PIVOT: Can hydroxyurea improve outcomes in HbSC?

Although hydroxyurea was associated with more dose-limiting toxicities than placebo, the agent was linked to a reduction in clinical adverse events and improvements in haematological parameters, compared with placebo, in the phase 2 PIVOT trial. These results suggest that hydroxyurea may serve as a disease-modifying therapy for patients with haemoglobin sickle cell disease (HbSC).

The phase 2 PIVOT trial randomised 214 patients between 5 and 50 years of age with HbSC to hydroxyurea or a placebo. Hydroxyurea was administered at a starting dose of 20 mg/kg, with 2 opportunities for dose escalation during the 12-month study period. The occurrence of dose-limiting toxicities (DLTs) was the main outcome of the study. Dr Yvonne Dei-Adomakoh (Korle-bu Teaching Hospital, Ghana) presented the findings [1].

DLTs were more prevalent in participants on hydroxyurea than in those on placebo (33% vs 11%; Δ22%; 95% CI 11–34%), not meeting the non-inferiority threshold of 15%. Thrombocytopenia (19% vs 1%), neutropenia (13% vs 0%), and high haemoglobin (11% vs 11%) were the most commonly reported DLTs in the study. “All cases were asymptomatic, mild, transient, and reversible,” emphasised Dr Dei-Adomakoh. The research team observed that a higher age at enrolment, a lower platelet count, and an increased spleen volume were associated with an elevated risk of developing DLTs. Interestingly, clinical adverse events such as vaso-occlusive pain, malaria, hospitalisation, and sickle-related events were less common among patients on hydroxyurea (IRR 0.70; 95% CI 0.48–0.92).

“Although hydroxyurea was associated with more DLTs than placebo, these events were all asymptomatic, mild, and reversible,” Dr Dei-Adomakoh summarised the findings. “Moreover, treatment with this drug led to fewer clinical adverse events than treatment with placebo. Since the PIVOT trial was not powered for efficacy, a phase 3 trial is needed to confirm the disease-modifying effect of hydroxyurea in HbSC.”

1. Dei-Adomakoh Y, et al. Double-blind, placebo-controlled randomized trial of hydroxyurea for HbSC: results of the prospective identification of variables as outcomes for treatment (PIVOT) trail. Plenary Scientific Session, 66^th ASH Annual Meeting, 7–10 December 2024, San Diego, CA, USA.

Medical writing support was provided by Robert van den Heuvel.

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Posted on 10 December 2024