Use Of Hydroxyurea In Children Research Articles

Do Difficulties In Swallowing Medication Impede The Use Of Hydroxyurea In Children?

IntroductionBarriers to hydroxyurea (HU) use exist for children with sickle cell disease (SCD). Anecdotally, some parents report that their children struggle to swallow HU capsules. We hypothesized that difficulties in swallowing capsules and other forms of daily medication may be a barrier to pediatric HU use. MethodsA self-administered survey of parents of children with SCD ages 5-17 years was conducted in pediatric SCD clinics at four different sites (see author affiliations). Parents submitted one survey for each eligible child. We assessed views on their child's medication regimen, including HU; how medications were swallowed; whether swallowing difficulties were perceived as barriers to medication adherence and whether children taking HU had fewer difficulties taking medication. Respondents were grouped by whether children were on HU therapy. Data were analyzed using descriptive statistics, chi square and Fisher exact tests. ResultsA total of 122 adults completed the survey, with 27-35 surveys obtained from each site. Of survey respondents, 98% were parents and 95% reported being the child's primary caregiver. Half of all children were ages 8-13 years, and 23% were 7 or younger. Groups were evenly divided by whether children were taking HU (n=61 in both groups). There were no significant differences between groups regarding parent or child age, number of children living in the home or choice of the Spanish version of the survey. Parents of children in the group taking HU had a higher level of education (p=0.04). We found 24% of all parents thought that swallowing medications was “hard to do”. Most (85%) parents reported that swallowing difficulties did not preclude daily medication use, with no differences by HU use. All (98%) children could swallow liquid medication, with two thirds reported as able to do so by age 1. In contrast, 76% of children could swallow pills, with 40% able to do so by age 4. No differences by HU use were found in overall ability or age to swallow pills, although more in the HU group could swallow large pills (78.4 vs. 54.2%, p=0.03). No differences between groups were found in ability to swallow capsules. Across all age groups, 26.5% of children could not swallow capsules. Only 20% of all children could swallow capsules by age 4. Of children taking HU, 71.4% used the capsule form. Only 17% of those children open the capsules to mix with a liquid or soft food to aid in swallowing. Few (11%) children in both groups had received training for medication swallowing; most of their parents perceived the training as helpful to their child. While 96% of the children were prescribed medication, children taking HU were more likely than the others to be taking any medication (100 vs. 85%, p=0.001), and twice as likely to take medication on a daily basis (98.4 vs. 51.6%, p=0.001). Parents of children taking HU more often reported that their children took multiple medications (<0.001), including more pills daily (p=0.02). Children on HU had a medication regimen of more than once daily (61.7 vs. 28.6%, p<0.001). ConclusionsBased on self-report, the majority of parents of children with SCD did not view medication swallowing as an impediment to daily use of medications, including HU. Children in the HU group reported less difficulty swallowing large pills, but were not different in their ability to ingest capsules, small pills or liquid medication. These data suggest that difficulty swallowing medication is not a barrier to HU use for most children. Nonetheless, a substantial proportion of children ages 5-17 cannot swallow capsules; children under 5 are especially challenged. Therefore, coaching for swallowing to improve HU uptake could be targeted to the modest proportion of children who need assistance. Moreover, a reliable source of liquid HU is still needed for children who cannot swallow capsules. Our findings also suggest that HU use is more likely in families committed to daily medication use and more complex medication schedules, or for children with medical needs requiring therapy beyond once daily HU. Clinicians should continue to educate families about the benefits of HU and address potential impediments such as swallowing HU capsules and complex medication regimens.This study received support from NIH 1R21NR013745 (Green and Smaldone, PIs). Disclosures:Off Label Use: Hydroxyurea for treating children with sickle cell disease is off-label use.

Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective

Hydroxyurea (HU) is the standard treatment for severely affected children with sickle cell disease (SCD). Starting dose is 15-20 mg/kg/day that can be escalated up to 35 mg/kg/day. Ethnic neutropenia is common in this area of the world that requires judicious usage of myelosuppressive drugs. Aim was to assess the efficacy of a lower initial dose of HU and cautious dose escalation regimen in patients with SCD. We assessed 161 patients with SCD on HU, at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, retrospectively from 1998 to 2008 and prospectively from 2009 to 2011. Starting dose of HU was 10-12 mg/kg/day, adjusted based on response or side effects. Patients were divided into two groups according to the dose of HU (10-15.9 mg/kg/day and 16-26 mg/kg/day). Nineteen patients were excluded for various reasons. Forty-four children were in the low-dose group and 98 were in the high-dose group. There was significant reduction in the annual number of admissions due to vaso-occlusive crisis in both groups (P < 0.001). However, the difference between the two groups was statistically insignificant (P > 0.05). In addition, there was an observed clinical improvement regarding the acute chest syndrome (ACS). Both groups had comparable significant improvements in their laboratory markers [e.g., hemoglobin (Hb), Mean Corpuscular Volume (MCV), and absolute neutrophil count (ANC)]. All 142 patients tolerated the treatment well. Reversible toxicities occurred in both low- and high-dose groups. In SCD patients, low-dose regimen of HU is a feasible option that ensured safety and yet did not affect efficacy.

