The Treatment of Sickle Cell Disease

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Sickle Cell Disease - What is New by Miguel R. Abboud, American University of Beirut Medical Center and Children’s Cancer Center of Lebanon, Beirut

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The Treatment of Sickle Cell Disease

  1. 1. Sickle Cell Disease What is New Miguel R. Abboud g American University of Beirut Medical Center and Children’s Cancer Center of Lebanon Beirut, Lebanon
  2. 2. Sickle cell at the beginning of the 20th century● 1910 – J.B. Herrick and Irons – “sickled cells” in the blood of Walter Clement Noel● 1927 Hahn and Gillespie – deoxygenated cells sickle● 1949 – Linus Pauling – electrophoresis – molecular structure
  3. 3. Haemoglobin S [6 (A3)GluVal]H. Wajcman Courtesy of Dr H. Wajcman.
  4. 4. STOP Prevnar Baby HUG SWiTCH SITT1998 1999 2000 2001 2003 2004 2006 2007 2008 Hydroxyurea Hydroxyurea Pulmonary Walk Phast in children in infants hypertension
  5. 5. National BMT in Phenotype matchingsickle cell SCD and Preop Transfusionscontrol act 1972 1979 1984 1986 1990 1995 Penicillin Adult phase III prophylaxis (Gaston) hydroxyurea CSSCD and newborn trial screening PPV (Charache)
  6. 6. Severity of SCD varies widely among patients Intermediate forms Pain of SCD f ACS Stroke Asymptomatic patients Severe forms of SCD Penicillin, folic acid, hydration Hydroxyurea Chronic blood transfusion Bone marrow transplantationACS = acute chest syndrome.
  7. 7. Complications of SCD in children Polymerization of deoxy-HbS Endothelial dysfunction Age (years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Bacteraemia Pain highly variable ACS ASS Stroke Chronic organ damage ? Castro O, et al. Blood. 1994;84:643-9. Gill FM, et al. Blood. 1995;86:776-83.ASS = acute splenic sequestration. Ohene-Frempong K, et al. Blood. 1998;91:288-94.
  8. 8. Prophylaxis with oral penicillin reducesmorbidity and mortality of p y y pneumoccocal infections● 125 SCD children aged 3–36 months● Randomly assigned to receive either 125 mg oral penicillin or placebo Placebo Penicillin group group pStreptococcus pneumoniae 13 2 0.0025infectionsDeath (S. pneumoniae) 3 0 0.003Incidence of S. pneumoniae 0.09 0 09 0.02 0 02 < 0.05 0 05septicaemia Gaston MH, et al. N Engl J Med. 1986;314:1593-9.
  9. 9. Goals of newborn screening● Reduce mortality rates from 38% due to Pneumococcal sepsis● Reduce incidence of complications such as splenic sequestration
  10. 10. South Carolina: Standard Newborn Screening Tests● PKU 1965 3 infants/year● hypothyroidism 1978 10● hemoglobin 1987 100● galactosemia 1992 1● CAH 1992 3● MCADD 2000 4
  11. 11. Interpreting results● fetal hemoglobin predominates until about age six months● small amounts of the adult hemoglobin type are produced in the third trimester● qualitative results listing the predominant hemoglobin first ( FA FS FAS FSA) FA, FS, FAS,● quantitative results in the first month of life are typically F 90% S 10% i ll F=90% S=10%
  12. 12. Earlier diagnosis positively impacts g p y p survival 100 HbSS diagnosed in newborn period 98 96 Survival (%) 94 HbSS diagnosed after newborn period 92 S 90 88 86 0 10 20 30 40 10 Months YearsHbSS = haemoglobin SS. Vichinsky E, et al. Pediatrics. 1988;81:749-55.
  13. 13. Causes of death in children with SCD Year Country Incidence Causes (range) Gill 1978–98 USA 1.1/100 pt-yr 11 sepsis (9 S.pn), 2 ASS, 1 CVA Thomas 1985 92 1985–92 France 0.29%/yr 0 29%/yr 15 sepsis (8 S pn) 3 ASS S.pn), ASS, (Paris) 3 CVA Quinn 1983–04 USA 0.59/100 pt-yr 5 sepsis (4 S.pn), 3 ACS, (Texas) 2 multi-organ failure, 1 CVA, 1 myocardial infarct Gill FM, et al. Blood. 1995;86:776-83. Thomas C, et al. Arch Pediatr. 1996;3:445-51.CVA = cerebrovascular accident; pt-yr = patient years; Quinn CT, et al. Blood. 2004;103:4023-7.S.pn = Streptococcus pneumoniae.
  14. 14. Clinical outcome in children with SCDliving in England: a neonatal cohort in g gEast London● 252 children identified during 1983–2005 by universal birth screening in East London● Followed in a hospital- and community-based programme● Estimated survival of children with SCD at 16 years: 99 0% (95% CI: 93 2 99 9%) 99.0% 93.2–99.9%)● Pneumoccal sepsis rate: 0.3 (95% CI: 0.1–0.8) episodes/100 pt-yr i d /100 t● Risk of overt stroke: 4.3% (95% CI: 1.5–11.4%) Telfer P, et al. Haematologica. 2007;92:905-12.
  15. 15. Preventive care ● Neonatal screening – immunization – penicillin prophylaxis ● Parents and patient education ● Annual TCD ultrasound in children > 1 year old ● I children > 5–10 years old, annual In hild 10 ld l echocardiogram, hepatic ultrasonography, ophthalmologic evaluation, and pulmonary hth l l i l ti d l function testsTCD = transcranial Doppler.
  16. 16. Need for pneumococcal conjugatevaccination in addition to daily penicillin prophylaxis in children with SCD h l i i hild ith● Incomplete level of adherence to penicillin prescription – in a Tennessee study, 25–30% of Medicaid p g programme enrollees were likely to receive p y penicillin for > 270 days per year1● Increase in percentage of p p g penicillin-resistant strains 1. Halasa NB, et al. Clin Infect Dis. 2007;44:1428-33.
