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Issue: February 10, 2010
February 10, 2010
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Access to care, pain relief still problems for sickle cell patients

Even though expert panels recommend hydroxyurea therapy and clinical trial data assure its safety and efficacy, confounding barriers continue to restrict its use.

Issue: February 10, 2010

For a disease that is associated with severe pain episodes, long-term organ damage, frequent hospitalizations, acute chest syndrome events, stroke and a shortened lifespan, sickle cell disease has not yet captured the public or professional attention that some physicians say is needed to ensure that all patients receive effective treatment.

According to physicians and researchers focused on sickle cell disease, increased awareness would result not only in needed funding for research and treatment programs, but also better education for physicians and their patients about hydroxyurea, the only medication that modifies the disease process.

Access to care is a major impediment, but there are others that continue to prevent patients with sickle cell disease from being treated with hydroxyurea. These barriers include lack of knowledge about its effectiveness as a therapeutic option, fears about short- and long-term risks associated with its use, and physician assumptions about the ability of the patient and/or parent to comply with the therapy and the subsequent monitoring that is required.

Hydroxyurea, approved by the FDA in 1998 for adults with severe sickle cell disease, has been used since the mid-1960s for other conditions. Although not yet approved for use in children and adolescents with sickle cell disease, evidence indicates that its off-label use is also effective and safe within that population. In the past 25 years, hydroxyurea’s efficacy and safety have been demonstrated in several clinical trials, but its use as therapy for sickle cell disease remains low.

Michael DeBaun, MD
Michael DeBaun, MD, Director of the Sickle Cell Medical Treatment and Education Center at St. Louis Children’s Hospital, has spent his professional life working with children with sickle cell disease.

Photo by Washington University School of Medicine Biostatistics Dept

HemOnc Today contacted several physicians, asking them to comment about the continuing barriers to more widespread use of the drug in adults and children with sickle cell disease.

Michael DeBaun, MD, director of the Sickle Cell Medical Treatment and Education Center at St. Louis Children’s Hospital, has spent his professional life working with children with sickle cell disease. He said access to care is a major factor in the underuse of hydroxyurea.

“Despite being common, when I was growing up, sickle cell disease was not something we talked about in the African-American community. When I went through medical school and residency, I realized that this population was underserved and there was a significant opportunity to provide new knowledge to improve the lives of children with this disease,” DeBaun said in a recent interview.

“The real challenge is resource allocation and having sufficient support across all federal agencies, not just the NIH but others, such as the CDC and HRSA, to provide synergistic programs to improve the lives of people with this disease,” according to DeBaun, Ferring Family Chair in Pediatrics, professor of neurology and biostatistics, Washington University School of Medicine.

Sickle cell disease affects 50,000 to 100,000 people in the United States, with one in 400 blacks and one in 19,000 Hispanics affected. Although most of these patients live with significant pain and often seek emergency department care for acute pain crises or other conditions directly related to sickle cell disease, they are often not given a prescription for hydroxyurea.

The 2008 NIH State-of-the-Science Conference Statement on Hydroxyurea Treatment of Sickle Cell Disease reported that surveys have found that “a large proportion of patients who have [sickle cell disease] are poor and from underserved communities. Most U.S. patients with [sickle cell disease] are ethnic minorities. For many, the limited resources and lack of culturally competent care by experienced clinicians set the stage for suboptimal care.”

These underserved populations often have no health insurance, limiting their access to hydroxyurea. The inability to pay for a drug that is relatively inexpensive but can cost at least $30 to $40 per month limits its use.

Access to care

Lack of access to quality care is a major factor driving the underuse of hydroxyurea among adults, according to Richard Lottenberg, MD, professor of medicine, division of hematology/oncology at the University of Florida, Gainesville. There are a limited number of physicians who are experts in the care of adults patients with sickle cell disease, Lottenberg told HemOnc Today.

“Even community practices that focus on oncology and hematology do not necessarily take care of a lot of patients with [sickle cell disease]. There are few adult-oriented providers with a major interest in sickle cell disease compared with the sizeable population,” he said.

Expertise with sickle cell disease among adults is often limited to academic health care centers or large urban medical centers, locations that are not accessible to many patients. A survey that Lottenberg and colleagues conducted of community-based hematology/oncology practices in Florida and North Carolina found that a significant number of them have few patients with sickle cell disease, even though those states have a high percentage of at-risk patients. For those practices that treat adults with sickle cell disease, only half prescribe hydroxyurea to more than 10% of their patients.

The survey findings are similar to other data showing that “only a fraction of patients who might benefit from hydroxyurea have received treatment,” according to the NIH statement.

Research published in Pediatrics in 2006 found that significant gaps remain in public and private support for research and clinical care of patients with sickle cell disease. Lauren A. Smith, MD, MPH, and colleagues reported that the level of private and federal support is eight times higher per person for patients with cystic fibrosis than for those with sickle cell disease.

“It is tragic and unjust for a particular group of patients to suffer avoidable complications and even death because effective new therapies have not been uniformly implemented,” Smith and colleagues said.

Is it effective?