Hydroxyurea for the treatment of sickle cell disease: Efficacy, barriers, toxicity, and management in children

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children.

The Impact of Hydroxyurea Therapy on the Prevalence of Retinopathy in a Pediatric Sickle Cell Cohort

Abstract 1057 Introduction:Approximately 15–17% of children with HbSS and 11% of those with HbSβ0thalassemia (HbSβ0thal) develop sickle retinopathy (SR) by 18 years of age. Sickle retinopathy is a spectrum of vascular lesions that insidiously evolve as a result of ischemia from vaso-occlusion of capillary and precapillary arterioles in the peripheral retina. These lesions are usually clinically silent but can progress to spontaneous vitreous hemorrhage or retinal detachment and lead to blindness. Therefore, periodic screening retinal exams are recommended for children and adults with sickle cell disease (SCD). Prior reports from Jamaica identified low fetal hemoglobin (HbF) concentration as a potential risk factor for retinopathy in HbSS patients. Hydroxyurea (HU), an increasingly utilized treatment in children with HbSS/HbSB0thal, increases %HbF levels. However, there are no reports describing the effects of HU therapy on the prevalence of retinopathy in children with SCD. In our institution, all children with SCD are referred to ophthalmology for a screening dilated fundoscopic exam (DFE) beginning at 10 years of age and then every 2 years. Objective:Define the prevalence of retinopathy in children with HbSS/HbSβ0thal and analyze the effects of treatment with HU and %HbF levels on the prevalence of retinopathy. Methods:After IRB approval, a retrospective chart review was performed on children with HbSS/HbSβ0thal who received a DFE without fluorescein angiography at St Jude Children’s Research Hospital between 2003 and 2010. Children who received chronic transfusion therapy or hematopoietic stem cell transplantation were excluded from analysis. Records of DFEs were reviewed for a diagnosis of non-proliferative or proliferative SR. Laboratory data were collected at multiple time points from patients’ electronic medical records, including: prior to initiation of HU, following two years of therapy with HU, and immediately prior to diagnosis of retinopathy. Time of observation was defined as birth to diagnosis of SR or to date of last DFE. Summary statistics are reported and the HU and non-HU groups are compared with the Wilcoxon-Mann-Whitney Exact test. Results:Of 182 children referred to ophthalmology, 142 (78%; 126 HbSS, 16 HbSβ0thal) received an initial DFE at a median age of 13.1 ± 3.3 years (range: 1.6–18.7 years). The median number of DFEs per patient was 1.7 ± 1.4 (range: 1–12) during the time of observation. Sickle retinopathy was diagnosed in 9.9% (14/142) of children, at an average age of 15 ± 2.5 years. Of the children who received a DFE, 63% (90/142) had initiated HU therapy at an average age of 9.8 ±4.8 years. The average age at initial DFE was not different in patients receiving HU (13.1 ± 3.2 years) and those who did not (13 ± 3.5 years). The total number of DFEs performed in both groups was also similar (1 ± 1.2 in HU-treated group vs. 1 ± 1.6 in untreated group). Retinopathy was diagnosed in 7.8% (7/90) of children who received HU and 13.5% (7/52) of children who did not (p=0.27). The median age at diagnosis of SR was similar for patients treated with HU (15.4 ± 2.5 years, range: 11.3–18.2 years) compared to untreated children (14.6 ± 2.6 years, range: 10.8–17.3 years; p=0.6). Among patients receiving HU, those who developed retinopathy started treatment at a later age, however the difference was not statistically significant (12.2 ± 5 years vs. 9.3 ± 4.5 years; p=0.23). Among the HU treated group, %HbF following 2 years of HU therapy was similar in those who developed SR (16.1 ± 7.7%) and those who did not (20.0 ± 6.8%; p=0.24). Conclusion:Although the average age at diagnosis with retinopathy in these children with HbSS/HbSβ0thal was similar to previously reported untreated pediatric cohorts, the overall prevalence of retinopathy was lower. Treatment with HU did not affect the development of retinopathy nor did %HbF levels in those treated with HU. More studies are necessary to analyze the effects of HU treatment on development of SR. In the meantime, continued adherence to screening guidelines for ophthalmology evaluations are necessary for children with HbSS and HbSβ0thal being treated with hydroxyurea. Disclosures:Off Label Use: Use of hydroxyurea in children with sickle cell anemia.