  17. 17. Invasive pneumococcal infections in children with SCD● 36.5 infections/1,000 pt-yr in SCD children 1 2 1–2 years of age, 20% meningitis, 15% deaths● 23-valent pneumococcal polysaccharide (PVC) efficacy: 80.4% (95% CI: 39 7–93 6) 80 4% 39.7–93.6)● 71% of serotyped isolates were PVC serotypes● 71% of nonvaccine serotypes were f i t penicillin-sensitive Adamkiewicz TV, et al. J Pediatr. 2003;143:438-44.
  18. 18. Pneumococcal conjugate vaccine reduces j grate of invasive pneumococcal disease in SCD Age Patients Rate of IPD % of (years) with IPD (n/100,000 pt-yr) pt yr) decrease p Pre-PCV era Post-PCV era <5y All 21 2,044 134 93.4 < 0.001 <2y 16 3,630 335 90.8 < 0.001 5y 16 161 99 38 0.36IPD = invasive pneumococcal disease;PCV = pneumococcal conjugate vaccination. Halasa NB, et al. Clin Infect Dis. 2007;44:1428-33.
  19. 19. Increase In IPD
  20. 20. Management of Febrile Episodes● Fever above 38.5 C needs prompt attention● PE: Palpate spleen● CBC retic, blood, urine culture, Chest X ray de te y sy pto at c, definitely if symptomatic, LP in meningitis e gts suspected, O2 saturation● Ceftriaxone 50 g/ g IV obse e for se e a Ce a o e 50mg/kg observe o several hours● Follow up the next day if febrile g p y give ceftriaxone if stable may continue on po antibiotic
  21. 21. Management of Febrile Episodes● High risk patients have fever >40C● Severe anemia, high WBC, appear toxic, previous Pneumococcal sepsis, thrombocytopenia● Poor compliance● ADMITT ceftriaxone 75mg/kg ce a o e 5 g/ g● Vancomycin not needed unless patient extremely unstable y● Hemolysis my be a complication of Rocephin
  22. 22. Annual investigations ● Complete physical examination ● Complete blood counts, liver p p profile, electrolytes, BUN, creatinine, y microalbuminuria, ferritin if transfused, calcium metabolism including vitamin D and PTH, Parvovirus B19 serology until positive ● Pulmonary function tests: routinely or as clinically indicated ● TCD from 2 to 16 years of age ● Hepatic ultrasonography after 3 y p g p y years of age g ● Hip radiograph and echocardiography after 6 years of age ● Ophthalmological evaluation by a trained ophthalmologist – patients with SC disease: after 6 years of age – patients with SS disease: after 10 years of age ● Academic performance ● Adherence to treatment and appointmentsBUN = blood urea nitrogen test; PTH = parathyroid hormone.
  23. 23. Treatment of complications● PAIN● Infections● Acute anaemia: ASS aplastic crisis ASS,● Severe vaso-occlusive events: ACS, strokes, priapism, organ failure● Pulmonary hypertension● Complications in high-risk pregnanciesTransfusion therapy is a cornerstone for management of py gSCD complications
  24. 24. Splenic Sequestration● Vaso-occlusion within the spleen-splenomegaly● Pooling of red cells-marked decrease in hemoglobin Risk of hypovolemic shock● Droping Hemoglobin dropping platelets Hemoglobin, increased reticulocyte count (may occur after Parvo infection low retic!!)● HbSS Young children- functional spleen at risk.● HbSC or S thal older patients at risk
  25. 25. Sequestration● 30% of children have one episode. Initial symptom in 20%● May lead to early death 10-15% mortality● Teach parents to follow spleen size● Transfuse for acute event-Hb overshoot as spleen shrinks l hi k● High rate (50%) recurrence splenectomy after first severe event
  26. 26. Risk factors for early death in patients with sickle cell anaemia who were 20 years of age or older* Variable Variable estimate ± SE p value† HbF (%) −0.09 ± 0.04 < 0.001 Acute chest syndrome‡ 0.80 ± 0.27 0.005 Renal f il R l failure 1.10 0.47 1 10 ± 0 47 0.03 0 03 Seizures 0.91 ± 0.42 0.04 White cell count 0.10 0.04 0 10 ± 0 04 0.01 0 01 *The values shown for the variable estimates reflect the associations between age-specific mortality risks and clinical profiles during the study in a multivariate model, with backward elimination, by proportional- hazards regression. †Lik lih Likelihood ratio, 1 d d ti degree of f d f freedom. ‡Scored as follows: < 0.2 episode per year = 1; ≥ 0.2 episode per year = 0.HbF = fetal haemoglobin. Platt O, et al. N Engl J Med. 1994;330:1639-44.
  27. 27. Causes of death in Athens cohort HU patients Non-HU patientsCause of death (13/131 = 9.9%) (49/199 = 24.6%)Liver dysfunction 1 10Pulmonary hypertension 8 8Stroke 3 10Sudden death 3 5Vaso-occlusion crisis 1 6Acute chest syndrome 1 5Sepsis 1 1Heart failure 2 2InterventionI t ti 1 2 Voskaridou E, et al. Blood. 2010;115:2354-63.
  28. 28. Hydroxyurea ● Potential to increase HbF ● Have salutary effects on the adverse risk factors ● Phase 3 randomized trial – 299 adults, 21 centres ● Decreased rate of painful crises by 50% ● Decreased rates of hospitalization for pain or ACS and d d decreased numbers t d b transfusions f i ● Led to FDA approval of hydroxyurea pp y yACS = acute chest syndrome;FDA = US Food and Drug Administration. Charache S, et al. N Engl J Med. 1995; 332:1317-22.
  29. 29. Hydroxyurea in SCD:multiple mechanisms of action Ware RE. Blood. 2010;115: 5300-11.
