Pediatr Blood Cancer 2015;62:1879–1880
HIGHLIGHT
by Charles T. Quinn, MD, MS*
Do Not Leave for Tomorrow What You Can Do Today
W
e have witnessed a remarkable improvement in the survival of children with sickle cell disease (SCD) over the past 40 years, especially in high resource countries in North America and Europe where we now expect the overwhelming majority of children with SCD to live to be adults.[1–3] Ongoing improvements in pediatric survival are also being realized in several other countries, including Brazil and Jamaica. Less is known about survival beyond childhood. In 1994, the Cooperative Study of SCD reported that median survival was 42 and 48 years for men and women with sickle cell anemia (the SCD genotypes HbSS and sickle-b˚-thalassemia).[4] Less than a decade later, statistical simulations using data from the Jamaican cohort suggested that median survival could have improved to 53 and 58 years for men and women with sickle cell anemia.[5] Unfortunately, these hopeful projections appear not to have been realized in the United States. Analysis of national death certificate data showed that the mortality rate for adults with SCD actually increased from 1979 to 2005 in the United States, concurrent with the sharp decline in early childhood mortality, and that the median age at death was 38 and 42 years for males and females in 2005.[6] We have not yet solved the problem of early mortality, only shifted much of the burden to young adults. Indeed, the period during and shortly after the transition to adult medical care, in particular, is associated with a high risk of death.[2] There are several possible explanations for this vulnerability, including the initially covert yet progressive accumulation of multi-organ injury throughout childhood that becomes manifest in young adulthood. Also, at least in the United States, there is a defective interface between pediatric and adult medical care and limited access to high quality medical care for adults with SCD. So, what can we do to improve the outlook for adults now? We do not have to wait idly for a sophisticated, universal cure, like gene therapy, to become available. The reduction in pediatric mortality was the result of relatively simple and inexpensive interventions, such as early diagnosis by newborn screening, prophylactic penicillin, immunizations, and educational interventions. There is also a relatively simple and inexpensive intervention that we can use now to improve outcomes for adults (and children). Multiple, independent lines of evidence indicate that hydroxyurea therapy decreases mortality in both children and adults with sickle cell anemia (hydroxyurea has not been studied well in other SCD genotypes).[7–10] Well before this survival benefit was recently documented, we have had ample evidence that hydroxyurea decreases morbidity and improves quality of life. Unfortunately, many clinicians, patients, and parents still avoid or delay the initiation of hydroxyurea out of inordinate fear of toxicity or a preference to wait for some inevitable complication of a serious
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25669 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
disease to occur first, rather than try to prevent it in the first place. The survival of adults with sickle cell anemia can be improved now by broad use of hydroxyurea. Moreover, early and pre-symptomatic initiation of hydroxyurea in young children could yield a generation of healthier adults with sickle cell anemia in the near future with less chronic organ injury and decreased risk of early mortality. This issue of Pediatric Blood and Cancer includes a manuscript by L^e et al. about the survival of patients with SCD in Belgium and the effects of disease-modifying therapies.[11] These investigators took advantage of a national registry, created in 2008, that provides over 5,000 patient-years of observation of 469 children and adults with SCD. The investigators showed a low overall mortality rate, similar to other cohorts in Europe and the United States, and that the use of hydroxyurea was associated with improved survival. While these observations are important and corroborate previous studies, L^e et al. also reported two novel and striking findings. First, mortality was lower in patients treated with hydroxyurea compared to those who underwent hematopoietic stem cell transplantation (HSCT). It is important to note that in Belgium, compared to the United States, the overall rate of HSCT for SCD is higher (19% in this study) and the age at time of HSCT is lower (median 6.9 years in this study). Second, there was no abrupt increase in mortality in young adults with SCD in Belgium as there is in the United States. Differences in these countries’ healthcare systems certainly account for some of this disparity. Belgium provides universal healthcare and has a well established network of pediatric and adult hematologists with shared standards of care. The study by L^e et al. has a number of biases and limitations, including the non-randomized comparison between hydroxyurea and HSCT, that temper the strength of some conclusions. Nevertheless, these provocative findings should prompt the use of hydroxyurea for all patients with sickle cell anemia. These data also suggest that universal healthcare in a single system for all ages can decrease the mortality of a vulnerable population. While this commentary has focused on hydroxyurea, it is not the only tool we can use now to improve outcomes. Chronic transfusion therapy coupled with appropriate chelation can prevent nearly all complications of SCD. HSCT is a reasonable cure, at least for those with HLA-matched sibling donors. These treatments, like Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Conflict of interest: Nothing to declare.