Therapeutic Phlebotomy in Children with Sickle Cell Anemia, Stroke, and Iron Overload: The SWiTCH Experience

Abstract 1044▪▪This icon denotes a clinically relevant abstract Background:Stroke With Transfusions Changing to Hydroxyurea (SWiTCH Clinical Trials.gov NCT00122980), an NHLBI-sponsored Phase III multicenter trial, compared chronic blood transfusions/chelation to hydroxyurea/phlebotomy for the reduction of recurrent stroke and improvement in iron overload management in children with sickle cell anemia (SCA) and history of overt stroke. To date, however, phlebotomy to manage iron overload has not been commonly performed in children, especially those with SCA. Objective:To describe the experience with SWiTCH phlebotomy procedures, including success rate, associated adverse events, and effect on liver iron stores. Methods:Quantitative liver iron concentration (LIC) was measured by liver biopsy at study entry. Only subjects with LIC > 5 mg Fe/gram dry weight liver (DWL) were eligible for randomization. Those randomized to hydroxyurea/phlebotomy received decreasing volumes of monthly transfusion during hydroxyurea dose escalation, which lasted 4–9 months. Phlebotomy was performed every 4±1 weeks after discontinuation of transfusions. The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) for Hb ≥ 8.0 gm/dL, and 5 mL/kg for Hb 7.0–7.9 gm/dL. Phlebotomy was held if Hb was <7.0 gm/dL. Phlebotomy was performed over 30 minutes with immediate normal saline replacement, typically using peripheral venous access. Exit LIC by liver biopsy was obtained in those completing 30 months of therapy. Ferritin was monitored monthly in all subjects using a centralized laboratory. Results:Sixty-seven children (mean age 13.0 ± 4.0 years; range 5.2–19.0 years) with history of previous stroke and transfusion therapy for an average of 7.4 ± 3.8 years (range 1.5–15.5 years) were randomized to the hydroxyurea/phlebotomy arm. Most of them had also received chelation therapy: 47 (71%) with deferoxamine for an average of 4.8 ± 3.2 years, and 57 (86%) with deferasirox for 1.5 ± 0.8 years prior to study entry. Their average entry LIC was 16.5 ± 9.4 mg/gram DWL. Sixty of 67 children (90%) successfully transitioned to hydroxyurea after 7.2 ± 2.4 months of transfusion overlap; one subject had a stroke during overlap and six failed to demonstrate adequate response/compliance to hydroxyurea to safely discontinue transfusions. These 60 subjects received an average of 8 ± 3 transfusions providing 63 ± 44 mL/kg PRBCs before completing transition and commencing phlebotomy, and 3 ± 3 transfusions providing 19 ± 20 mL/kg PRBCs after starting phlebotomy, for various clinical indications. During the course of the study, a total of 935 phlebotomies were performed (mean 16 per subject) removing an average total volume of 127 ± 74 mL/kg per subject. The mean pre-phlebotomy Hb level on hydroxyurea (9.1 gm/dL) was not significantly different than the mean pre-transfusion Hb during the transfusion overlap period (9.0 gm/dL). Mean ferritin for these 60 subjects on the hydroxyurea/phlebotomy arm decreased from 3523 ± 2150 ng/mL at study entry to 2227 ± 1646 ng/mL (p<0.0001) at exit; and decreased in 50 of 60 subjects. For the 23 patients on the hydroxyurea/phlebotomy arm who completed 30 months of study treatment, the average LIC was unchanged (18.5 mg Fe/gram DWL at entry compared to 18.1 mg Fe/gram at exit, p=0.817). However, average ferritin level for these subjects was significantly lower at exit (4216 ± 2799 ng/mL vs 2356 ± 2032 ng/mL, respectively, p=0.0003). Of 968 protocol-directed phlebotomy procedures, 935 (97%) were performed; 94% of which were at full prescribed volume. Of the 33 phlebotomy procedures that were not performed, 11 were held due to Hb < 7.0 gm/dL and 9 due to poor venous access. There were only 33 grade 2 adverse events (3.5% prevalence) reported in 12 subjects and no serious adverse events. The most common complication was hypotension (9 events; 5 subjects) followed by dizziness, syncope, headache and weakness. Six subjects had a recurrent stroke but there was no temporal relationship to the phlebotomy procedures. Conclusions:Therapeutic phlebotomies were well-tolerated and did not result in worsening anemia or stroke recurrence in this cohort of children with SCA and previous stroke switched to hydroxyurea. Although ferritin levels decreased significantly, we did not demonstrate an overall decrease in LIC in this heavily iron overloaded cohort, most likely due to continued iron loading with transfusions in the overlap period and subsequent short duration of phlebotomy. Disclosures:Off Label Use: Use of hydroxyurea in children with sickle cell anemia.

