, clinical and hematological response and toxicity. Nine children and adolescents, five girls and four boys, with a median age of 13 years (range 8 to 16) were enrolled in the study during a period of 24 months. All patients completed at least 15 months of therapy. Hb F was significantly increased, from a mean of 7.0 +/- 3.9% to 13.7 +/- 5.3% (p = 0.028). Clinically, all patients responded significantly with a reduction of 80% in the number of vaso-occlusive crises (VOC), 69% in hospital admissions, 76% in hospitalization days and 67% in transfusion requirements, without significant toxicity. We concluded that, in our population, HU proved to be effective in increasing Hb F levels, and in decreasing hospitalizations for VOC and transfusion requirements with no major side effects. Long-term clinical follow-up is important to certify benefit maintenance.     

Optimizing the Dose of Hydroxyurea Therapy for Patients with β-Thalassemia Intermedia (Hb E-β-thalassemia): A Single Center Study from Eastern India

Over the past 20 years, hydroxyurea (HU) has emerged as an important therapeutic agent to augment Hb F and thus total hemoglobin (Hb) in Hb E [β26(B8)Glu→Lys; HBB: c.79G>A]-β-thalassemia (Hb E-β-thal), albeit used in varying doses with little consensus on its optimal dose. We report the interim analysis findings of a broader study to assess the impact of Comprehensive Thalassemia Care, of which the present report was a part. Sixty-one Hb E-β-thal patients who were transfusion independent or requiring occasional transfusions [β-thal intermedia (β-TI)] were randomized to one of two groups; A (n?=?32) and B (n?=?29) to receive 10 and 20?mg/kg/day HU, respectively. The primary objective of the study was to assess the differences in responses to different doses of HU. Secondary end points were to see the tolerability and safety of HU in different doses. Good response (GR) was defined as a rise of Hb by >1.0?g/dL; intermediate response (IR) as a rise in Hb by 0.6–1.0?g/dL anytime during the study period. No response (NR): rise in Hb by <0.5?g/dL in 12 weeks or drop in Hb level from the previous value. Over a follow-up period of 24 weeks, we had 18 (56.2%) GRs, nine (28.2%) IRs and five (15.6%) NRs, while the number of GRs, IRs and NRs in group B were five (17.2%) 12 (41.4%) and 12 (41.4%), respectively. Adverse effects were more common in group B, making this dose (20?mg/kg/day) of HU more myelo-suppressive than Hb F inducing.     

Pain and other non‐neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: Results from the SWiTCH clinical trial

To compare the non‐neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI‐sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) ( ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA‐related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2–19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non‐neurological AEs were similar in the two treatment arms, including SCA‐related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA‐related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso‐occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy. Am. J. Heamtol. 88:932–938, 2013. © 2013 Wiley Periodicals, Inc.     

Hydroxyurea treatment of sickle cell anemia in hospital-based practices

In a published randomized clinical trial, hydroxyurea (HU) improved clinical outcomes in patients with sickle cell anemia (SCA). The mean treatment duration of that trial was 21 months. Here we attempt to determine whether the benefits associated with HU therapy of SCA have led also to successful patient acceptance of HU treatment in community practices, and whether successful clinical outcomes persist beyond 2 years. This is an observational retrospective chart study of the computerized medical records of 60 men and women with SCA who had HU treatment for at least 3 months and who were treated at teaching hospital subspecialty clinics in Baltimore, Maryland, and Washington, D.C. Thirty had remained on therapy for at least 24 months. Admissions declined in this group by 30% (P = 0.04). Declines were seen also in transfusion requirements (-58%, P = 0.07). In 17 of these 30 patients, at least 48 months of follow-up records were available. Fourteen of these remained on therapy the entire period, with similar and sustained reductions in admissions and transfusions. We conclude that hydroxyurea therapy of SCA applied in community settings leads to declining admissions and transfusion rates in many individuals for 4 years or more.     

Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial

Hydroxyurea (HU) enhances the synthesis of fetal hemoglobin (HbF) and can improve the clinical course of some adult patients with sickle cell anemia (SCA). In a randomized trial, we studied the biologic effects and the clinical benefit of HU in children and young adults with severe SCA. Twenty-five patients (median age, 9 years) were randomized to receive either HU (at the initial dosage of 20 mg/kg/d) or a placebo for 6 months and were then switched to the other arm for the next 6 months. Among the 22 evaluable patients (median age, 8 years), significant increases in HbF and mean corpuscular volume occurred during the HU treatment period. The white blood cell and reticulocytes counts decreased significantly, but these changes were not clinically relevant. Sixteen of 22 patients (73%) experienced a complete disappearance of events requiring hospitalization. The number of days of hospitalization as well as the number of hospitalizations for patients on HU, as compared with those for the patients receiving placebo, were significantly reduced. We conclude that treatment with HU in children and young adults is feasible, well-tolerated, and improves the clinical course of SCA. The long-term effects of HU require further investigation.     

Molecular characteristics of pediatric patients with sickle cell anemia and stroke

Cerebrovascular accidents (CVA) are serious complications of sickle cell anemia (SS) in children. Factors that predispose children to this complication are not well established. In an effort to elucidate the risk factors associated with CVA in SS, we have determined the alpha-globin genotype and the beta(S) haplotype of children with this complication. Among 700 children with SS followed at Children's Hospital of Michigan, 41 (6%) are on chronic transfusions because of stroke due to cerebral infarction. The mean age of patients with CVA at the time of stroke was 5.6 +/- 3.2 years (mean +/- SD). The male/female ratio was 2/3. Only 8 of 41 patients (19.5%) had one alpha-gene deletion, compared to the reported prevalence of 30% in African-Americans. None of the patients had two alpha-gene deletions, and two (5%) had five alpha-genes. These findings are different than those in our adult patients with SS, where the prevalence of -alpha/-alpha and alphaalphaalpha/alphaalpha is 4% and <2%, respectively. Ten different beta(S)-haplotypes were detected in the patients studied. The majority of the patients (31%) were doubly heterozygous for the Ben/CAR haplotypes followed by Ben/Ben, Ben/Sen, and CAR/CAR haplotypes, respectively. The prevalence of these haplotypes, with the exception of the CAR/CAR haplotype, was higher in females than males. All the patients with CAR/CAR haplotype were males, had four alpha-genes, and ranked third in prevalence. Three patients were heterozygous for the Cameron haplotype. The Cameron and atypical haplotypes were more prevalent than reported in patients with SS at large. The data suggest that CVA in children seems to occur more frequently in females and in patients with certain beta(S) haplotype. alpha-Gene deletion seems to offer a protective effect against this complication. Neonates with four or more alpha-genes whose beta(S) haplotype is Ben/CAR, atypical, or CAR/CAR seem to be at a higher risk for CAV than other patients. A prospective study on a larger group of patients with or without CVA may clarify this issue.     

Outcome of overt stroke in sickle cell anaemia,a single institution's experience

Stroke is a traumatic complication in sickle cell anaemia (SCA) that is associated with significant morbidity and a risk of recurrent overt stroke of 2·2–6·4 events per 100 patient‐years. A retrospective study was performed on all paediatric SCA patients diagnosed with a history of overt stroke between 1997 and 2010. A total of 31 children with SCA had new onset overt stroke. The mean age of the active patients (n = 27) was 17·9 years (range 6·8–27·6 years) with a total period of observation of 305 patient‐years. Twenty‐two of 27 (81%) were receiving long term red blood cell transfusions and 16 (59%) were taking the anti‐platelet agent, aspirin, since diagnosis of the stroke. Two of 27 (7%) patients had a second overt stroke with an overall risk of recurrent stroke of 0·66/100 patient‐years (one stroke was ischaemic and the other haemorrhagic). In patients taking aspirin with 180 patient‐years of follow up, the recurrence rate of haemorrhagic stroke was 0·58/100 patient‐years. We have an excellent outcome for overt stroke in paediatric SCA patients with a low rate of recurrent stroke. Further studies are needed to determine the risk‐benefit ratio of aspirin therapy in the prevention of recurrent stroke in paediatric SCA.     