  30. 30. The Hydroxyurea ResponsePatient1Patient2 Pre-treatment Dose Maximum Tolerated Escalation Dose
  31. 31. Acute chest syndrome● A new pulmonary infiltrate involving at least one complete lung segment not consistent with atelectasis p g g● One or more of – chest pain – fever – tachypnoea, wheezing, cough – hypoxaemia compared with baseline● Complicates 30% of admissions for painful vaso-occlusive vaso occlusive crises● Most common post operative complication in patients post-operative with SCD
  32. 32. Medoff BD et al. Case 17-2005: A 22-Year-Old Woman with Back and Leg Painand Respiratory Failure. 2005;352(23):2425-34.
  33. 33. ACS is associated with higher mortality in patients with SCD-SS Survival of patients with SCD SS b occurrence of ACS S i l f ti t ith SCD-SS by f events within first 2 years of follow-up 1.0Surviva probability 8.0 6.0 al 4.0 40 2.0 No ACS (n = 1,764)S ACS (n = 419) 0 0 10 20 30 40 Age (years) Castro O, et al. Blood. 1994;84:643-9.
  34. 34. Prediction of Late events Quinn, C. T. et al. Blood 2007;109:40-45Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
  35. 35. Flowchart for the management of ACS.Miller S T Blood 2011;117:5297-5305
  36. 36. Flowchart for the diagnosis of ACS.Miller S T Blood 2011;117:5297-5305
  37. 37. Role of Steroids● Corticosteroids: Rationale – Multiple studies have shown an inflammatory milieu in ACS – Increased levels of adhesion molecules such as VCAM-1, – SPLA2 which can release f hi h l free f tt acid l di t more VCAM 1 fatty id leading to VCAM-1 – High levels of cytokines like IL-8 and G-CSF – Asthma may a role and need to be treated adequately● Clinical reality – Dexamethasone 0.3 mg/kg q 12hrs for 4 doses • Shorter hospital stays less transfusions • increased rates of readmission • 2 CNS bleeds – Lower dose prednisone better tolerated no increase readmissions – There is a trend to less steroid use – Are asthmatic patients with SCD being under treated? Bernini JC et al Blood 1998 92:3082 Kumar R et al JPHO 2010 32:91 Sobota A et al AJH 2010 85:24 Strousse JJ et al PBC 2007 50:1006
  38. 38. Prevention of ACS: hydroxyurea vs HSCT ● MSH –h d hydroxyurea hi hl effective i th prevention of acute highly ff ti in the ti f t chest syndrome episodes ● HSCT – no new episodes of acute chest syndrome – stabilization of pulmonary functionHSCT = haemopoietic stem cell transplantation.
  39. 39. Transfusion to prevent ACS ● In the STOP study, 63 children were randomly assigned to chronic transfusions and 67 to observation based on cerebral blood velocity by TCD. Mean follow-up of 19.6 months ● Based on intent-to-treat analysis: hospitalization rates for ACS 4.8 in transfused group versus 15.3 per 100 patient-years non-transfused patient years in non transfused group (p = 0 0027) 0.0027) ● Transfusions also protective for pain when analyzed as to treatment received 9 7 versus 27 1 events per 100 9.7 27.1 patient-years (p = 0.014) ● Transfusion remain protective of ACS 2.2 versus 15.7 events per 100 patient-years (p = 0.0001)TCD = transcranial Doppler. Miller ST, et al. J Pediatr. 2001;139:785-9
  40. 40. ACS: an iatrogenic condition● Multi-modal pain intervention in a large tertiary centre● Standardized orders staff caregiver education● 332 admissions, 159 before and 173 after● ACS rates declined from 25% to 12% p = 0.003● Time to ACS increased from 0 8 to 1 7 days 0.8 1.7 p = 0.047 Reagan M, et al. Pediatr Blood Cancer. 2011;56:262-6.
  41. 41. BABY HUG – Objectives j • Primary: To determine whether hydroxyurea can prevent or reduce chronic organ damage to the spleen and kidneys in very young children with sickle cell anemia • Secondary: To investigate safety; to determine hematologic effects and effects on other h t l i ff t d ff t th measures of organ function; to examine effects on adverse events d t
  42. 42. Clinical Outcomes: BABY HUG compared with MSH BABY HUG† MSH HU PL p HU PL pn 96 97 152 147pain 177 372 0.002 2.5/y 4.5/y <0.001ACS 8 27 0.017 25 51 <0.001dactylitis 24 123 <0.001 — — —hospitalization* 232 321 0.050 1.0/y 2.4/y —transfusion‡ 35 60 0.033 48 73 0.001 †data indicate no of episodes no. *in BABY HUG, all hospitalizations; in MSH, hospitalization for pain only ‡in BABY HUG, no. of transfusions; in MSH, no. of pts. receiving transfusion
  43. 43. Hydroxyurea vs transfusions● Hydroxyurea – one randomized t i l of h d d i d trial f hydroxyurea i adults with in d lt ith SCD – many non-randomized trials of HU in children● Blood transfusion – randomized trials of transfusions in SCD: STOP, STOPII STOP STOPII, and Preop Transfusion study dP T f i t d – Acute Chest Study not randomized
  44. 44. Toxicity of hydroxyureaToxicity Outcome Level of evidenceLeg ulcers Comparable HighLeukaemia Comparable LowOther cancers Comparable LowSpermatogenesis p g Defects InsufficientPregnancy Comparable Insufficient
  45. 45. Silent versus ischaemic infarcts in SCD Silent IschaemicTransfusion therapy lowers risk for newsilent infarcts or stroke for children with both abnormal TCD ultrasonographic velocity and silent infarct Pegelow CH, et al. Arch Neurol. 2001;58:2017-21.
  46. 46. Aims and study design Aim: to compare 30 months of hydroxyurea and phlebotomy (alternative) withtransfusions and deferasirox (standard) for the prevention of secondary stroke and reduction of transfusional iron overload 161 paediatric patients with sickle cell anaemia (83 male, 78 female), documented stroke and iron overload enrolled in SWiTCH (US10) 134 patients randomized 1:1 Alternative arm Standard arm 67 patients 67 patients Hydroxyurea + phlebotomy Transfusions + deferasirox Prediction: increased occurrence of recurrent stroke events in alternative arm counter-balanced by better management of iron overload with phlebotomy Ware RE, Helms RW. Blood. 2010;116:[abstract 844].