Optimizing Hydroxyurea Use in Children with Sickle Cell Disease: Least Tolerated Dose Is Effective

Abstract 4851 Background:Hydroxyurea (HU) is an antimetabolite that effectively ameliorates the course of sickle cell disease (SCD). Starting dose is usually 20 mg/kg/day and the dose is escalated up to 35 mg/kg/day in most of the centers. In Oman, due to high level of consanguinity, ethnic neutropenia affects around 10% of population rendering higher doses difficult to maintain in most of the patients. Materials and Methods:161 patients (age 2–16 years, 61% male and 39% female) with SCD at Sultan Qaboos University Hospital, Muscat, Oman, were started on HU for clinically severe course (defined as: annual vaso occlusive crisis admissions more than 3, and/or occurrence of acute chest syndrome) with starting dose of 15 mg/kg and a mean dose of 18 mg/kg/day. All patients were included in the study except for 19 patients who were excluded for various reasons (8 lost follow up, 6 stopped HU by parents, and 5 stopped due to side effects: dizziness, abdominal pain, and myelosuppression). Remaining 142 patients were followed up for median treatment duration of 4 years (range, 1.5–10 years). Patients were assessed for clinical and laboratory response to HU. Results:There was significant reduction in the annual number of admissions due to vaso occlusive crisis (P <0.001, Wilcoxon Signed Ranks Test) with a mean of 4.7 and 1.5 before and after HU use respectively.There was also observed clinical improvement regarding the incidence of acute chest syndrome. Only 12 out of 39 patients initiated on HU for acute chest syndrome had a recurrent attack during a follow up period of 3–7 years.The laboratory parameters were consistent with previous reports: significant increase in hemoglobin level, fetal hemoglobin (HbF) level, Mean Corpuscular Volume, whereas significant decrease in platelet, absolute neutrophil, and absolute reticulocytic counts.All 142 patients tolerated the treatment well. Observed side effects included abdominal pain, dizziness, rash, tremor in one patient each. Of note, 21 patients (11.1%) developed neutropenia (ANC<1000 × 10^9/l) while 7 patients (3.7%) had thrombocytopenia (<100 × 10^9/l) which interrupted the treatment for period ranging from 3 weeks to 3 months only. Conclusion:In SCD patients with background of ethnic neutropenia, lower starting dose and limited range of dose escalation of HU ensured safety and yet did not affect efficacy. Disclosures:No relevant conflicts of interest to declare.

Hydroxyurea Treatment of Young Children with Sickle Cell Anemia: Safety and Efficacy of Continued Treatment – the BABY HUG Follow-up Study

Abstract 7▪BABY HUG [Clinical Trials #NCT00006400], an NIH-NICHD sponsored randomized placebo-controlled trial showed that hydroxyurea (HU) administered to 9–18 month old children with sickle cell anemia (SCA) provides substantial clinical benefit. Benefits include a decrease in pain crises, acute chest syndrome events, need for transfusion and hospital admission; hematologic improvement include higher total and fetal hemoglobin concentration, larger red cell size, and lower WBC counts with toxicity limited to transient reduction in absolute neutrophil count (ANC) [Lancet 2011; 377:1663–72]. The parent or guardian of all 176 children who completed at least 18 months of randomized treatment were offered participation in an initial observational BABY HUG Follow-Up Study and 163 (93%) consented to participate. Clinical and laboratory data were collected every 6 months by structured abstraction of the medical record regarding use of clinically prescribed HU (dose escalation recommended), blood counts, clinical imaging, and sickle cell-related events. At the time of enrollment the family did not know their child’s randomized study treatment assignment; 133 (82%) initially chose clinical prescription of open-label HU. Acceptance of HU has remained high through 36 months of follow-up; during each 6 month data collection period 68–75% of participants reported having taken HU.Only 2 patients have left the study (due to relocation) and more than 93% of expected data have been collected. Preliminary analyses as of May 2011, including 417 patient years (pt-yrs) of follow up, demonstrate that in comparison to participants not taking HU, children who continue to take HU have statistically lower rates of pain crises requiring emergency department (ED) visits, episodic transfusions, and hospital admissions for any reason, including acute chest syndrome or febrile illness (see table). The substantial decrease in acute chest syndrome episodes is similar to the effect demonstrated with HU use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of HU therapy in older children and adults. The decrease in the rate of admission for febrile events in HU-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain. There was no difference in hospitalization rates for painful events including dactylitis. Two patients in the non-HU group had a stroke. There were no differences between groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up children taking HU had persistently higher hemoglobin and MCV, and lower WBC and ANC than those not taking HU.Event Rate per 100 pt-yrsHUNo HUp valueED visit for Pain Crisis28.853.60.004Episodic Transfusion18.334.00.010Hospital Admission (any cause)74.9133.20.001Acute Chest Syndrome (admission)9.522.30.0001Febrile Illness (admission)30.764.3<.001Pain Crisis (admission)18.630.40.102Results of these analyses including growth and development assessments will enhance our understanding of the impact of HU use in children with SCA starting at a very young age. The accruing data from the BABY HUG Follow-Up Study demonstrate a continuation of the substantial benefits of early HU therapy with no discernable additional toxicities. Ongoing follow up of this cohort is essential to fully define these benefits as children grow, and to observe for late toxicity. Disclosures:Off Label Use: Hydroxyurea is not indicated for treatment of children with sickle cell disease. Use of this medication was for clinical indications and not mandated by this observational study.