Bone marrow transplantation in a young child with sickle cell anemia

Bone marrow transplantation (BMT) is the only curative therapy available for hemoglobinopathies. BMT was performed on a young child with sickle cell anemia (SCA) after approximately 9 months of transfuslon therapy following her initial stroke. The patient received a matched sibling donor (sickle trait) BMT. The conditioning regimen consisted of busulfan 4 mg/kg/day × 4, cyclophosphamide 50 mg/kg/day × 4. Graft vs. host disease prophylaxis was daily cyclosporine for 6 months. There were no significant complications during BMT. Engraftment occurred on day + 17 and the patient was transfusion independent since day +45. Pre-BMT cerebral arteriography showed multiple stenotic cerebral vessels and a moya-moya pattern. Perfusion MRI demonstrated reduced capillary perfusion. Approximately 170 days after BMT the patient experienced episodes of transient left-sided weakness and speech problems. Neuroimaging revealed progression of large vessel pathology by angiography despite significant improvement in cortical perfusion (MR perfusion scan). Molecular analysis by PCR and DNA fingerprinting confirmed absence of mixed mosaicism. Rheologic evaluation showed normal corrected bulk viscosity. It is possible that progression of large vessel pathology and return of clinical symptoms in the face of normal rheologic parameters may be due to worsening of the already damaged cerebral vessels by the BMT conditioning regimen. Further evaluations of patients with SCA undergoing BMT after a stroke are needed to answer this question. © 1995 Wiley-Liss, Inc.     

Prevention of recurrent cerebral ischemic events in patients with patent foramen ovale and cryptogenic strokes or transient ischemic attacks

BACKGROUND: Patent foramen ovale (PFO) is found in up to 50% of patients less than 55 years of age who have had a stroke. Therapeutic options include no therapy, antiplatelet therapy, warfarin and surgical closure of the PFO. OBJECTIVES: To determine the relative and attributable risks of PFO for recurrent cerebral ischemic events in young patients with stroke or transient ischemic attacks. The predictors of recurrent cerebral ischemic events and the effects of different therapies on recurrence rates were sought. DESIGN: Follow-up of a retrospective cohort of patients with cryptogenic stroke or transient ischemic attacks identified from an echocardiography database. SETTING: University-based regional neurology referral centre. PATIENTS: Consecutive group of 90 patients less than 60 years of age who underwent transesophageal echocardiography following a cryptogenic transient ischemic attack (TIA) or stroke (cerebrovascular accident [CVA]) between 1991 and 1997. INTERVENTIONS: Structured telephone interviews and chart reviews. RESULTS: Fifty-two patients had a PFO, and 38 patients did not have a PFO. During a mean follow-up of 46 months, 19 recurrent cerebral ischemic events (12 TIA and seven CVA) occurred in 14 patients with PFO, and eight recurrent events (three TIA and five CVA) occurred in six patients without PFO. The recurrence rates were 12% and 5%/patient/year in the PFO and control groups, respectively, for a crude recurrence rate ratio of 2.39 (95% CI 1.01 to 6.32, P < 0.03). The attributable risk of PFO in recurrent neurological events was 7%/patient/year. In a Cox regression model, predictors of recurrent neurological events were presence of PFO (hazard ratio 5.27, 95% CI 1.58 to 17.6, P < 0.007), history of migraine (hazard ratio 4.54, 95% CI 1.11 to 18.52, P < 0.035), hypertension requiring therapy (hazard ratio 3.5, 95% CI 1.33 to 9.01, P < 0.01), and antiplatelet or no therapy instead of warfarin therapy (hazard ratio 2.88, 95% CI 1.11 to 8.7, P < 0.04). Fourteen patients underwent surgical closure of PFO; there were no neurological recurrences during a mean follow-up of 43 months (crude incidence rate difference 12%/patient/year, 95% CI 6.6 to 17.9, P < 0.02). CONCLUSIONS: Patients with PFO had a significantly higher rate of recurrent cerebral ischemic events than those without PFO. Surgical PFO closure prevented any recurrences during a mean follow-up of 43 months. Warfarin was better than antiplatelet therapy or no therapy in preventing recurrences.     