  47. 47. Results: stroke recurrence rate The difference in stroke rates between the two arms was greater than expected Treatment arm Transfusions + Hydroxyurea + deferasirox phlebotomyStroke incidence 0/66 (0%) 7/67 (10%) Ware RE, Helms RW. Blood. 2010;116:[abstract 844].
  48. 48. Author conclusions● Transfusions and chelation remain the gold standard treatment for secondary stroke prevention in p y p paediatric SCD patients● Phlebotomy is not superior to deferasirox in reducing iron overload● Pre study stroke predictions were inaccurate Pre-study● Study was terminated early as reduction of LIC by phlebotomy could not compensate for the marked increase in secondary stroke risk with hydroxyurea Ware RE, Helms RW. Blood. 2010;116:[abstract 844].
  49. 49. Predictive value of TCD for stroke Predictive value of TCD for strokeRight MCA Left MCA 220 cm/s 130 cm/s● The probability of remaining stroke-free over time of follow-up or start of f f ff f chronic transfusion (~ 70 months) was greatest with normal baseline TCDThe risk of stroke was higher with abnormal TCD than with normalor conditional TCD (p < 0.01) Adams RJ, et al. Blood. 2004;103:3689-94.
  50. 50. Importance of TCD in SCD● Yearly stroke risk – baseline risk from CSSCD ~ 0.5–1% 0.5 1% – if prior stroke ~ 30% – TIA lower baseline Hb prior and recent ACS TIA, Hb, (CSSCD study, no prior stroke) but yearly risk not quantitated – abnormal TCD 10–13% per year – MRI “silent lesions” ~ 2–3% per y p year – severe arterial lesions on angiography? • assumed to be bad, but yearly risk has not been quantitated
  51. 51. Blood transfusion prevents first stroke in sickle cell anaemia● Kaplan-Meier estimate of the 100 probability of not having a stroke ree among 130 patients with sickle cell rcent of remaining stroke-fr anaemia at high risk of stroke as 80 determined by transcranial Doppler.● Patients were randomized to chronic g long-term transfusion therapy or 60 standard care● There was a significant benefit from g 40 transfusion therapy (p = 0.02)● One patient in the standard-care group who had an intracerebral Per 20 Transfusion haematoma was excluded Standard care● The tick marks represent the lengths of observation in patients who did not 0 have a stroke h t k 0 5 10 15 20 25 30 Months Data from Adams RJ, et al. N Engl J Med. 1998;339:5-11.
  52. 52. Identification and management of stroke risk g in children with SCD: NIH guidelines Child with HbSS, aged > 2 years, with no symptoms Evaluate Neuropsychological TCD educational needs testing unavailable na ailable based on results TCD High risk based on other information† Abnormal Normal (< 200 cm/s) Low risk Protocol treatment or ( 200 cm/s) clinical trial Confirm abnormal Repeat TCD every Observation Or treatment options 3–12 months* • Observation for MRI/MRA progression Abnormal • HU Chronic transfusion examination • Transfusion • Other (e.g. antiplatelet agents)*Optimal frequency of re-screening not established;younger children with velocity closer to 200 cm/s should bere-screened more frequently.†Prior transient ischaemic attack, low steady-state Hb, rateand recency of ACS, elevated systolic blood pressure. www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf. Accessed Nov 2010.
  53. 53. Early TCD screening● A study from France confirmed benefits of early TCD screening● Reduced incidence of strokes with aggressive management in a newborn screening cohort ti b i h t● TCD yearly● MRI/A yearly after age 5 years
  54. 54. Diagram of the CHIC SCA newborn cohort SCA (SS/Sb0) – newborn between May 1998 and A il 2007 b b t M d April (n = 256) Never seen (n = 7) Seen in the CHIC centre (n = 249) Moved to another place (n = 24) France (n = 21) Africa (n = 3) Lost to follow-up (n = 3) TCD parental refusal (n = 2)Patients too young for TCD ( = 3) y g (n ) TCD screened (n = 217) Dead (n = 4) Africa (n = 3) Other place in France (n = 11) Still followed at CHIC centre (n = 198) Lost to follow-up (n = 1) Bernaudin F, et al. Blood. 2011;117:1130-40.
  55. 55. Patient therapy● HU for patients with recurrent ACS or pain or normal TCD and Hb < 7 g/dL● Transfusions for abnormal TCD in 45 patients● HSCT for patients with sibling donors Bernaudin F, et al. Blood. 2011;117:1130-40.
  56. 56. Cumulative risk of overt stroke 10 8 Risk of stroke (%) ) 6 s 4 2 0 0 2 4 6 8 10 12 14 16 18 Age (years)Number at risk 217 188 148 103 84 64 49 32 16 7 Bernaudin F, et al. Blood. 2011;117:1130-40.
  57. 57. Early TCD screening and intensification of transfusion therapy allows > 5x reduction of stroke risk by age 18 years 100 100Risk of abnormal mal-MRA) Risk of stenosis 80 80 TCD (%) 60 60 s D (abnorm a 40 40 20 20 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Number at risk Age (years) Number at risk Age (years) 217 216 186 154 120 94 82 77 67 57 50 44 39 29 24 132 132 131 128 114 96 79 67 60 53 49 38 28 20 17 100 100 CD/stenosiis/ 80 80Risk of silent CNS risk (stroke/ troke (%) roke (%) 60 60 40 40 abnormalTC k k str silent st 20 20 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Age (years) Age (years) a Number at risk Number at risk 129 129 127 125 112 94 76 63 51 43 40 33 25 17 13 217 215 184 155 126 96 74 69 58 47 42 39 36 27 23 Bernaudin F, et al. Blood. 2011;117:1130-40.