Increased prevalence of osteonecrosis of the femoral head in children and adolescents with sickle‐cell disease

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Hydroxyurea Use Among Infants with Sickle Cell Disease: A Survey of Pediatric Hematologists-Oncologists In the United States

AbstractAbstract 1640A National Institutes of Health expert panel concluded that barriers to hydroxyurea (HU) therapy for patients with sickle cell disease (SCD) exist at multiple levels, including that of healthcare providers.1 Despite calls for more widespread use of HU among infants with SCD, only a small fraction of those who meet currently accepted criteria for HU administration are actually prescribed therapy.1 To address this disparity, we assessed barriers to HU therapy as perceived by Pediatric Hematologists-Oncologists in the United States. This study was approved by the institutional review board. We surveyed 400 Pediatric Hematologists/Oncologists from varying regions in the United States. Prospective participants were emailed a link to an anonymous online survey. To ensure an optimal response rate, two-follow up emails were sent at two week intervals to those who did not initially respond. Our survey instrument was evaluated for content validity by 5 Pediatric subspecialists from geographically diverse areas of the country and included both public and private settings. Response rate was equal to (complete responses+ partial responses)/(complete responses + partial responses + nonresponse + implicit refusals). In this study, a complete response was defined as 80% or more of questions answered and a partial response as less than 80% of questions answered. The response rate for this survey was 25% (n=99). Respondents' primary areas of practice included pediatric hematology (27.5%; n=22), general pediatric hematology oncology (57.5%, n=46) and pediatric oncology (15%, n=12). Respondents' practices ranged in the size of their sickle cell populations from 3 to 1600 (median=300). The vast majority of respondents agreed or strongly agreed that HU was an effective treatment for children with SCD (98%, n= 83). Most respondents (55%, n=45) reported the age range of 1–5 years as the youngest age at which they initiated HU therapy among their patients, 17% (n=14) had initiated therapy in a patient between 6months and 1 year of age. Common independent criteria for HU initiation included recurrent acute chest syndromes (94%, n=78), vaso-occlusive crises (93%, n=77), other pulmonary disease (including increased tricuspid regurgitation velocities) (66%, n=55) and priapism (58%, n=48). Interestingly, 30% (n=25) of respondents used patient/family request as an independent criterion for HU therapy. Compliance/adherence (89%, n=72), need for frequent monitoring (78%, n=68) and family concerns regarding toxicity (76%, n= 63) were the most commonly reported barriers to the effective use of HU therapy among patients with SCD. While, 57.8% (n=48) of respondents agreed/strongly agreed that HU is an effective drug for the prevention of organ damage among infants with SCD, only 32% (n= 26) supported the prophylactic use of HU for infants (>6 months) with severe sickle genotypes (SS, SB0), regardless of disease severity. Respondents were most concerned about cytopenias (68%, n=55), fertility (46%, n=37), risk of malignancy (27%, n=22), gastrointestinal disturbances (26%, n=21) and avascular necrosis (17%, n=14). The majority of respondents agreed/strongly agreed that a prospective randomized controlled clinical trial is needed to establish the long-term safety and efficacy profile of HU treatment before prophylactic therapy is offered to infants with severe sickle cell genotypes, irrespective of their disease severity (78%, n=63), or to infants with SCD regardless of genotype and disease severity (82%, n=67). Respondents identified lack of funding for (71%, n=73) and family/patient mistrust towards a clinical trial (45%, n=46) as the major barriers to conducting a prospective study. The majority of respondents (94%, n=78) supported the establishment of a registry for all patients with SCD who are on HU therapy. While most respondents believe HU to be an effective drug for the treatment of patients with SCD and for prevention of associated organ damage, there is concern for potential toxicities of therapy. Most respondents support a prospective randomized controlled clinical trial and/or establishment of a registry for the use of prophylactic HU therapy among infants with SCD.1. Brawley OW, Conrelius LJ, Edwards LR, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Internal Med. 2008; 148:932-938. Disclosures:Off Label Use: off-label use of hydroxyurea in children.