Several clinical trials have investigated the efficacy of hydroxyurea therapy for adults and children. In an extensive review of the literature conducted by the Agency for Healthcare Research and Quality (AHRQ) as background for the NIH State-of-the-Science Conference Statement, investigators found strong evidence that the drug is effective in adults and adolescents for increasing hemoglobin level, fetal hemoglobin (HbF), mean corpuscular volume and leukocyte count.

Using data from several trials, including the Multicenter Study of Hydroxyurea — the single randomized clinical trial that has examined efficacy of hydroxyurea in adults — investigators found high-grade evidence that hydroxyurea treatment decreases pain crises and hospitalizations, the need for blood transfusion therapy, and episodes of acute chest syndrome in adults and adolescents.

Russell E. Ware, MD, PhD
Russell E. Ware

According to Russell E. Ware, MD, PhD, who presented an update about advances in the use of hydroxyurea at the 51st American Society of Hematology Annual Meeting, “hydroxyurea has many features of an ideal drug for sickle cell disease.”

Its ability to increase fetal hemoglobin levels is most important for patients with sickle cell disease. “The percent HbF has been shown to be a powerful predictor of clinical severity in sickle cell disease, higher levels of HbF help ameliorate the hemolytic anemia, plus help prevent recurrent vaso-occlusive events and chronic organ damage,” he said.

“Pharmacological induction of HbF helps prevent intracellular sickling, which decreases vaso-occlusion and reduces hemolysis,” according to Ware, the Lemuel Diggs Endowed Chair in Sickle Cell Disease and chair of the department of hematology at St. Jude Children’s Research Hospital in Memphis, Tenn.

Efficacy in children

The AHRQ literature review, conducted by investigators at the Johns Hopkins University Evidence-Based Practice Center in Baltimore, found high-grade evidence that hydroxyurea increases fetal hemoglobin levels in children, with starting values of 5% to 10% to treatment values that averaged 15% to 20%. Although evidence for efficacy is limited in children, the available evidence “does not contradict the findings in adults that hydroxyurea improves hematologic variables and decreases hospitalization rates,” according to the report.

HUG-KIDS, published in 1999, was one of the key NIH-sponsored trials showing that response to hydroxyurea in children is similar to that in adults. Data from the Belgian Registry, published in Blood in 2005, showed significant benefit with hydroxyurea and a possible benefit for primary stroke prevention. The registry included 426 patient-years of follow-up on 127 children treated with hydroxyurea.

The HUSOFT extension study included the 21 infants who had completed the original HUSOFT trial. Seventeen patients completed four years of hydroxyurea therapy, and 11 patients completed six years. After four years, the therapy was associated with increased hemoglobin concentration, percent HbF and mean corpuscular volume, as well as decreased reticulocytes, white blood cells and platelets.

Patients assigned hydroxyurea therapy had 7.5 acute chest syndrome events per 100 person-years compared with 24.5 events per 100 person-years among historical controls (P=.001). These treated patients also had better spleen function than expected and improved growth rates, the researchers reported in a 2005 issue of Blood.

BABY HUG is a phase-3, multicenter, randomized, double blind, placebo-controlled study of daily oral hydroxyurea use in infants aged 9 to 17 months with sickle cell disease. The trial is investigating whether hydroxyurea prevents onset of chronic end organ damage in these very young children. The major results from that trial are expected in 2010, according to Ware.

Researchers at Columbia University were recently awarded a grant from the NIH’s National Center for Research Resources to conduct four clinical/translational studies of hydroxyurea use in patients with sickle cell disease aged 5 to 21 years. The research, according to Nancy S. Green, MD, associate director of the Irving Institute for Clinical and Translational Research at Columbia, will focus on “how to predict which children are more likely to respond to hydroxyurea … and how providers and families may be better informed about the drug and, when appropriate, encouraged to use it.”

Adverse effects and risks

Concern about the potential adverse effects and long-term risks associated with hydroxyurea therapy is another major barrier to its use in more patients, even though clinical trial data have been encouraging. “Although accumulating data do not support any risks for patients with [sickle cell disease], misinformation seems pervasive, especially among the lay community,” Ware said.

The AHRQ literature review found that myelosuppression is an adverse effect but is temporary and reversible. In children and adolescents, there can be mild neutropenia, as well as occasional worsening anemia or thrombocytopenia. The review found a high level of evidence that the therapy does not lead to leg ulcers in patients treated for sickle cell disease.

Periodic monitoring is required for patients placed on hydroxyurea to manage these temporary and reversible adverse effects. Leukopenia can predispose the patient to infection, and thrombocytopenia can predispose to bleeding, but these effects can be managed by reducing the dose or discontinuing its use.

The National Toxicology Program Center for the Evaluation of Risks to Human Reproduction evaluated whether hydroxyurea has potential to cause adverse effects on reproduction and development. In the 2007 report, the expert panel reached several conclusions about the use of hydroxyurea for sickle cell disease:

  • No evidence indicates therapeutic doses affect growth or development in children aged 5 to 15 years.
  • Data are not sufficient to evaluate possible effects on growth and development in infants and children younger than 5 years.
  • Data are insufficient to evaluate effects on puberty.
  • There is serious concern that therapeutic doses may adversely affect sperm production.
  • There is some concern that exposure of pregnant women to hydroxyurea may result in birth defects, abnormalities of fetal growth or abnormal postnatal development in offspring.