  58. 58. Conclusions● Early TCD and transfusions effective in preventing strokes but not silent infarcts● Most patients who develop silent infarcts have normal TCD l● Different strategies needed
  59. 59. Neurocognitive function in infants SCA 13 14 Controls hs)BINS raw score (9 month 12 12 11 ( BINS raw score 10 10 w w 9 8 8 R2 = 0 913 0.913B B R2 = 0 229 0.229 7 6 7.0 8.0 9.0 10.0 11.0 12.0 30 70 110 150 Haemoglobin (g/dL) MCA velocity Hogan AM, et al. Br J Haematol. 2005;132:99-107.
  60. 60. Approach to neurological complications in SCD Abnormal Abnormal Overt Silent infarct TCD neuropsychology stroke on MRI (↓FSIQ)BMT Chronic Education Hydroxyurea(CBT) transfusion support SWiTCH SIT trial trial Intervention of proven value Intervention of possible value Efficacy of ‘intervention of p y possible value’ under investigation g Adapted from Wang W. Curr Opin Hematol. 2007;14:191-7.
  61. 61. Special issues in transfusion of sickle cell patients1. Avoid hypervicosity – sudden elevated blood pressure – congestive heart failure – alteration in metal status – attributed to increase in whole blood viscosity – see at Hb > 12 g/dL hct > 33% g/dL,2. Delayed haemolytic transfusion reactions3. Iron distribution may be different than in thalassaemia patients – less cardiac and endocrine iron deposition
  62. 62. Approaches to transfusion therapyApproach ApplicationsSimple transfusionTransfusion of additional units of blood Severely anaemic patientswithout removal of sickle blood Hb levels < 8–9 g/dLAutomated exchange transfusion(erythrocytapheresis)Sickle cells are removed and replaced Preferred when rapid alterationwith normal red cells of Hb levels is requiredRapid partial exchange transfusionWhole blood removed from one arm Widely appropriatewhile donor cells transfused into other de Montalembert M, et al. Am J Hematol. 2011;86:72-5. .
  63. 63. Effectiveness of transfusions in SCDCriterion Outcome Level of evidencePainful iP i f l crises Decreased D d Low LHospitalizations Decreased LowAcute chest syndrome Decreased HighNeurological events Decreased HighProteinuria Decreased Low
  64. 64. Decrease in serum ferritin levels with 5 years of deferasirox therapy Serum ferritin (µg/L) Deferasirox dose (mg/kg/day) In ti t I patients receiving deferasirox for ≥ 4 years, median serum ferritin i i d f i f di f iti significantly decreased by −591 μg/L (p = 0.027; n = 67) Vichinsky E, et al. Blood. 2010;116:[abstract 845]. Data presented at ASH 2010.
  65. 65. Results of BMT in 4 large seriesAuthorA th N Median A M di Age TRM% Rejection R j ti EFS% %Walters et al 59 9.4 (3.3-14) 6 10 85Bernaudin et 87 8.8 (2.2-22) 6.9 7 86alPanepinto et 67 10 (2 27) (2-27) 3 late 13 85al deathsVermylen et 50 7.5 (0.9-23) 7 10 82al l Walters et al Blood 2000; 95: 1918 Updated EBMT 2008 Bernaudin et al Blood 2007; 110: 2749 Panepinto et al BJH 2007; 137: 479 Vemylen et al BMT 1998; 22: 1
  66. 66. Who was Transplanted● Despite different age criteria most transplant were in the pediatric age group● Patients with severe disease. Different definitions
  67. 67. Bernaudin et al Blood al.2007Panepinto et al. BJHP i t t l2007Vermylen et al. BoneMarrow Transplant 1998McPherson et al. BoneMarrow Transplant 2011.Locatelli et al. Blood2003
  68. 68. HSCT in adult SCD patients • A modified conditioning protocol for allogeneic haemopoietic stem cell transplantation that does not ablate the bone marrow was used to treat 10 adults who had severe sickle cell disease • The sickle cell phenotype was eliminated in 9 of the 10 recipients • No deaths, no major adverse events, and no graft-versus-host disease occurred among the recipients g pHLA typing performed in 169 siblings and 112 patients 88 patients did not have matched related donors p 24 patients were eligible 4 were excluded for major ABO incompatibility 1 died before HSCT 8 are receiving optimizing medical therapy 1 is in pre-HSCT evaluation 10 underwent transplantation Hsieh MM, et al. N Engl J Med. 2009;361:2309-17.
  69. 69. CDC-WHO Survey of 22 Countries in MENA region● 17/22 Responded● 8/17 Have management guidelines● 5/17 NBS programs one excludes hemoglobinopathies● 8/17 Have awareness programs● 7/8 Provide penicillin and 8/8 hydroxyureaEMBMT 255 HSCT All for thalassemia
  70. 70. Conclusions● There have been significant advances in the management of sickle cell disease leading to increased survival and a decrease in complications● Transfusions play a major role in preventing complications and end-organ dysfunction● Hydroxyurea is very useful in these patients, but its role may be limited in certain circumstances● HSCT is limited by availability of donors
  71. 71. β-Thalassaemia intermedia● “Highly diverse” group of β-thalassaemia syndromes where red blood cells are sufficiently short-lived to cause anaemia, without patients necessarily requiring regular bl d transfusions i il ii l blood f i● The severity of the clinical phenotypes varies between those of β thalassaemia β-thalassaemia minor (TI) and β-thalassaemia major (TM) β thalassaemia● TI arises from defective gene(s) leading to partial suppression of β-globin protein production Mild Severe Completely asymptomatic Presentation at age 2–6 years until adult life Retarded growth and development Taher A, et al. Br J Haematol. 2011;152:512-23. Guidelines for the clinical management of thalassaemia. 2nd rev. ed. TIF 2008.
