Correspondence

Therapy for Globin-Chain Disorders

N Engl J Med 1993; 329:364July 29, 1993

Article

To the Editor:

The clinical evaluation of treatments for disorders of globin-chain synthesis1-4 has entered an exciting new era. Decisions about the design and application of future trials will dramatically influence the rapidity of the advance against sickle cell disease and beta-thalassemia. An expanding list of experimental treatments for sickle cell disease includes hydroxyurea, erythropoietin, butyrate, and bone marrow transplantation. There is a real danger, however, that in five years we will still know little about which, if any, of these approaches is best suited to a particular patient. It is difficult to enroll sufficient numbers of patients in adequate clinical trials. In addition, enthusiasm for a particular therapy is lost when occasional patients have adverse effects.

All experimental trials in sickle cell disease and beta-thalassemia should be coordinated through a trials group sponsored by the National Institutes of Health. Approved experimental protocols should be integrated into a pyramid of trials, stratified with regard to entry criteria and the risk of treatment toxicity. Trials involving therapies with which there is much experience and little apparent toxicity, such as erythropoietin and hydroxyurea, would form a first tier. They would enroll symptomatic patients who do not adequately benefit from standard therapy. Trials involving approaches with which there is little experience and an undefined risk of toxicity, such as butyrate, new drugs, and bone marrow transplantation (for sickle cell disease), would be prioritized. Enrollment would be made available to patients who do not respond adequately to first-tier therapy (an estimated 50 percent of all patients). Promising treatments would eventually be evaluated as first-tier regimens as experience with their use in more severely affected patients increased. This system would allow patients who respond to first-tier therapy to incur less risk. Patients who are difficult to treat could readily be switched to other investigational regimens.

A patient registry should be established. This would facilitate switching between protocols, monitoring for late toxic effects, and analyzing patient characteristics associated with response to various treatments.

Were this proposal implemented, definitive clinical trials could be performed with maximal efficiency, the most promising therapeutic approaches could be evaluated most rapidly, and individual patients would incur treatment risks proportional to the severity of their disease.

C. Anthony Blau, M.D.
University of Washington Medical Center, Seattle, WA 98105

4 References

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   Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med 1990;322:1037-1045
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2. 2

   Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992;79:2555-2565
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   Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993;328:73-80
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   Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993;328:81-86
   Full Text | Web of Science | Medline