Because of the concerns related to pregnancy, patients of child-bearing age should be placed on a contraceptive if they are treated with hydroxyurea. According to Ware, the recently published 10-year follow-up data from the Multicenter Study of Hydroxyurea provided additional information and reassurance about several of these concerns.

Fears also remain about potential development of malignancies with hydroxyurea therapy. According to the AHRQ review, “… limited evidence suggests that hydroxyurea treatment in adults with sickle cell disease does not increase the risk for leukemia.”

In the NIH State-of-the-Science Conference Statement, the expert panel noted that cases of leukemia and other types of cancer have been reported among children and adults who have been treated with hydroxyurea for sickle cell disease. “These cases are rare and seem to be no more common than among the general population. The risk for cancer does not seem to differ for people with [sickle cell disease] who have received hydroxyurea and those who have not,” the panel said. “The currently available data are reassuring with respect to the risks for both short- and long-term harms of hydroxyurea.”

Assumptions about compliance

Some physicians assume that certain patients with sickle cell disease will not be adherent with the therapy and will not return for the required monitoring. Lottenberg said if adults with sickle cell disease are fortunate enough to find a physician who can treat their disease, they often are not informed about “the risks associated with having frequent or prolonged hospitalizations or told that hydroxyurea can make a substantial difference.”

He and colleagues have developed a video intended to inform patients about the benefits and risks of hydroxyurea therapy, which includes questions that patients should ask their physicians. Patients who viewed the video had a stronger desire to learn more about hydroxyurea and said they had a stronger interest in asking their health care providers about the therapy.

Physicians also should examine why some patients are not being compliant. Because hydroxyurea dosing can vary, physicians should optimize dosing to help the patient get relief, “rather than making the assumption that the patient is not responding to the therapy,” Lottenberg said.

“I’ve seen a reluctance to increase the dose, so I encourage physicians to spend time with their patients and explain that they need to take the medication on a regular basis at appropriate doses to see if it will work for them,” he said.

Compliance challenges in children

Compliance is a more complicated issue within the pediatric population, mainly because any use of hydroxyurea is off-label use. Although there are more specialists who care for children with sickle cell disease in comparison with the number who treat the adult population, there is no established dosing schedule for children, according to DeBaun.

“Perhaps we could provide the drug every three days or just on the weekends and have the same impact as daily administration. Formal studies are needed to better understand how best to administer hydroxyurea to maximize adherence, therapeutic benefit and minimize toxicity,” DeBaun said.

“Our biggest challenge when to employ strategies for improving their adherence with a drug that is effective in preventing pain, and when to take them off the drug if they are not adherent,” he said. “Meeting that challenge requires that the child’s parent or caregiver understand that the drug should be taken daily, that the child must return to the physician’s office each month for testing, and that the therapy must be ongoing.

“For select parents, we have elected to have the school nurse administer the drug five days a week because we have more confidence that the child will receive the drug then when we ask the parents to provide daily administrations. This is not an optimal strategy, but nine months worth of hydroxyurea therapy is better than no consistent therapy for 12 months,” he said.

DeBaun said his center prescribes hydroxyurea for children who have high rates of pain “after their parents have shown they know how to take long- and short-acting opioids as part of the pain action plan (similar to an asthma action plan) and after we have excluded other comorbidities, such as asthma, that may be contributing to the pain.”

If a child starts therapy with hydroxyurea but then is not adherent “you have subjected them to all the risks, but none of the benefit,” DeBaun said. His center’s strategy for making sure families are compliant with therapy includes several tactics.

First, parents are educated about the disease. Also, quarterly education sessions are held for parents and relatives, and an in-school program focuses on improving the education of children who, because of sickle cell disease, may have a high rate of absenteeism. “Because children with sickle cell disease are at risk of silent stroke and injuries to the brain, we focus on making parents advocates for their children and encourage them to help teachers and administrators understand the disease,” he said.

Fast Facts

DeBaun’s center extends support to its adolescent patients through a monthly mentorship program that culminates in their serving as counselors at a camp for children with sickle cell disease. Without this system-wide support, adolescents on hydroxyurea therapy often become nonadherent as they transition to adult care, if they can find it.

It is this type of comprehensive, system-wide approach that the NIH consensus panel called for last year, recognizing that significant barriers remain for people with sickle cell disease to be appropriately treated. “The burden of suffering is tremendous among many patients with [sickle cell disease],” the panel said. “These patients experience disease-related pain on many days of their lives and usually do not seek medical attention until their symptoms are overwhelming.”

Calling hydroxyurea an “important major advance,” the panel said all patients with sickle cell disease should have a principal health care provider who is either a hematologist or is in frequent consultation with one. Nationwide, they said, there is an “urgent need for centers specializing in the treatment of [sickle cell disease] to organize and network together to improve patient access to quality care.” – by Kathy Holliman

POINT/COUNTER
Is patient compliance a significant barrier to hydroxyurea treatment of children with sickle cell disease?

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