  72. 72. Pathophysiology summarized Excess free Formation of haem α-globin chains Denaturation and haemichromes Degradation g Iron-mediated toxicity Ineffective erythropoiesis Membrane Ineffective Haemolysis binding of Chronic anaemia and erythropoiesis haemolysis IgG and C3 Removal of damaged red cells Iron overload Increasederythropoietin Reduced tissue Anaemia Splenomegaly synthesis oxygenation Skeletal Erythroiddeformities, Increased I d marrow Iron overloadosteopenia expansion iron absorption Olivieri NF, et al. N Engl J Med. 1999;341:99-109.
  73. 73. Overview on Practices in Thalassemia Intermedia Management Aiming for Lowering Complication rates Complication-ratesAcross a Region of Endemicity: the OPTIMAL CARE study ● Retrospective review of 584 TI patients from 6 comprehensive care centres in the Middle East and Italy N = 127 N = 153 N = 200 N = 51 N = 12 N = 41 Taher AT, et al. Blood. 2010;115:1886-92.
  74. 74. The OPTIMAL CARE study: overall study population Frequency Parameter n (%) Age (years) < 18 172 (29.5 ) 18–35 288 (49.3) > 35 124 (21.2) Male : female 291 (49.8) : 293 (50.2) Frequency Treatment Splenectomized 325 (55.7) n (%) Serum ferritin (µg/L) Hydroxyurea 202 (34.6) < 1,000 376 (64.4) Transfusion 1,000–2,500 179 (30.6) Never 139 (23.8) > 2,500 29 (5) Occasional 143 (24.5) Complications Regular 302 (51.7) Osteoporosis 134 (22.9) Iron chelation EMH 124 (21.2) None 248 (42.5) Hypogonadism 101 (17.3) Deferoxamine 300 (51.4) Cholelithiasis 100 (17.1) Deferiprone 12 (2.1) Thrombosis 82 (14) Deferiprone + deferoxamine 3 (0.5) (0 5) Pulmonary hypertension 64 (11) Deferasirox 21 (3.6) Abnormal liver function 57 (9.8) Leg ulcers 46 (7.9) yp y Hypothyroidism 33 (5.7) ( ) Heart failure 25 (4.3) Diabetes mellitus 10 (1.7)EMH = extramedullary haematopoiesis. Taher AT, et al. Blood. 2010;115:1886-92.
  75. 75. 120 Treatment-naive patients 12.0 Haemoglob (g/dL) 10.0 8.0 bin 6.0 Age vs haemoglobin level 4.0 (r = −0.679, p < 0.001) 2.0 0.0 0 20 40 60 Age (years) 3000 3,000Serum ferritin (µg/L) 2,500 2500 2,000 2000 1,500 1500 Age vs serum ferritin level g 1,000 1000 (r = 0.653, p < 0.001) 500 500 0 0 0 20 40 60 Age (years) Taher A, et al. Br J Haematol. 2010;150:486-9.
  76. 76. Complications vs age Complications in 120 treatment-naive patients with TI <<10 years 10 years 11–20 years 11-20 years 21-32 years 21–32 years > 32 years >32 years 45 * 40.0 40 35 33.3 * * * 30.0 %) equency (% 30 26.7 26.7 25 * 23.3 23.3 20 16.7 16.7 20.0 20.0 20.0 * 16.7 16.7 16.7 20.0 Fre 15 13.3 13.3 13.3 13.3 13.3 10.0 10.0 10.0 10.0 10.0 10 6.7 6.7 6.7 6.7 6.7 6.7 5 3.3 3.3 3.3 3.3 3.3 3.3 3.3 0 0 0 0 0 0* = statistically significant trend.HF = heart failure;PHT = pulmonary hypertension;ALF = abnormal liver function; DM = diabetes mellitus. Taher A, et al. Br J Haematol. 2010;150:486-9.
  77. 77. Splenectomy● Less common than in the past – before age 5 years it carries a high risk of infection and is therefore not generally recommended● Main indications include – growth retardation or poor health – leukopenia – thrombocytopenia thromboc topenia – increased transfusion demand – symptomatic splenomegaly● Primarily done in regularly transfused TM patients Taher A, et al. Br J Haematol. 2011;152:512-23. Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.
  78. 78. Thromboembolic events in a large cohort of TI patients ● Patients (N = 8,860) – 6,670 with TM Venous 48 66 – 2,190 with TI Stroke 28 9 ● 146 (1.65%) thrombotic events 23 DVT Type of event 39 – 61 (0 9%) with TM (0.9%) PE 8 – 85 (3.9%) with TI 12 11 ● Risk factors for developing PVT 19 T thrombosis in TI were STP 0 TM (n = 61) 8 – age (> 20 years) TI (n = 85) Others 30 12 – previous thromboembolic event – family history 0 20 40 60 80 – splenectomy Thromboembolic events (%)DVT = deep vein thrombosis;PVT = portal vein thrombosis; STP = superficial thrombophlebitis. Taher A, et al. Thromb Haemost. 2006;96:488-91.
  79. 79. Multivariate analysis Parameter Group OR 95% CI p value NRBC count ≥ 300 x 106/L Group III 1.00 Referent Group II 5.35 2.31–12.35 < 0 001 0.001 Group I 11.11 3.85–32.26 Group I had significantly higher NRBC, platelets, Platelet count ≥ 500 x 109/L Group III 1.00 Referent PHT occurrence and were mostly non-transfused occurrence, Group II 8.70 3.14–23.81 < 0.001 Group I 76.92 22.22–250.00 PHT Group III 1.00 Referent Group II 4.00 0.99–16.13 0.020 Group I 7.30 1.60–33.33 Transfusion naivety Group III 1.00 Referent Group II 1.67 1 67 0.82 3.38 0 82–3 38 0.001 0 001 Group I 3.64 1.82–7.30NRBC = nucleated red blood cell;OR = adjusted odds ratio; CI = confidence interval. Taher A, et al. J Thromb Haemost. 2010;8:2152-8.
