Changing the Clinical Paradigm of Hydroxyurea Treatment for Sickle Cell Anemia Through Precision Medicine
Min Dong
Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Search for more papers by this authorCorresponding Author
Patrick T. McGann
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
Correspondence: Patrick T. McGann ([email protected])
Search for more papers by this authorMin Dong
Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Search for more papers by this authorCorresponding Author
Patrick T. McGann
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
Correspondence: Patrick T. McGann ([email protected])
Search for more papers by this authorAbstract
Sickle cell anemia (SCA) is a common and devastating inherited blood disorder, affecting millions of people across the world. Without treatment, SCA results in tremendous morbidity and early mortality. Hydroxyurea is the primary and most well-established pharmacologic therapy with proven benefits to ameliorate the clinical course of SCA, primarily due to its ability to increase the expression of fetal hemoglobin (HbF), which prevents sickling of red blood cells. The optimal induction of HbF depends upon selection and maintenance of the proper dose that maximizes benefits and minimizes toxicity. Due to the significant interpatient variability in hydroxyurea pharmacokinetics, pharmacodynamics, and dosing, most patients treated with hydroxyurea receive suboptimal doses and have only modest treatment responses. Recognizing this variability, using a precision medicine approach, we developed and prospectively evaluated an individualized dosing model for children with SCA, designed to optimize the hydroxyurea dose and clinical response. We utilize novel laboratory methods and a sparse sampling strategy requiring only 10 μL of blood collected 15 minutes, 60 minutes, and 180 minutes after a test dose. We use Bayesian adaptive control to estimate hydroxyurea exposure and to select an individual, optimal starting dose. This dosing model has resulted in HbF responses >30–40%, levels beyond what is achieved with traditional weight-based dosing and trial and error dose escalation. This hydroxyurea dosing strategy, if widely implemented, has the potential to change the treatment paradigm of hydroxyurea therapy and improve outcomes for the millions of patients with SCA across the world.
Conflict of Interest
The authors declared no competing interests for this work.
References
- 1Piel, F.B. et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381, 142–151 (2013).
- 2Hassell, K.L. Population estimates of sickle cell disease in the U.S. Am. J. Prev. Med. 38(4 suppl.), S512–S521 (2010).
- 3McGann, P.T., Nero, A.C. & Ware, R.E. Clinical features of beta-thalassemia and sickle cell disease. Adv. Exp. Med. Biol. 1013, 1–26 (2017).
- 4Forget, B.G. Progress in understanding the hemoglobin switch. N. Engl. J. Med. 365, 852–854 (2011).
- 5Oneal, P.A. et al. Fetal hemoglobin silencing in humans. Blood 108, 2081–2086 (2006).
- 6Benz, E. Anemia: pathophysiology, diagnosis, and management. In Anemias, Red Cells, and the Essential Elements of Red Cell Homeostasis (eds. E. Benz, N. Berliner and F. Schiffman) (Cambridge University Press, Cambridge 2017).
- 7Sankaran, V.G. & Orkin, S.H. The switch from fetal to adult hemoglobin. Cold Spring Harb. Perspect. Med. 3, a011643 (2013).
- 8Marcus, S.J. & Ware, R.E. Physiologic decline in fetal hemoglobin parameters in infants with sickle cell disease: implications for pharmacological intervention. J. Pediatr. Hematol. Oncol. 21, 407–411 (1999).
- 9Watson, J. A study of sickling of young erythrocytes in sickle cell anemia. Blood 3, 465–469 (1948).
- 10Ngo, D.A. et al. Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin. Br. J. Haematol. 156, 259–264 (2012).
- 11Forget, B.G. Molecular basis of hereditary persistence of fetal hemoglobin. Ann. N. Y. Acad. Sci. 850, 38–44 (1998).
- 12Buchanan, G.R. "Packaging" of fetal hemoglobin in sickle cell anemia. Blood 123, 464–465 (2014).