Academic Community Standards for Chronic Transfusion Therapy In Children with Sickle Cell Anemia and Abnormal Transcranial Doppler Velocities

AbstractAbstract 2643Children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities receive chronic transfusion therapy in an effort to prevent a primary stroke. Typically the goal is maintaining sickle hemoglobin (HbS) <30%, however this goal may be difficult to achieve in actual clinical practice. The NHLBI-sponsored TCD With Transfusions Changing to Hydroxyurea (TWiTCH) trial will compare standard therapy (transfusions) with alternative therapy (hydroxyurea) for the prevention of primary stroke. The transfusions will be given according to current transfusion practices at the participating academic sites. To determine the current academic community standards for primary stroke prophylaxis in children with SCA, 32 potential clinical sites collected data for children with abnormal TCD velocities who are receiving chronic transfusion therapy to prevent a primary stroke. The eligibility criteria included all children with SCA, age 4.0–15.9 years who were on chronic transfusion therapy to prevent a primary stroke due to previous abnormal TCD examination. After IRB-approval, subject and transfusion-related data were collected for all TWiTCH-eligible patients over the 12-month period from 9/1/2008 to 8/31/2009. Variables included year of birth, gender, year chronic transfusions began, TCD velocities that led to transfusion therapy, weight, %HbS transfusion goal, type and volume, pre-transfusion hemoglobin concentration and %HbS, and interval between transfusions. Data were analyzed both “per transfusion” and “per patient.” A total of 3970 transfusions were administered to 340 pediatric patients (mean approximate age at time of survey 10.2 ± 4.1 years, M: F = 0.9:1) over the 12-month period, with a mean of 11.6 ± 2.8 transfusions per patient. The average of the highest TCD velocity that led to transfusion therapy was 221 ± 27 cm/sec. Maximum velocities for right and left hemispheres were 201.2 ± 35.3 and 207.7 ± 31.8 cm/sec, respectively, supporting equal susceptibility. The mean approximate age at the start of transfusion therapy was 6.2 ± 2.6 years with average transfusion duration of 4.0 years. Most children (79%) received primarily simple transfusions, while 19% had primarily exchange transfusions (11% manual and 8% automated), and 2% multiple transfusion types. The transfusion goal was HbS <30% at almost all sites (84%). An equal number of patients developed erythrocyte alloantibodies (13.6%) and autoantibodies (13.7%). Transfusions were considered late if administered later than 7 days beyond the scheduled date. On average, late transfusions were given 1.3 ± 5.5 days after the 7 day allowable window. The average pre-transfusion hemoglobin concentration was 9.0 ± 0.9 gm/dL. The average pre-transfusion %HbS was 34.1 ± 11.2%, with a median value of 32.9%. The 75th percentile for HbS values was 40.9%, while the 90th percentile was 49.5%. There were profound differences among institutional pre-transfusion %HbS values, ranging from 23 ± 14% HbS at one institution where 103 transfusions were given to 9 patients during the 12-month period to 48 ± 15% at another institution where 95 transfusions were administered to 9 patients during the same time frame. These data indicate that current transfusion practice to prevent primary stroke varies among academic pediatric institutions, and 30%HbS is not an easily attainable goal for the TWiTCH study that includes chronic transfusion therapy within the Standard Arm. As a result of this analysis, the TWiTCH study will recommend chronic transfusions with the goal of maintaining HbS <30%, but only record a protocol violation when the HbS value exceeds 45%. Disclosures:Off Label Use: It will include the use of hydroxyurea in children with sickle cell anemia.

Assessment of Genotoxicity Associated with Hydroxyurea Therapy in Children with Sickle Cell Anemia.

