Painful vaso-occlusive episodes (VOE) constitute the most frequent acute complication of sickle cell disease (SCD). However, despite the high economic and personal burden of hospitalization for VOE, there exists no therapeutic approach for VOE other than pain management and hydration. Hydroxyurea (HU) is frequently used continuously to augment levels of fetal hemoglobin (HbF) in patients with SCD, in association with clinical amelioration. However, in addition to its cytostatic effects, HU has immediate anti-inflammatory effects that inhibit vaso-occlusive processes in the microcirculation of mice with SCD, mediated by stimulation of cyclic guanosine monophosphate (cGMP) signaling (Almeida et al., Blood 120(14):2879, 2012). The Hydroxyurea in the Emergency Room to Lessen Pain in Sickle Cell Crisis (HELPS) study (NCT03062501) was a phase II, single-center, randomized, open-label interventional Study (Phase II) designed to evaluate, primarily, the safety of moderate-to-high daily doses of HU in SCD patients in the acute phase of VOE management. Thirty HbSS patients were included in the study within 24h of VOE onset at the Hemorio, Rio de Janeiro, Brazil. Inclusion criteria were: Arrival at the ER within 8h previous to inclusion, confirmed VOE associated with a pain scale score of > 6 within the last 24h, and a pain score of >4 at the time of inclusion. Patients with baseline neutrophil counts < 3.0 (103mm-3) and platelet (PLT) counts < 90 (103mm-3) were excluded from the study due to concerns regarding myelosuppression. Females not in use of contraception, patients hospitalized for VOE within the last 4 weeks and those that had received transfusions in the last 8 weeks were also excluded. Fifteen patients were randomized to the non-intervention arm to receive the center's standard of care, while 15 were randomized to the intervention arm to receive 30-45 mg/kg HU immediately upon study inclusion, and up to two more daily HU doses (if still hospitalized), plus standard of care. During hospitalization, pain scores were recorded every 6 hours, blood counts, and transaminases were determined at 24 h. Adverse events (CTCAE version 4.03), pain medication administered, and length of stay were recorded. Patients were recalled for a post-VOE visit at 7 days after the last HU dose for evaluation for physical exam, late adverse events, blood counts, and transaminases. Twenty-nine patients concluded the study, with 14 patients in the non-intervention arm and 15 in the intervention arm (aged 31.3±10.1 yrs). Four and three patients in each group (respectively) were on continuous HU therapy upon inclusion, and one patient in the non-intervention arm continued taking HU (20 mg/kg/day) throughout the study. Patients in the intervention arm each received up to three daily administrations of HU (mean dose, 31±5 mg/Kg/day; mean number of doses administered, 1.6 per patient). One patient experienced emesis within 2 h of first dose and did not receive a top-up dose. With regard to preliminary safety data, adverse events did not differ significantly between the arms; 4 grade 1-2 events occurred in each of the groups within 24 h of inclusion (all nausea/emesis) and nausea and/or pain were reported in 5 and 3 patients in the non-intervention and intervention arms, respectively, throughout the study. One serious adverse event (death due to sepsis) occurred in the non-intervention arm. Transaminases, red blood cell count, Hb and hematocrit did not differ significantly between the two arms at 24h after inclusion and at the post VOE consultation (number returning; 13 and 12, respectively). No myelosuppression was seen, but the intervention group had a significant decrease in leukocyte count and an increase in PLT count at 7 days post HU, compared to baseline (WBC; 11.9±4.8, 16.4 ±7.0 x 103mm-3: PLT; 570±275, 428±139 x 103mm-3, P<0.05, respectively). Sample numbers were too small to detect any statistically significant decrease in length of stay, pain scores, or opioid usage. However, data indicate that the use of up to three consecutive daily doses of approximately 30 mg/kg HU in the acute phase of the management of SCD patients with VOE is feasible and safe, independently of whether patients already take HU on a continuous basis. Results will aid in the design of larger multicenter trials to evaluate the potential efficacy of the use of oral or intravenous HU during hospitalization for SCD VOE.
Financial Support: FAPESP, Brazil.
Disclosures
Fertrin: Agios Pharmaceuticals, Inc.: Research Funding.
OffLabel Disclosure:
Use of up to 3 doses of hydroxyurea (30-45 mg/kg/day) in patients with sickle cell disease hospitalized for acute painful vaso-occlusive episodes.
SAT-LB18 A Randomized Controlled Trial of Vosoritide in Children With Achondroplasia
