SICKLE CELL DISEASE TO TREAT OR NOT TO TREAT COHEM Barcelona September 8, 2012 Sujit Sheth, M.D. Pediatric Hematology Oncology
Disclosures None
Outline Morbidity and mortality Definitive therapies Risk benefit analysis
Scope of Issue Worldwide >275,000 births/yr 1 1% of all births in Africa, ~6M affected 1 Wide phenotypic variability Decreased life expectancy Significant morbidity, poor QOL Enormous cost treatment, QALYs 3 1. Modell B et al. Bull WHO 2008 Jun;86(6):480-7. 2. Grosse SD et al. Am J Prev Med 2011;41(6S4):S398 S405 3. Braithwaite et al., Medical Care 2008;46:349-356
Survival (US) Genotype Sex Median Survival (yrs) 1970 1980 1990 2000 SS M 10 20 30 42 SS F 12 22 35 48 SC M 60 SC F 68 Platt et al, NEJM 1994
Age at Death 1979-2006 (US) In 2006 - Mean age at death was 39yrs, 35% alive at age >45 yrs Am J Prev Med 2010;38(4S):S512 S521
Data sparse Mortality non-us 3.4% under-5 mortality, 6.4% in Africa 1 Excess childhood mortality in Africa ~ 50-90% (HbSS) 2 -? most undiagnosed Infection, splenic sequestration, stroke (Poor data to support malaria as cause) 1. Modell B et al. Bull WHO 2008 Jun;86(6):480-7. 2. Grosse SD et al. Am J Prev Med 2011;41(6S4):S398 S405
Morbidity Childhood Infarctive Stroke Growth Pain crisis Acute chest syndrome Splenic sequestration Infectious risk Avascular necrosis Progressive organ dysfunction Adulthood Hemorrhagic stroke Pulmonary hypertension Avascular necrosis Sickle hepatopathy Sexual dysfunction/infertility Eye Leg ulcers Organ failure
Quality of Life Episodic / chronic pain Pulmonary disease CNS complications Repeated hospitalizations Organ dysfunction Reduced life expectancy Socioeconomic issues cost, productivity
Health Related QOL Review 39 studies, only 5 prospective Generic HRQL instrument not specific Adults and children with SCD have significantly impaired HRQL that is comparable to or worse than other chronic diseases.even in their baseline state of health. Panepinto JA and Bonner M. Pediatr Blood Cancer 2012; 59: 377-385
Effects on the Brain Prevalence of silent infarcts 1 27% by age 6yrs, 37% by 14 yrs Overt Stroke infarctive, hemorrhagic 2-5% by 6yrs preventable in children 2 Loss of global intellectual function 3 Worse if overt stroke Not preventable by supportive therapies 1. DeBaun MR et al, Blood 2012; 119(20): 4587-96 2. Adams RJ et al. N Engl J Med.1998;339(1):5-11 3. Wang W et al, J Pediatr 2001; 139(3): 391-397
Pulmonary disease Acute Chest Syndrome High mortality (>adults), recurrent Lung disease (obstructive and restrictive) Chronic hypoxia Pulmonary hypertension 1 20% of adults Mostly lethal within 3 yrs No prevention or effective treatment 1. Gladwin MT. N Engl J Med 2004; 350: 886 95.
Supportive Therapy Infection prophylaxis Pain management Transfusion when indicated Treatment of complications Will not prevent ongoing disease effect on organs and tissues
Success of Supportive Therapy Hassell KL. Am J Prev Med 2010;38(4S):S512 S521
Definitive Therapy Regular transfusions / stroke prevention Hydroxyurea Surgery Hip coring EDAS (encephaloduroarteriosynangiosis) Stem cell transplantation Gene therapy
Transfusion therapy Benefit for overt stroke Unclear for silent infarct Complications alloimmunization, iron overload Fails to prevent vascular disease if overt stroke or Moya-Moya 1 If discontinued, stroke risk goes back up 2 High cost - $40,000/yr in 2000 3 1. Bishop S et al. Blood Cells Mol Dis. 2011;47(2):125-8 2. Abboud MR et al. Blood 2011; 118(4):894-8 3. Wayne AS et al. Blood 2000; 96(7): 2369-2372
Hydroxyurea Reduction in severity and frequency of complications improves QOL 1,2 Safe to start early 1 Acceptable long-term safety profile 3 Reduced mortality 4? Beneficial effect on organ function? Role in stroke, PHT 1. Wang AC et al. Lancet 2011; 377: 1663 72 2. Thornburg CD et al. J Pediatr Hematol Oncol 2011; 33(4): 251-4 3. Steinberg MH et al. Am J Hematol 2010. 85:403 408 4. Voskaridou E et al. Blood 2010; 115(12): 2354-2363
Stem Cell Transplantation Only cure, prevents disease progression Excellent results when matched sibling donor Short term mortality risk, longer term morbidity risk steadily improving Prevention of organ damage if done early, no reversal if done late Advances Non-ablative / reduced intensity preparation Alternative donor MUD, UCB, haplo-identical Overall, long term cost benefit
SCT - survival Study Vermylen 1998 Walters 2000 Locatelli 2003 Panepinto 2007 Bernaudi n 2007 Lucarelli 2011 Hsieh 2009 1 * Bhatia 2012* # n 50 50 11 67 87 11 10 18 Overall Survival 93 94 100 97 92 90 100 100 Disease Free Survival 85 84 90 85 86 90 90 100 Rejection 10 10 9 13 5 10 10 0 Lucarelli G et al. Cold Spring Harb Perspect Med. 2012 1. Hsieh MM et al. NEJM 2009; 361(24): 2309-2317. * Matched sibling donors only # Unpublished data, 2006-2012, children only
Emerging therapies Approach Examples Rees DC et al. Lancet 2010; 376: 2018 31
Cost In US 113,000 admissions/yr 1 $488 million costs (hospitalization only) 1 As life expectancy increases More admissions Higher costs of treating organ failure Loss of productivity Adults - 30% on disability, 50% unemployed 2 1. Steiner C, Miller J. HCUP Statistical Brief #21. December 2006 2. Ballas SK et al. J Natl Med Assoc 2010; 102: 993
Quality-Adjusted Life Years (QALYs) 5 yr old with abnormal TCD lifelong transfusion and chelation adds 16 QALYs? HU? Stem cell transplant? QALYs from supportive care 1 QALY = $203,000 ($109,000-$297,000) Braithwaite et al., Medical Care 2008;46:349-356
Reasons TO TREAT High morbidity and mortality limited effect of supportive therapy Poor QOL, particularly related to CNS Reduced life expectancy Cost to family and society Good rates of success with HU Improved success rates of curative therapy stem cell transplantation