Abstract 2554Poster Board II-531 Introduction:Hydroxyurea induces fetal hemoglobin (HbF), improves laboratory parameters, and reduces acute clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety remain incompletely defined. One long-term safety concern is that hydroxyurea may elicit DNA alterations via genotoxic damage. During normal erythropoiesis, red blood cells (RBC) extrude their nucleus as they develop into functional reticulocytes. Occasionally, membrane bound DNA remains in the cell after erythrocyte maturation and these inclusion bodies are known as micronuclei (MN) or Howell-Jolly Bodies. MN-containing reticulocytes are formed at higher frequency upon exposure to genotoxic agents. Patients with SCA have increased basal MN production while also having decreased MN clearance due to diminished splenic filtrative function. In a previous small cross sectional study, we showed that hydroxyurea exposure further increases MN production in SCA patients. To better address this long-term safety issue of hydroxyurea, we evaluated MN production and clearance both in a large cross-sectional and prospective study of children with SCA on hydroxyurea therapy. Patients and Methods:A high-throughput flow cytometric technique was used to detect and quantitate MN within circulating erythrocyte subpopulations. After written informed consent, venous blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (HUSTLE, ClinicalTrials.gov NCT00305175). A total of 105 subjects had at least 1 MN measurement, including 37 subjects with serial measurements at baseline and at follow-up time points up to 24 months of hydroxyurea exposure. MN were quantified in both reticulocytes (MN-CD71(+)) and mature RBC (MN-RBC), and then tested for associations with individual subject laboratory and clinical data. Results:In cross-sectional analysis of 293 samples from 105 children with SCA and a median of 2 years hydroxyurea exposure (range 3 months – 12 years), hydroxyurea therapy significantly lowered %CD71(+) reticulocytes (mean fold reduction 0.53 ± 0.44, p < 0.001). Compared to baseline values, hydroxyurea treatment increased levels of MN in both reticulocytes (%MN-CD71(+), mean fold increase 1.80 ± 0.91, p < 0.05) and mature RBC (%MN-RBC, mean fold increase 1.89 ± 1.39, p<0.01). The increase in MN-CD71(+) was evident by 6 months of hydroxyurea treatment, but did not significantly escalate further with up to 12 years of continued drug exposure (Fig. 1). [Display omitted] To prospectively determine the genotoxic effect of hydroxyurea, serial measurements over 2 years were performed on 37 patients. After 9 months on hydroxyurea therapy all subjects were on a stable maximum tolerated dose (MTD, average 25.1 mg/kg/day); 15 of 37 children had > 3.0 fold increase in %MN-CD71(+) while 22 of 37 had < 3.0 fold increase (Mean 3.68 ± 0.65 vs. 1.52 ± 0.52, p < 0.001). The observed inter-individual variation was associated with the predicted laboratory effects of hydroxyurea; increases in %MN-CD71(+) were positively correlated with MTD values of HbF (r2=0.22, p=0.005), mean corpuscular volume (r2=0.35, p=0.002), and mean corpuscular hemoglobin (r2=0.29, p=0.006) but negatively correlated with absolute neutrophil count (r2=0.14, p=0.02) and bilirubin levels (r2=0.20, p=0.008). There were no significant associations between %MN-CD71(+) and gender, age, or hydroxyurea dosage although %MN-RBC clearance decreased with age. Conclusions:A highly sensitive and quantitative flow cytometric technique can detect circulating MN-containing erythrocytes and this technique may be used to assess the in vivo genotoxic effect of any drug. Children with SCA have high basal MN production that is probably related to the degree of erythropoiesis in these patients. Hydroxyurea therapy was associated with genotoxicity but with substantial inter-patient variability in hydroxyurea induced %MN-CD71(+) levels. The increases in %MN-CD71(+) are observed within 6 months of starting hydroxyurea therapy but persist at the same level in patients with up to 12 years of continued drug exposure. Correlations between increased %MN-CD71(+) and predicted hydroxyurea effects on other laboratory parameters suggest that hydroxyurea induces measurable genotoxicity that may be related to individual patient sensitivity and efficacy of hydroxyurea within the bone marrow. These patients will be monitored further to confirm that hydroxyurea does not pose any long term safety issues. Disclosures:Off Label Use: Off label use of hydroxyurea in children with sickle cell anemia. Avlasevich:Litron Laboratories: Employment. Dertinger:Litron Laboratories: Employment.

Hydroxyurea in Children with Sickle Cell Disease: Practice Patterns and Barriers to Utilization.