  80. 80. Time-to-thrombosis (TTT) since splenectomy Time to thrombosis 1 1 ombosis- ombosis- NRBC count Platelet count 0.8 < 300 x 106/L 0.8 < 500 x 109/L ≥ 300 x 106/L val val ≥ 500 x 109/L The median TTT following splenectomy was 8 years (range 1 33 years) (range, 1–33 free surviv free survivCumulative thro Cumulative thro 0.6 0.6 0.4The median TTT was significantly shorter in patients with an NRBC 0.4 0.2 count ≥ 300 x 106/L, a platelet count ≥0.2 x 109/L , and who were 500 transfusion naive 0 0 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Duration since splenectomy (years) Taher A, et al. J Thromb splenectomy (years) Duration since Haemost. 2010;8:2152-8. 1 1 hrombosis- hrombosis- Transfused Pulmonary hypertension 0.8 Yes 0.8 Yes No No vival vival 0.6 0.6 free surv free survCumulative th Cumulative th 0.4 0.4 0.2 0.2 0 0 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Duration since splenectomy (years) Duration since splenectomy (years) Taher A, et al. J Thromb Haemost. 2010;8:2152-8.
  81. 81. Silent brain MRI findings in 30 splenectomized adults with TI (cont.) White matter lesions ● 18 patients (60%) had evidence Parameter n (%) of one or more WMLs on brain Number MRI all involving the subcortical Single 4 (22.2) white matter Multiple* 14 (77.8) Location ● 11 patients (37%) had evidence Frontal 17 (94.4) (94 4) of mild cerebral atrophy 10 of atrophy, Parietal 9 (50) whom had associated WMLs Temporal 1 (5.6) Occipital 3 (16.7) Internal capsule 1 (5.6) (5 6) External capsule 5 (27.8) Size** White matter lesions and brain Small (< 0.5 cm) 10 (55.5) atrophy are a common finding in Medium (0.5–1.5 cm) ( ) 7 (38.9) ( ) Large (> 1.5 cm) § 1 (5.6) adult, splenectomized, TI patients d lt l t i d ti t *Mean of 5 ± 10 lesions (range: 2 to > 40 lesions). **For patients with multiple lesions, the largest lesion was used to define size. §Th possibility of misreading confluent multiple l The ibilit f i di fl t lti l lesions was excluded i l d d radiologically based on lesion shape.WML = white matter lesions. Taher AT, et al. J Thrombosis Haemost. 2010;8:54-9.
  82. 82. Risk factors for white matter lesions No. of abnormalities Occasionally transfused 0 1 >1 1.1 6 1.0 bility of abnormality 5 0.9 4 3 0.8 2 1 0.7 07 Patients (n) ) 0 0.6 0.5 Non-transfused 6 0.4 5Probab P 4 0.3 3 0.2 2 1 0.1 0 10 15 20 25 30 35 40 45 50 55 60 ≤ 30 30–40 40–50 > 50 Age (years) Age (years) Increasing age and transfusion naivety are associated with a higher incidence and multiplicity of white matter lesions Taher AT, et al. J Thrombosis Haemost. 2010;8:54-9.
  83. 83. Recommendations for iron chelation therapy in TIAge < 4 years Age ≥ 4 years Haemoglobin HaemoglobinObservation < 9 g/dL ≥ 9 g/dL EvidenceMonitor LIC guidelines for LIC Initiate based Continue Monitor and and chelation is serum ferritin transfusions currently in preparation! observation serum ferritin Transfusions LIC > 7 mg Fe/g dry wt LIC > 7 mg Fe/g dry wt > 10 units or serum ferritin or serum ferritin > 500 µg/L /L > 500 µg/L /L Start iron Start iron Start iron chelation h l ti chelation h l ti chelation h l ti therapy therapy therapy Taher A, et al. Br J Haematol .2009;147:634-40.
  84. 84. Summary● Our understanding of the molecular basis and pathophysiology of TI significantly increased● Iron overload and hypercoagulability are recently receiving increasing attention in TI● Despite that various treatment options are available, no clear guidelines exist● S Several studies are challenging th role of splenectomy yet l t di h ll i the l f l t t highlighting the benefit of transfusion, iron chelation therapy, and fetal haemoglobin induction in the management of TI; thus these approaches merit large prospective evaluation● The role of antiplatelets/anticoagulants in TI merits investigation
  85. 85. Early TCD screening and intervention● Predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort p y (n = 217, SS/S0), who were early and yearly screened with TCD since 1992● MRI/MRA every 2 years after age 5 years (or earlier in case of abnormal TCD)● Transfusions for abnormal TCD and/or stenoses● Hydroxyurea to symptomatic patients no macrovasculopathy● HSCT for those with HLA genoidentical donor● Mean follow-up was 7.7 years (1,609 patient-years) Bernaudin F, et al. Blood. 2011;117:1130-40.
  86. 86. Cumulative risks● Cumulative risks by 18 years of age – stroke: 1.9% (95% CI 0.6–5.9) compared with 11% – abnormal T (95% CI 22.8–38) plateau at age 9 years – stenosis: 22.6% (95% CI 15.0–33.2) – SI: 37.1% (95% CI 26.3–50.7) age 14 years● Cumulating all events – the cerebral risk by 14 years of age was 49.9% (95% CI 40.5–59.3)● P di ti f t Predictive factors for cerebral risk f b l i k – baseline reticulocytes count – lactate dehydrogenase● Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by 18 years of age from 11% to 1.9%● In contrast the 50% cumulative cerebral risk suggests the need for contrast, more preventive intervention Bernaudin F, et al. Blood. 2011;117:1130-40.
  87. 87. Early TCD screening and intensification of transfusion therapy allows > 5x Cumulative risk Early TCD Screening Followed by reduction of py stroke risk by 18 years of age 100 100 %) A B ormal TCD (% 90 90 80 80 (abnormal MRA) (%) 70 70 nosis 60 60 50 50 M Risk of sten Risk of abno 40 40 30 30 20 20 10 10 0 0 R 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Number at risk Age (years) Number at risk Age (years) 217 216 186 154 120 94 82 77 67 57 50 44 39 29 24 132 132 131 128 114 96 79 67 60 53 49 38 28 20 17 silent stroke) (%) 100 C 100 D %) ) Risk of silent stroke (% 90 90 ke/abnormal 80 80 70 70 60 60 50 50 D/stenosis/s 40 CNS risk (strok 40 30 30 20 20 10 10 0 0 S TCD 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Number at risk Age (years) Number at risk Age (years) 129 129 127 125 112 94 76 63 51 43 40 33 25 17 13 217 215 184 155 126 96 74 69 58 47 42 39 36 27 23 Bernaudin F, et al. Blood. 2011;117:1130-40.