- 13Steinberg, M.H., Chui, D.H., Dover, G.J., Sebastiani, P. & Alsultan, A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 123, 481–485 (2014).
- 14Strouse, J.J. & Heeney, M.M. Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children. Pediatr. Blood Cancer 59, 365–371 (2012).
- 15Lanzkron, S. et al. Systematic review: hydroxyurea for the treatment of adults with sickle cell disease. Ann. Intern. Med. 148, 939–955 (2008).
- 16Charache, S. et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 75, 300–326 (1996).
- 17Steinberg, M.H. et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am. J. Hematol. 85, 403–408 (2010).
- 18McGann, P.T. & Ware, R.E. Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain? Curr. Opin. Hematol. 18, 158–165 (2011).
- 19Steinberg, M.H. Treating sickle cell anemia: a new era dawns. Am. J. Hematol. https://doi.org/10.1002/ajh.25724. [e-pub ahead of print].
- 20Elford, H.L. Effect of hydroxyurea on ribonucleotide reductase. Biochem. Biophys. Res. Commun. 33, 129–135 (1968).
- 21Baliga, B.S., Pace, B.S., Chen, H.H., Shah, A.K. & Yang, Y.M. Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors. Am. J. Hematol. 65, 227–233 (2000).
- 22Ware, R.E. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 115, 5300–5311 (2010).
- 23Platt, O.S. Hydroxyurea for the treatment of sickle cell anemia. N. Engl. J. Med. 358, 1362–1369 (2008).
- 24Cokic, V.P., Andric, S.A., Stojilkovic, S.S., Noguchi, C.T. & Schechter, A.N. Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. Blood 111, 1117–1123 (2008).
- 25King, S.B. A role for nitric oxide in hydroxyurea-mediated fetal hemoglobin induction. J. Clin. Invest. 111, 171–172 (2003).
- 26Pule, G.D., Mowla, S., Novitzky, N. & Wonkam, A. Hydroxyurea down-regulates BCL11A, KLF-1 and MYB through miRNA-mediated actions to induce gamma-globin expression: implications for new therapeutic approaches of sickle cell disease. Clin. Transl. Med. 5, 15 (2016).
- 27Mnika, K. et al. Hydroxyurea-induced miRNA expression in sickle cell disease patients in Africa. Front. Genet. 10, 509 (2019).
- 28Lanzkron, S., Haywood, C. Jr, Hassell, K.L. & Rand, C. Provider barriers to hydroxyurea use in adults with sickle cell disease: a survey of the Sickle Cell Disease Adult Provider Network. J. Natl. Med. Assoc. 100, 968–973 (2008).
- 29Cabana, M.D. et al. Barriers to pediatric sickle cell disease guideline recommendations. Glob. Pediatr. Health 6, 2333794X1984702 (2019).
10.1177/2333794X19847026 Google Scholar
- 30Haywood, C. Jr et al. Examining the characteristics and beliefs of hydroxyurea users and nonusers among adults with sickle cell disease. Am. J. Hematol. 86, 85–87 (2011).
- 31Su, Z.T., Segal, J.B., Lanzkron, S. & Ogunsile, F.J. National trends in hydroxyurea and opioid prescribing for sickle cell disease by office-based physicians in the United States, 1997–2017. Pharmacoepidemiol. Drug Saf. 28, 1246–1250 (2019).
- 32Brousseau, D.C. et al. Hydroxyurea use for sickle cell disease among Medicaid-enrolled children. Pediatrics 144, e20183285 (2019).
- 33McGann, P.T. & Ware, R.E. Hydroxyurea therapy for sickle cell anemia. Expert Opin. Drug Saf. 14, 1749–1758 (2015).
- 34Antonioli, E. et al. Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN. Am. J. Hematol. 87, 552–554 (2012).
- 35Diav-Citrin, O., Hunnisett, L., Sher, G.D. & Koren, G. Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature. Am. J. Hematol. 60, 148–150 (1999).