Abstract 242Despite the Multicenter Study of Hydroxyurea (MSH) in sickle cell disease (SCD) documenting the efficacy of hydroxyurea (HU), it is underutilized in adults. Little is known about practice patterns of HU use in children with SCD and barriers to utilization. The objectives of this study were to: 1) evaluate practice patterns of HU utilization in children with SCD and 2) identify barriers to its use. We emailed a pilot-tested survey to members of the American Society of Pediatric Hematology/Oncology. The survey included provider demographics, characteristics of SCD population, criteria used to prescribe HU, and barriers to HU utilization. Descriptive statistics were performed and Spearman correlation used to evaluate factors associated with HU utilization. Thirty-one percent (n=350) of 1128 surveys were returned; 63% (220 of 350) care for children with SCD (97% physicians, 3% nurse practitioners). The median years in practice of these providers was 12 (IQR 5–20). Half of providers were female and 84% practiced in an urban teaching hospital. Half of providers have >100 SCD patients in their practice, with 43% stating SCD patients make up >20% of their practice. Most (87%) had heard of the NHLBI guidelines for SCD published in 2002, 78% had read these guidelines and 61% were aware of the HU Consensus Conference (NIH, 2008). Only 8% of providers have 50–90% of their SCD patients on HU, 54% have 10–30% of SCD patients on HU and 10% have fewer than 10% of SCD patients on HU. Most providers (90%) felt HU was effective or very effective for prevention of pain. Table 1 shows the most common criteria used to start HU. Over half of providers initiated HU therapy in patients aged <4 yrs. Twenty-six percent of providers reported more than 20% of their patients/families refused HU due to: fear of cancer (51%) and other side effects (62%), don't want to take medication (49%), required laboratory monitoring (28%), and don't think it will work (17%). Not all providers prescribed HU to eligible patients and their reasons are shown in Table 2. Provider utilization correlated with awareness of the NHLBI recommendations (r=0.4; p<0.0001) and the HU Consensus Conference (r=0.3; p<0.0001). Our survey suggests substantial variation in HU utilization in children with SCD. Many recommend HU for complications other than pain, despite insufficient evidence for its efficacy for these complications. The absence of a randomized trial of HU in children and the lack of formal guidelines may have led to HU use for indications not studied in the MSH trial. Many providers use frequent pain at home as criteria to start HU, reflecting emerging SCD pain literature and expansion of MSH criteria. Provider-related barriers to prescribing HU focus on reproductive issues (teratogenesis and infertility in males) despite low or insufficient evidence to support these concerns and patient compliance (with HU and the required laboratory monitoring). Common patient-related barriers included carcinogenesis, fear of side effects, and not wanting to take a medication. Barriers to HU use exist both on the part of providers and patients. Evaluating the potential unknown toxicities of HU that influence practice, exploring whether access to care contributes to potential noncompliance, and encouraging adherence research may decrease these barriers. In addition, studies to determine the effectiveness of HU for SCD complications other than pain are urgently needed as HU is currently used for a variety of complications for which this drug may or may not be effective.Table 1Criteria used by providers to start HUCriteriaProportion (%)Acute Chest Syndrome88≥3 painful episodes/year86Requiring hospitalization only42At home or requiring hospitalization44Chronic pain requiring frequent narcotic use70Priapism48Pulmonary Hypertension43Symptomatic Anemia40Stroke36Renal Failure15Ankle Ulcers12Low hemoglobin F levels9Elevated WBC count without evidence of infection6Table 2Provider-related barriers to HU useBarrierProportion (%)Patient compliance with taking medication86Patient compliance with blood tests85Lack of contraception in females85Patient's anticipation of side effects75Patient is too young68Concern for male infertility46Lack of formal guidelines for use in children30Provider discomfort with carcinogenic potential27Cost18Lack of time/resources to explain risks/benefits16Not FDA approved in children12Doubt effectiveness of HU11 Disclosures:No relevant conflicts of interest to declare.

Eficácia e toxicidade da hidroxiuréia em crianças com anemia falciforme

A anemia falciforme e uma doenca genetica caracterizada pelo alto indice de morbimortalidade, considerada como a mais grave entre as doencas falciformes. As opcoes terapeuticas mais eficazes atualmente disponiveis para tratamento desta hemoglobinopatia sao transplante de medula ossea (TMO) e hidroxiureia (HU). O TMO apesar de ser a medida curativa e considerado de alto risco por apresentar diversos graus de complicacoes e significativo nivel de mortalidade. O uso de HU em criancas portadoras de anemia falciforme tem proporcionado reducao de complicacoes clinicas e aumento significativo na expectativa de vida, por promover elevacao dos niveis de hemoglobina fetal, da concentracao de hemoglobina e do VCM, bem como reducao da hemolise e de eventos vaso-oclusivos. Desse modo, a HU e considerada como melhor opcao terapeutica atualmente disponivel. Porem, por ser apontada como droga potencialmente carcinogenica, ha questionamentos quanto aos beneficios e toxicidades quando utilizada por longo periodo. Este trabalho teve como proposta, avaliar por meio da revisao literaria, os riscos, beneficios e efeitos adversos da hidroxiureia em criancas.