Low fixed-dose hydroxyurea in severely affected Indian children with sickle cell disease

There is limited data on the efficacy of hydroxyurea (HU) in Indian sickle cell anemia patients who have severe manifestations despite high fetal hemoglobin (Hb F). Sixty sickle cell anemia children (5-18 years) with more than three episodes of vasoocclusive crises or blood transfusions per year were randomized to receive HU (n = 30) or placebo (n = 30) therapy. Fixed dose (10 mg/kg/day) of HU was administered for 18 months and the patients were followed-up monthly with clinical assessment and laboratory monitoring. In the HU group, hemoglobin (Hb) and Hb F levels increased significantly along with a significant decrease in the number of painful crises, blood transfusion requirements and hospitalizations compared to the placebo group. No major adverse events were observed in this study. In conclusion, low-fixed dose HU therapy was effective for the treatment of Indian sickle cell anemia children. However, there is a need for long-term studies to evaluate the efficacy and toxicity in a larger number of Indian sickle cell anemia patients.     

Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia

Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The reported effects of these agents in increasing total Hb, however, have been inconsistent and there have been no studies on the combination of these medications. We describe the clinical response, as determined by increases in total Hb and decreased transfusion needs, in five patients with thalassemia intermedia treated with HU alone or in combination with SPB. All of the patients responded with increased levels of Hb F, but the responses in total Hb varied. Of the five patients, two had a marked response in total Hb in excess of 3 g/dl, two responded modestly with an increase in total Hb of 1-2 g/dl, and one did not respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day) and higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increases in Hb. Sodium phenylbutyrate was added to treatment with HU in two patients, but failed to produce an increase in total Hb despite increasing Hb F levels. Of the four patients who responded to HU with an increase in total Hb, all reported symptomatic improvement and three have not required further transfusions. We conclude that low-dose HU therapy in patients with thalassemia intermedia may increase total Hb levels sufficiently to eliminate the need for transfusions. We, therefore, recommend a trial of HU for thalassemia intermedia patients in whom chronic transfusion therapy is being contemplated.     

Oral cyclic megadose methylprednisolone therapy for chronic immune thrombocytopenic purpura in childhood

The objectives of this study were to investigate the effectiveness of oral megadose methylprednisolone (OMMP) therapy in children with chronic immune thrombocytopenic purpura (ITP). Twenty-two patients were given oral methylprednisolone daily for 7 d (30 mg/kg for 3 d and then 20 mg/kg for 4 d). OMMP therapy was repeated once per month if the platelet count was less than 20,000/mm3 at the 30th day of therapy, for up to six courses. The number of platelets of all patients increased gradually during the OMMP therapy, with a peak number at the 7th day, then decreased until the 14th day, and remained relatively stable until 12 months. During the study no patient had a platelet count less than 20,000/mm3 at the 3rd day and 50,000/mm3 at the 7th day. Although the number of platelets was gradually decreased between the 7th and 14th days, it remained above 100,000/mm3 for at least 12 months in the nine patients, and above 20,000/mm3 in the four patients. None of these 13 patients required hospitalization or therapy during the follow-up period. All of the patients tolerated the medication well. None of them reported side-effects that were severe enough to discontinue therapy. We conclude that OMMP therapy is a safe, easy and effective therapy in children with refractory chronic ITP, and it may provide long-term remission in about two thirds of the patients.     

Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group.

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted.     

Gene interactions and stroke risk in children with sickle cell anemia

Stroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.