You Make the Call: Would you prescribe voxelotor to a patient with SCD who has a history of CVA and occlusive retinopathy? Free

Theodore Wun, MD
Chief, Division of Hematology and Oncology
Associate Dean for Research
Professor of Medicine
UC Davis Medical Center

CLINICAL DILEMMA

I have a 31-year-old male patient with sickle cell disease (SCD) who has a history of the following complications: acute chest syndrome, a cerebral vascular accident (CVA) nine years ago that resulted in temporary blindness, severe occlusive retinopathy, and priapism (occurred twice, the last time being 2018).

I started him on oral hydroxyurea (HU) about 10 months ago and increased the dose from 500 mg per day to 1,000 mg per day after six months. His calculated weight-based dose is 1,700 mg per day, so I’m slowly titrating upwards.

Now, his hemoglobin (Hb) is 8.9 g/dL, so I’m considering voxelotor. I haven’t seen contraindication for voxelotor in patients with a history of cerebral vascular disease and occlusive retinopathy. Based on his Hb, is he a good candidate, and at what Hb level would voxelotor not be needed?

EXPERT OPINION

Before addressing the specific question about the use of voxelotor, I would like to make some observations about this young man’s history, as I assume he has homozygous hemoglobin S (HbSS) or HbS/beta-zero thalassemia. First, he has had several vascular complications and acute chest syndrome, which may have been associated with vasculopathy. Second, he had an ischemic stroke at age 21, when transcranial doppler (TCD) screening is no longer recommended. Prior to routine TCD screening, the peak age of ischemic stroke was in the early teens. Ischemic strokes also occur in adults at significantly higher rates after age 40 years. Extrapolating evidence from studies of stroke in pediatric SCD, it would have been the standard of care to place this young man on indefinite chronic red blood cell exchange (RCE) after his ischemic stroke, barring another identified cause of the stroke (e.g., cardioembolic). There is no mention of whether he is on chronic RCE. It’s possible that he was started on RCE but stopped for various reasons, such as lack of venous access, red cell alloimmunization (making continued RCE not feasible), or patient fatigue.

When I assume care of a patient with a history of stroke who has been off red blood cell transfusions (simple vs. RCE) for more than two to three years, I have a balanced conversation about whether to restart and most often patients prefer not to resume RCE. In these cases, I usually order imaging of the cerebral vasculature. If there is evidence of vasculopathy, I recommend RCE and aspirin; if there is no vasculopathy and no moyamoya disease, I recommend aspirin alone. This patient should also be seen by an ophthalmologist who is familiar with eye complications of SCD.

Essentially all adult patients with sickle cell anemia should be prescribed HU, although its cerebrovascular protective effect in adults has not been established. Prior to starting additional disease-​modifying therapy, I try to maximize HU dose. In adults, I start at 1,000 mg daily and escalate in increments of 500 mg every two months until we reach a maximal tolerated dose (MTD), while ensuring the absolute neutrophil count is greater than 1,500/mm³, absolute reticulocyte count is greater than 100,000/mm³, and platelet count is greater than 100,000/mm³ on monthly lab assessments. In the 1995 multicenter study of HU by Charache et al.,¹ the maximal dose was 35 mg/kg/day, but I consider going even higher if blood counts are above parameters and there is no evidence of non-hematologic toxicities. Heterocellular aggregates of leukocytes, platelets, and reticulocytes likely contribute to pathophysiology,² so optimizing HU to the MTD can be beneficial. Treatment with HU also reduces the hemolytic anemia component of SCD, which can result in improved Hb levels. Although fetal hemoglobin (HbF) induction is typically not as high in adults as in children, I have seen HbF increases of 20% to 25% in adults and Hb increases by 2 to 3 g/dL with HU.

Voxelotor decreases hemolysis and increases Hb levels by increasing the oxygen affinity of Hb S. Voxelotor was approved by the U.S. Food and Drug Administration based on sustained increases in Hb of more than 1 g/dL in 51% of patients in a randomized phase III trial.³ Eligibility criteria included a baseline Hb between 5.5 and 10.5 g/dL. There were concerns that raising Hb levels above 11 g/dL might increase whole blood viscosity to the point of increased pain events or other ischemic complications. However, there was no evidence for this in the voxelotor trial. Studies are ongoing to determine other clinically relevant endpoints with voxelotor treatment.

In summary, my main goal for this patient is to prevent further vascular complications. I would dose escalate HU to the MTD. If he is not on chronic RCE, I would have a discussion about starting. I would also start low-dose aspirin (if no contraindications) and refer him to an ophthalmologist to follow his retinopathy. I would start voxelotor if symptomatic anemia worsened, if hemolysis markers increased despite HU, or if he became intolerant to HU.

The author thanks Oyebimpe Adesina, MD, MS, for her review of this article.

References

1. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332(20):1317-1322.
2. Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: a review. JAMA. 2022;328(1):57-68.
3. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519.

NEXT MONTH'S CLINICAL DILEMMA

In the pediatric setting, is it worthwhile to conduct variant hemoglobin testing in a patient who has been diagnosed with or is in treatment for iron deficiency? I am concerned about this from a Choosing Wisely perspective, as many such test orders in our system are in the setting of known iron deficiency or where it is highly likely based on red cell indices and blood counts. Discussion around this topic has been sensitive, given that these patients are children, not adults. Among the argument against testing is a call for the minimization of needle sticks, though this does not address the question of whether the testing should be done at all.

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