Correspondence to: Charles T. Quinn, Division of Hematology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220. E-mail: [email protected] Received 19 June 2015; Accepted 23 June 2015
1880 hydroxyurea, are also under-utilized. Additionally, the acceptance and implementation of established measures to predict and prevent progressive neurologic morbidity, such as overt stroke and silent cerebral infarction, have proceeded much too slowly. While we may not be able to fix the healthcare system in the United States any time soon, we do have a number of disease-modifying therapies available for immediate and broad use. Hydroxyurea, in particular, should be considered a safe and effective drug for all patients with sickle cell anemia. Act now. Prescribe hydroxyurea today. What are you still waiting for?
REFERENCES 1. Telfer P, Coen P, Chakravorty S, Wilkey O, Evans J, Newell H, Smalling B, Amos R, Stephens A, Rogers D, Kirkham F. Clinical outcomes in children with sickle cell disease living in England: A neonatal cohort in East London. Haematologica 2007;92:905–912. 2. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood 2010;115:3447–3452.
Pediatr Blood Cancer DOI 10.1002/pbc
3. van der Plas EM, van den Tweel XW, Geskus RB, Heijboer H, Biemond BJ, Peters M, Fijnvandraat K. Mortality and causes of death in children with sickle cell disease in the Netherlands, before the introduction of neonatal screening. Br J Haematol 2011;155:106–110. 4. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–1644. 5. Wierenga KJ, Hambleton IR, Lewis NA. Survival estimates for patients with homozygous sickle-cell disease in Jamaica: A clinic-based population study. Lancet 2001;357:680–683. 6. Lanzkron S, Carroll CP, Haywood C. Mortality rates and age at death from sickle cell disease: U. S., 1979– 2005. Public Health Rep 2013;128:110–116. 7. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA 2003;289:1645–1651. 8. Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, Sinopoulou K, Balassopoulou A, Loukopoulos D, Terpos E. 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 2010;115:2354–2363. 9. Lobo de CLC, Pinto JFC, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of hydroxcarbamide therapy on survival of children with sickle cell disease. Br J Haematol 2013;161:852– 860. 10. Castro O, Nouraie M, Oneal P. Hydroxycarbamide treatment in sickle cell disease: Estimates of possible leukaemia risk and of hospitalization survival benefit. Br J Haematol 2014;167:687–691. 11. L^e PQ, Gulbis B, Dedeken L, Dupont S, Vanderfaeillie A, Heijmans C, Huybrechts S, Devalk C, Efira A, Dresse MF, Rosen L, Benghiat S, Ferster A. Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment. Pediatr Blood Cancer [current issue - citation needed].
HIGHLIGHT
by Charles T. Quinn, MD, MS*
Do Not Leave for Tomorrow What You Can Do Today
W
e have witnessed a remarkable improvement in the survival of children with sickle cell disease (SCD) over the past 40 years, especially in high resource countries in North America and Europe where we now expect the overwhelming majority of children with SCD to live to be adults.[1–3] Ongoing improvements in pediatric survival are also being realized in several other countries, including Brazil and Jamaica. Less is known about survival beyond childhood. In 1994, the Cooperative Study of SCD reported that median survival was 42 and 48 years for men and women with sickle cell anemia (the SCD genotypes HbSS and sickle-b˚-thalassemia).[4] Less than a decade later, statistical simulations using data from the Jamaican cohort suggested that median survival could have improved to 53 and 58 years for men and women with sickle cell anemia.[5] Unfortunately, these hopeful projections appear not to have been realized in the United States. Analysis of national death certificate data showed that the mortality rate for adults with SCD actually increased from 1979 to 2005 in the United States, concurrent with the sharp decline in early childhood mortality, and that the median age at death was 38 and 42 years for males and females in 2005.[6] We have not yet solved the problem of early mortality, only shifted much of the burden to young adults. Indeed, the period during and shortly after the transition to adult medical care, in particular, is associated with a high risk of death.[2] There are several possible explanations for this vulnerability, including the initially covert yet progressive accumulation of multi-organ injury throughout childhood that becomes manifest in young adulthood. Also, at least in the United States, there is a defective interface between pediatric and adult medical care and limited access to high quality medical care for adults with SCD. So, what can we do to improve the outlook for adults now? We do not have to wait idly for a sophisticated, universal cure, like gene therapy, to become available. The reduction in pediatric mortality was the result of relatively simple and inexpensive interventions, such as early diagnosis by newborn screening, prophylactic penicillin, immunizations, and educational interventions. There is also a relatively simple and inexpensive intervention that we can use now to improve outcomes for adults (and children). Multiple, independent lines of evidence indicate that hydroxyurea therapy decreases mortality in both children and adults with sickle cell anemia (hydroxyurea has not been studied well in other SCD genotypes).[7–10] Well before this survival benefit was recently documented, we have had ample evidence that hydroxyurea decreases morbidity and improves quality of life. Unfortunately, many clinicians, patients, and parents still avoid or delay the initiation of hydroxyurea out of inordinate fear of toxicity or a preference to wait for some inevitable complication of a serious
