Voxelotor Withdrawal and Its Impact on Sickle Cell Crisis

New findings are raising concerns about the abrupt discontinuation of voxelotor in patients with sickle cell disease (SCD), after a small study documented a surge in severe complications following the drug’s withdrawal. The observations come at a pivotal moment for the SCD community, after Pfizer halted distribution of voxelotor (marketed as Oxbryta®) worldwide and discontinued ongoing clinical trials in September 2024.

Sickle cell disease is a genetic blood disorder caused by a mutation in the HBB gene, which leads to the production of abnormal hemoglobin S (HbS). Under low oxygen conditions, HbS tends to polymerize, distorting red blood cells into a rigid, sickle shape that obstructs blood vessels and breaks down prematurely. This cascade results in chronic anemia, painful vaso-occlusive crises (VOCs), and complications such as acute chest syndrome, stroke, and reduced lifespan.

Voxelotor, approved by the FDA in 2019, represented a major advance in SCD care. The drug works by increasing hemoglobin’s affinity for oxygen, thereby inhibiting polymerization of HbS, preventing sickling, and improving red blood cell (RBC) survival. Clinical trials had demonstrated meaningful increases in hemoglobin levels, reductions in hemolysis markers, and a potential improvement in patients’ quality of life.

However, following Pfizer’s global withdrawal of the drug, physicians were required to stop therapy abruptly. This prompted clinicians to investigate how sudden cessation might impact patient stability. In a new analysis of 11 adults with SCD who had been treated with voxelotor for an average of nearly four years (191 weeks), researchers observed a sharp rise in complications shortly after the drug was stopped.

Eight of these patients (73%) developed a vaso-occlusive crisis within a median of just 4.7 days following discontinuation. Laboratory results confirmed an accelerated hemolytic response: hemoglobin levels dropped significantly, while reticulocyte counts, bilirubin, and lactate dehydrogenase (LDH) levels rose, indicating heightened red cell breakdown. Nearly half of the patients required red blood cell transfusions, and one patient developed acute chest syndrome—a serious lung complication necessitating intensive care, mechanical ventilation, and blood exchange transfusions.

Notably, the three patients who did not experience a crisis had either shorter prior exposure to voxelotor or underwent a slower tapering process, suggesting that the speed of withdrawal may play a role in precipitating adverse events.

The researchers highlighted the underlying biology that might explain these observations. Preclinical studies have shown that voxelotor-treated deoxygenated blood maintains improved viscosity and RBC deformability compared to untreated samples. By keeping hemoglobin in an oxygenated state, the drug reduces the time RBCs spend in hypoxic environments, lowering the risk of polymerization and sickling. Abrupt removal of voxelotor may therefore rapidly reverse these protective effects, destabilizing previously compensated red blood cells and triggering crises.

Based on these findings, clinicians are now advised to approach discontinuation of voxelotor cautiously. Gradual tapering, particularly in patients with a robust hemoglobin response or long-term use, may allow red blood cell morphology to adjust more safely, reducing the likelihood of acute complications.

While the study is limited by its small size and observational nature, it underscores the need for careful transition strategies in managing patients who have been stabilized on voxelotor. More broadly, it highlights the complexities of withdrawing a therapy that directly alters the fundamental mechanics of sickle cell disease. As research continues into next-generation treatments, these insights could inform safer clinical protocols and help mitigate risks during necessary changes in therapy.