Benefits of hydroxyurea in hemoglobin SC: Results of the open-label phase of the prospective identification of variables as outcomes for treatment (PIVOT) trial

Abstract Introduction: Hydroxyurea treatment is the standard of care for people with sickle cell anemia (HbSS or HbS/beta-zero thalassemia) with numerous well-documented clinical and laboratory benefits, but its use in HbSC disease has fewer clinical data to guide therapy. PIVOT is a prospective, Phase 2, double-blind, placebo-controlled trial of hydroxyurea for children and adults with HbSC disease designed to identify toxicities and treatment outcomes (PACTR 202108893981080). We reported the primary results of PIVOT, with acceptable dose-limiting toxicities (DLT) and substantial clinical benefits of hydroxyurea compared to placebo after 12 months of blinded treatment. We now describe the results of an additional 12 months of open-label hydroxyurea treatment in all participants. Methods: PIVOT is conducted in Accra Ghana at Korle Bu Teaching Hospital's Department of Child Health (children) and Ghana Institute of Clinical Genetics (adults). People with HbSC disease between 5.0 – 50.0 years of age were eligible but those with recent transfusion, cytopenias, pregnancy, or current disease-modifying therapy were excluded. After 12 months of randomized treatment with either hydroxyurea (Siklos®) or placebo, all participants were offered an additional 12 months of open-label hydroxyurea. Hematological effects, incidence rates of sickle-related adverse events, hospitalizations, transfusions, malaria, and prevalence of DLT were analyzed based on initial treatment assignment. Results: A total of 198 of the original 212 randomized participants completed 12 months of blinded treatment. Of these, 196/198 (96 from the hydroxyurea arm, and 100 from the placebo arm) enrolled in the open-label phase, and 185 participants (93 hydroxyurea; 92 placebo) completed 12 months of hydroxyurea for an additional 85.7 pt years and 89.9 pt yrs of open-label treatment, respectively. The hydroxyurea arm was receiving 19.3 ± 2.2 mg/kg/day at Month 12, and 18.8 ± 2.6 at Month 24, while the placebo arm started at 21.3 ± 2.9 mg/kg/day of active treatment at Month 12 and was receiving 20.9 ± 3.7 at Month 24. DLTs occurred in 35/107 (33%) participants in the hydroxyurea arm during the blinded phase, mostly mild asymptomatic neutropenia or thrombocytopenia and in 22/96 (23%) during the open-label phase. In contrast, DLT were recorded in 11/105 (10%) of the placebo arm during the blinded phase and increased to 26/100 (26%) during the open-label phase, again mostly mild asymptomatic neutropenia or thrombocytopenia. In the original hydroxyurea arm, laboratory benefits from the blinded phase were maintained throughout the open-label phase, with hemoglobin = 11.2±1.3 g/dL, MCV = 91±14 fL, HbF = 10.1±9.2%, and ANC = 2.5±1.1 x 109/L at Month 24. Clinical benefits were also sustained including low rates of acute vaso-occlusive pain (0.56/pt yr), malaria infections (0.20/pt yr), and hospitalizations (0.11/pt yr). In the original placebo arm, laboratory benefits accrued after Month 12 and were statistically indistinguishable from the hydroxyurea arm at Month 24 (all p-values >0.05). Clinical benefits also started after Month 12, with significant decreased rates at Month 24 of acute pain (1.51 à 0.55/pt yr, a 64% reduction, IRR 0.36, 95% CI 0.25-0.51, p<0.0001), malaria (0.39 à 0.29/pt yr, a 25% reduction, IRR 0.75, 95% CI 0.43-1.29, p=0.297), and hospitalizations (0.31 à 0.23/pt yr, a 26% reduction, IRR 0.78, 95% CI 0.43-1.4, p=0.398). The rate of transfusions was low in both treatment arms (0.02 and 0.04/100 pt yrs, respectively). By Month 24, study participants from both original treatment arms had almost equivalent laboratory effects and clinical benefits. Conclusions: After the blinded treatment phase of PIVOT, 12 months of open-label hydroxyurea led to striking laboratory and clinical benefits in the original placebo arm with only mild and transient DLT. Salutary increases in MCV and HbF, as well as decreases in ANC were observed and were accompanied by fewer painful vaso-occlusive events, malaria infections, and hospitalizations. These open-label data confirm the blinded phase PIVOT data and document that hydroxyurea is associated with tolerable DLT and sustained disease-modifying clinical benefits for both children and adults with HbSC. These dosing parameters, safety profile, and rate reduction in clinical events will inform a planned definitive phase 3 trial to prove the efficacy of hydroxyurea for people with HbSC disease.