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25669 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
disease to occur first, rather than try to prevent it in the first place. The survival of adults with sickle cell anemia can be improved now by broad use of hydroxyurea. Moreover, early and pre-symptomatic initiation of hydroxyurea in young children could yield a generation of healthier adults with sickle cell anemia in the near future with less chronic organ injury and decreased risk of early mortality. This issue of Pediatric Blood and Cancer includes a manuscript by L^e et al. about the survival of patients with SCD in Belgium and the effects of disease-modifying therapies.[11] These investigators took advantage of a national registry, created in 2008, that provides over 5,000 patient-years of observation of 469 children and adults with SCD. The investigators showed a low overall mortality rate, similar to other cohorts in Europe and the United States, and that the use of hydroxyurea was associated with improved survival. While these observations are important and corroborate previous studies, L^e et al. also reported two novel and striking findings. First, mortality was lower in patients treated with hydroxyurea compared to those who underwent hematopoietic stem cell transplantation (HSCT). It is important to note that in Belgium, compared to the United States, the overall rate of HSCT for SCD is higher (19% in this study) and the age at time of HSCT is lower (median 6.9 years in this study). Second, there was no abrupt increase in mortality in young adults with SCD in Belgium as there is in the United States. Differences in these countries’ healthcare systems certainly account for some of this disparity. Belgium provides universal healthcare and has a well established network of pediatric and adult hematologists with shared standards of care. The study by L^e et al. has a number of biases and limitations, including the non-randomized comparison between hydroxyurea and HSCT, that temper the strength of some conclusions. Nevertheless, these provocative findings should prompt the use of hydroxyurea for all patients with sickle cell anemia. These data also suggest that universal healthcare in a single system for all ages can decrease the mortality of a vulnerable population. While this commentary has focused on hydroxyurea, it is not the only tool we can use now to improve outcomes. Chronic transfusion therapy coupled with appropriate chelation can prevent nearly all complications of SCD. HSCT is a reasonable cure, at least for those with HLA-matched sibling donors. These treatments, like Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Conflict of interest: Nothing to declare.
Correspondence to: Charles T. Quinn, Division of Hematology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220. E-mail: [email protected] Received 19 June 2015; Accepted 23 June 2015
1880 hydroxyurea, are also under-utilized. Additionally, the acceptance and implementation of established measures to predict and prevent progressive neurologic morbidity, such as overt stroke and silent cerebral infarction, have proceeded much too slowly. While we may not be able to fix the healthcare system in the United States any time soon, we do have a number of disease-modifying therapies available for immediate and broad use. Hydroxyurea, in particular, should be considered a safe and effective drug for all patients with sickle cell anemia. Act now. Prescribe hydroxyurea today. What are you still waiting for?
REFERENCES 1. Telfer P, Coen P, Chakravorty S, Wilkey O, Evans J, Newell H, Smalling B, Amos R, Stephens A, Rogers D, Kirkham F. Clinical outcomes in children with sickle cell disease living in England: A neonatal cohort in East London. Haematologica 2007;92:905–912. 2. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood 2010;115:3447–3452.
Pediatr Blood Cancer DOI 10.1002/pbc
3. van der Plas EM, van den Tweel XW, Geskus RB, Heijboer H, Biemond BJ, Peters M, Fijnvandraat K. Mortality and causes of death in children with sickle cell disease in the Netherlands, before the introduction of neonatal screening. Br J Haematol 2011;155:106–110. 4. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–1644. 5. Wierenga KJ, Hambleton IR, Lewis NA. Survival estimates for patients with homozygous sickle-cell disease in Jamaica: A clinic-based population study. Lancet 2001;357:680–683. 6. Lanzkron S, Carroll CP, Haywood C. Mortality rates and age at death from sickle cell disease: U. S., 1979– 2005. Public Health Rep 2013;128:110–116. 7. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA 2003;289:1645–1651. 8. Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, Sinopoulou K, Balassopoulou A, Loukopoulos D, Terpos E. 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 2010;115:2354–2363. 9. Lobo de CLC, Pinto JFC, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of hydroxcarbamide therapy on survival of children with sickle cell disease. Br J Haematol 2013;161:852– 860. 10. Castro O, Nouraie M, Oneal P. Hydroxycarbamide treatment in sickle cell disease: Estimates of possible leukaemia risk and of hospitalization survival benefit. Br J Haematol 2014;167:687–691. 11. L^e PQ, Gulbis B, Dedeken L, Dupont S, Vanderfaeillie A, Heijmans C, Huybrechts S, Devalk C, Efira A, Dresse MF, Rosen L, Benghiat S, Ferster A. Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment. Pediatr Blood Cancer [current issue - citation needed].
