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Increasing hydroxyurea dose reduces hospitalizations for sickle cell anemia

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February 7, 2018

Jeremie Estepp

Children with sickle cell anemia who received higher hydroxyurea doses to increase average fetal hemoglobin levels above 20% had fewer hospitalizations than those with levels below 20%, according to results of a prospective observational study published in American Journal of Hematology.

“Most children with sickle cell anemia treated with hydroxyurea can safely achieve and maintain fetal hemoglobin levels over 20% when adherent to therapy and escalated toward a maximally tolerated dose,” Jeremie Estepp, MD, assistant member of the department of hematology at St. Jude Children’s Research Hospital, told HemOnc Today. “Our analysis showed that by using this approach, hospitalizations for the average patient fell to less than one every couple of years rather than four to six annually. This frees children from the fevers, pain and other symptoms of this disease and gives them and their families more chances to enjoy childhood and adolescence.”

Sickle cell anemia is the most common inherited blood disorder, affecting about 300,000 babies worldwide each year and about 100,000 residents in the United States. It occurs most often in black and Hispanic individuals who inherit a mutation that affects the hemoglobin protein that red blood cells use to carry oxygen throughout the body. In sub-Saharan Africa, an estimated 50% to 90% of children with sickle cell anemia die by the age of 5 years.

Hydroxyurea therapy is well tolerated as a liquid or capsule and is recommended for all children with sickle cell anemia beginning at 9 months of age, independent of disease severity. It safely reduces the incidence of acute vaso-occlusive complications and the need for transfusions and hospitalizations, potentially improving overall mortality.

The primary mechanism of action of hydroxyurea is induction of red blood cell fetal hemoglobin, which is required for clinical benefit and appears to be dose dependent. However, the optimal dosing strategy of hydroxyurea therapy is controversial.

In the HUSTLE trial — or Hydroxyurea Study of Long-Term Effects — researchers analyzed the long-term clinical effects of hydroxyurea escalated to a maximum tolerated dose — either 35 mg/kg daily or 2,000 mg daily — among 230 children with sickle cell anemia (57.4% male; 93% HbSS; mean age at initiation, 7.8 years).

“Hydroxyurea therapy was initiated at 20 mg/kg per day and increased in 5 mg/kg increments every 8 to 12 weeks until a goal absolute neutrophil count was attained,” Estepp said. “The goal neutrophil count for the HUSTLE study was 2,000 to 4,000 x 106/L.”


Patients had a mean fetal hemoglobin percentage at enrollment of 9.7% (median, 7.9%; range, 1-32.9).

At the time of data censoring, 75.2% of patients attained maximum tolerated dose.

During 610 patient-years of follow-up, the mean attained fetal hemoglobin percentage at maximum tolerated dose was greater than 20% for up to 4 years of follow-up. With hydroxyurea at the maximum tolerated dose, the mean fetal hemoglobin reached 26.7% and median levels reached 21.7% (interquartile range, 16.2-27.8).

When fetal hemoglobin percentage values were 20% or lower, children had twice the odds of hospitalization for any reason (P < .0001) — including vaso-occlusive pain (P < .01) and acute chest syndrome (P < .01) — and had more than four times the odds of admission for fever (P < .001).

Thirty-day readmission rates were not affected by fetal hemoglobin percentage.

Neutropenia appeared rare (2.3% of all laboratory monitoring), transient and benign. Thus, attaining fetal hemoglobin above 20% appeared associated with fewer hospitalizations without significant toxicity.

“The most frequent adverse events observed with hydroxyurea therapy are myelosuppression, most frequently neutropenia,” Estepp said. “These events are self-limiting and resolve when the therapy is withheld. We have seen no serious infections during the brief times children have had low neutrophil counts.”

There are some concerns regarding toxicities with long-term exposure with hydroxyurea, Estepp told HemOnc Today, including most notably the concern of fertility preservation.

“This is currently an unanswered question, but investigators are actively evaluating that concern now,” he said.

The findings underscore the need to improve and expand access to hydroxyurea in the United States and internationally.

St. Jude researchers are leading a multicenter trial to determine if toddlers with sickle cell disease would also benefit from a similar dosing strategy compared with standard dosing.

“We are currently evaluating the effects of hydroxyurea on specific organ damage and the impact that genetics has on sickle cell-related complications and responses to therapy,” Estepp said. – by Chuck Gormley


For more information:

Jeremie Estepp , MD, can be reached at St. Jude Children’s Research Hospital, Department of Hematology, MS 802, 262 Danny Thomas Place, Memphis, TN 38105-3678; email:


Disclosures: Estepp reports funding support from Eli Lilly and Pfizer and consultant roles with Daiichi Sankyo and Global Blood Therapeutics. Please see the full study for all other authors’ relevant financial disclosures.



itj+ Perspective

Michael Rutledge DeBaun

Michael Rutledge DeBaun

Now that the FDA has approved hydroxyurea (Siklos, Addmedica) for the prevention of acute vaso-occlusive pain for children at least 2 years of age with sickle cell disease, the critical unanswered question is what hydroxyurea dose maximizes the benefit and minimizes the toxicity for these patients. Estepp and colleagues conducted an informative longitudinal observation cohort study that places us one step closer to ultimately answering this question. The primary goal of the HUSTLE study — conducted at St. Jude Children’s Research Hospital — included to describe long-term clinical benefits of hydroxyurea therapy after reaching the maximum tolerated dose.

Despite the strengths of the study, the results leave an important unanswered question. Namely, did those participants with fetal hemoglobin levels at or below 20% not respond to hydroxyurea therapy with evidence of good adherence, or did this group of participants simply not adhere? We have high confidence that participants with fetal hemoglobin levels greater than 20% were adherent to hydroxyurea therapy, as long their baseline fetal hemoglobin was considerably less than 20%. However, for those participants with fetal hemoglobin levels at or below 20%, we simply do not know if the participants did not respond to hydroxyurea therapy with evidence of good adherence, or whether the participants did not adhere to daily therapy. Could both have been the case?

Fortunately, we have both direct and indirect methods to address hydroxyurea adherence. Given that hydroxyurea therapy is an antimetabolite, similar to all antimetabolite therapies, we expect those adherent to hydroxyurea therapy to have a significant increase in the mean cell volume of at least 10 fluid ounces from baseline. Indirect measurement of adherence in this study could have been assessed from the hydroxyurea dispensation records, which were available for 96% of the participants and used to determine the medication possession ratio.

The researchers did not use mean cell volume or medication possession ratio — to measure adherence to hydroxyurea — to determine the association with fetal hemoglobin level or evaluated in the regression models to predict total hospitalizations. Another practical limitation in titrating hydroxyurea therapy to fetal hemoglobin greater than 20% is that fetal hemoglobin level is a relatively expensive undertaking and not readily obtainable in Africa or India, where 90% of the children with sickle cell disease are born. Clearly, an optimal strategy for titrating the dose of hydroxyurea must include all children with sickle cell disease, not just those born in high-income countries. We look forward to the next step, where the team from St. Jude or others provide optimal and practical strategies for dosing hydroxyurea therapy among children with sickle cell disease.

Michael Rutledge DeBaun, MD, MPH

Vanderbilt University School of Medicine
Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease
Monroe Carell, Jr. Children’s Hospital at Vanderbilt

Disclosures: DeBaun reports no relevant financial disclosures.