10.1002/(SICI)1096-8652(199902)60:2<148::AID-AJH12>3.0.CO;2-I CASPubMedWeb of Science®Google Scholar
- 36Ballas, S.K. et al. Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia. J. Natl. Med. Assoc. 101, 1046–1051 (2009).
- 37Ware, R.E., Marahatta, A., Ware, J.L., McElhinney, K., Dong, M. & Vinks, A.A. Hydroxyurea exposure in lactation: a pharmacokinetics study (HELPS). J. Pediatr. 222, 236–239 (2020).
- 38Hankins, J.S. et al. From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. Medicine (Baltimore) 93, e215 (2014).
- 39Voskaridou, E. et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 115, 2354–2363 (2010).
- 40Rodriguez, G.I. et al. A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea. Blood 91, 1533–1541 (1998).
- 41de Montalembert, M. et al. Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica 91, 1685–1688 (2006).
- 42Ware, R.E. et al. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118, 4985–4991 (2011).
- 43Paule, I. et al. Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen. Orphanet J. Rare Dis. 6, 30 (2011).
- 44Yawn, B.P. et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312, 1033–1048 (2014).
- 45Platt, O.S., Orkin, S.H., Dover, G., Beardsley, G.P., Miller, B. & Nathan, D.G. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J. Clin. Invest. 74, 652–656 (1984).
- 46Ware, R.E. Optimizing hydroxyurea therapy for sickle cell anemia. Hematol. Am. Soc. Hematol. Educ. Prog. 2015, 436–443 (2015).
- 47Alvarez, O. et al. Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr. Blood Cancer 59, 668–674 (2012).
- 48Ware, R.E. et al. Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial. J. Pediatr. 156, 66–70 e61 (2010).
- 49Dong, M., McGann, P.T., Mizuno, T., Ware, R.E. & Vinks, A.A. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Br. J. Clin. Pharmacol. 81, 742–752 (2016).
- 50Sheiner, L.B., Beal, S., Rosenberg, B. & Marathe, V.V. Forecasting individual pharmacokinetics. Clin. Pharmacol. Ther. 26, 294–305 (1979).
- 51Sheiner, LB, Beal, SL. NONMEM Users Guide. San Francisco: Division of Pharmacology, University of California; 1979.
- 52Marahatta, A., Megaraj, V., McGann, P.T., Ware, R.E. & Setchell, K.D. Stable-isotope dilution HPLC-electrospray ionization tandem mass spectrometry method for quantifying hydroxyurea in dried blood samples. Clin. Chem. 62, 1593–1601 (2016).
- 53Fuchs, A., Csajka, C., Thoma, Y., Buclin, T. & Widmer, N. Benchmarking therapeutic drug monitoring software: a review of available computer tools. Clin. Pharmacokinet. 52, 9–22 (2013).
- 54McGann, P.T. et al. Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia. Am. J. Hematol. 94, 871–879 (2019).
- 55Charache, S. et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 79, 2555–2565 (1992).
- 56Dover, G.J. et al. Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production. Blood 67, 735–738 (1986).
- 57Charache, S. et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N. Engl. J. Med. 332, 1317–1322 (1995).
- 58Creary, S.E. & Strouse, J.J. Hydroxyurea and transfusion therapy for the treatment of sickle cell disease: a pocket guide for the clinician <https://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/3468.aspx> (2014).
- 59McGann, P.T. Sickle cell anemia: an underappreciated and unaddressed contributor to global childhood mortality. J. Pediatr. 165, 18–22 (2014).
- 60Opoka, R.O. et al. Novel use of hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood 130, 2585–2593 (2017).
- 61Tshilolo, L. et al. Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa. N. Engl. J. Med. 380, 121–131 (2019).
- 62John, C.C. et al. Hydroxyurea dose escalation for sickle cell anemia in Sub-Saharan Africa. N. Engl. J. Med. 382, 2524–2533 (2020).