Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Sorafenib and bevacizumab for recurrent metastatic hepatoblastoma: stable radiographic disease with decreased AFP.

We report the use of sorafenib and bevacizumab in combination for a patient with recurrent metastatic hepatoblastoma (HB). This combination demonstrated activity against our patient's refractory HB that had been extensively treated with multiple prior chemotherapeutic regimens. The patient had stabilization of radiographic disease coupled with an 83% decrease in his alpha-fetoprotein level. Given the response in this setting and the paucity of other available options, consideration could be given to using this combination as therapy in patients with recurrent HB who have failed more traditional agents.

Barriers to hydroxyurea use from the perspectives of providers, individuals with sickle cell disease, and families: Report from a U.S. regional collaborative.

Sickle cell disease (SCD) is an inherited blood disorder that affects about 100,000 people in the U.S., primarily Blacks/African-Americans. A multitude of complications negatively impacts quality of life. Hydroxyurea has been FDA approved since 1998 as a disease-modifying therapy for SCD, but is underutilized. Negative and uninformed perceptions of hydroxyurea and barriers to its use hinder adherence and promotion of the medication. As the largest real-world study to date that assessed hydroxyurea use for children and adults with SCD, we gathered and analyzed perspectives of providers, individuals with SCD, and families. Participants provided information about socio-demographics, hospital and emergency admissions for pain, number of severe pain episodes interfering with daily activities, medication adherence, and barriers to hydroxyurea. Providers reported on indications for hydroxyurea, reasons not prescribed, and current laboratory values. We found that hydroxyurea use was reported in over half of eligible patients from this large geographic region in the U.S., representing a range of sickle cell specialty clinical settings and practices. Provider and patient/caregiver reports about hydroxyurea use were consistent with one another; adults 26 years and older were least likely to be on hydroxyurea; and the likelihood of being on hydroxyurea decreased with one or more barriers. Using the intentional and unintentional medication nonadherence framework, we found that, even for patients on hydroxyurea, challenges to taking the medicine at the right time and forgetting were crucial unintentional barriers to adherence. Intentional barriers such as worry about side effects and "tried and it did not work" were important barriers for young adults and adults. For providers, diagnoses other than HgbSS or HgbS-ß0 thalassemia were associated with lower odds of prescribing, consistent with evidence-based guidelines. Our results support strengthening provider understanding and confidence in implementing existing SCD guidelines, and the importance of shared decision making. Our findings can assist providers in understanding choices and decisions of families; guide individualized clinical discussions regarding hydroxyurea therapy; and help with developing tailored interventions to address barriers. Addressing barriers to hydroxyurea use can inform strategies to minimize similar barriers in the use of emerging and combination therapies for SCD.

Barriers to Pediatric Sickle Cell Disease Guideline Recommendations.

National guidelines recommend that providers counsel all patients with sickle cell anemia about hydroxyurea (HU) therapy and screen children with sickle cell anemia annually for the risk of stroke with transcranial Doppler (TCD). We surveyed a national convenience sample of sickle cell disease clinicians to assess factors associated with low adherence. Adherence was 46% for TCD screening. Low adherence was associated with a lack of outcome expectancy (eg, a belief that there would be poor patient follow-up to TCD testing; P < .05). Adherence was 72% for HU counseling. Practice barriers (eg, lack of support staff or time) and a lack of agreement with HU recommendations were associated with low adherence (P < .05). This study demonstrates that different types of strategies are needed to improve TCD screening (to address follow-up and access to testing) versus HU counseling (to address physician agreement and practice barriers).