  88. 88. Ongoing studies● Positron emission tomography (PET) – preliminary results • 18 (60%) had abnormal MRI findings • 19 (63.3%) had abnormal PET findings • 26 (86.7%) had abnormal MRI, abnormal PET, or both ( ) , ,● Magnetic resonance angiography ag et c eso a ce a g og ap y Taher AT, et al. Blood. 2009;114:[abstract 4077].
  89. 89. Cardiac iron overload in 19 Lebanese TI patients Population: 19 transfusion independent TI patients vs 19 polytransfused TM patients Parameter TI (n = 19) TM (n = 19) p value Mean age ± SD, years 32.8 ± 7.9 33.0 ± 7.4 0.861 (range) (18–51) (17-49) Male/female M l /f l 11/8 11/8 – Mean Hb ± SD, g/dL 8.9 ± 2.3 9.9 ± 1.6 0.241 (range) (4.9–13.1) (7.1–12.2) Mean SF ± SD, µg/L 1,316.8 ± 652.3 3,723.8 ± 2,568.8 0.001 (range) (460–3157) (827–10,214) Mean LIC ± SD, mg Fe/g dry wt , g g y 15.0 ± 7.4 15.7 ± 9.9 0.095 (range) (3.4–32.1) (1.7–32.6) Mean cardiac T2* ± SD, ms 47.3 ± 7.1 21.5 ± 15.2 < 0.001 (range) (35.0–66.9) (35 0 66 9) (5.1–50.7) (5 1 50 7) Results: T2* was normal in all TI patients despite similar LIC with TMSF = serum ferritin. Taher A, et al. Am J Hematol 2010;85:288-90.
  90. 90. NTBI in TI 35 Splenectomized 3,500 Splenectomized Non-splenectomized Non-splenectomized 30 3,000 /L)LIC (mg Fe/g dry wt) 25 2,500 2 500 w Serum ferritin (µg/ 20 2,000 15 1,500 , m 10 1,000 y = 0.7787x + 6.7383 y = 74.121x + 728.69 5 500 R2 = 0.1301 R2 = 0.1556 0 0 -5 0 5 10 15 -5 0 5 10 15 NTBI (µmol/L) NTBI (µmol/L) Significant correlations were observed between NTBI and both serum ferritin and LIC, confirming the value of this method for assessing iron overload in TI Taher AT, et al. Br J Haematol. 2009;146:569-72.
  91. 91. Silent infarcts● Prevalence: 22% ● Risk factors – low haemoglobin● Fronto parietal areas Fronto-parietal – high reticulocytes● Associated with neuro- – seizures cognitive dysfunction – low rate of painful crises l f i f l i – leukocytosis● Deep white matter p – thrombocytosis – SEN haplotype● Small size – prior silent infarcts● Risk factor for stroke ● Management – transfusions ? SITT
  92. 92. Strokes are a devastating complication of SCDGeneralized brain atrophy in rare cases Rare venous system clots “borderzone” infarction Arteriolar thickening and capillary dilatation Small white matter lesions visible on MRI Cortical vessel dilatationLarge cerebral infarcts Lenticulostriate arteries form “moyamoya”Subcortical infarction Proximal arterial stenosis at ICA, MCA, ACA Intraventricular and Most common site of intraparenchymal occlusive disease is here haematoma Ophthalmic arterySubarachnoid haemorrhage Aneurysms, often multiplefrom aneurysm rupture on “circle of Willis” Dilatation of vertebrobasilar Fat embolism system due to collateral flow Cervical ICA usually unaffected
  93. 93. Transfusions after a stroke● There is often progression of vasculopathy●N New silent i f t il t infarcts● The reasons are not clear
  94. 94. Children with SCD receiving regular blood transfusion therapy for secondary py y prophylaxis of strokes 53 children enrolled 13 children excluded 40 children met criteria Second overt strokes for analysis (n = 7) No second overt strokes Silent infarcts (n = 33) (n = 8) TIAs without new No new MRI lesions MRI lesions TIAs ft TIA after silent infarct il t i f t (n = 1) (n = 21) (n = 1) TIAs with silent infarct on next MRI (n = 2)MRI = magnetic resonance imaging;TIA = transient ischaemic attack. Hulbert ML, et al. Blood. 2011;117:772-9
  95. 95. Survival free of new overt or silent cerebral infarcts in children with SCD while on transfusion therapy for secondary stroke prophylaxis 1.0 10 1.0 10 Proportion free of new silent Proportion fr of new 0.8 0.8 cerebral infarcts cerebral infarcts 0.6 0.6 ree 0.4 0.4 0.2 0.2 P 0 0 0 2 4 6 8 10 0 2 4 6 8 10 Time from initial stroke Time from initial stroke (years) (y (years)) 1.0 Proportion free of new 0.8 kes With cerebral vasculopathy overt strok 0.6 06 e 0.4 Without cerebral vasculopathy 0.2 P 0 0 2 4 6 8 10 Time from stroke (years) Hulbert ML, et al. Blood. 2011;117:772-9.
  96. 96. Survival free of detection of new silent cerebral infarcts in children with SCD while on transfusion therapy for secondary stroke prophylaxis 1.0 0.8 08 Proportion fre of new silent 0.6 w 0.4 cts ee bral infarc 0.2 No cerebral vasculopathy p y With cerebral vasculopathy cereb 0 0 2 4 6 8 10 Time from initial stroke (years) Hulbert ML, et al. Blood. 2011;117:772-9.
  97. 97. Coates TD. Blood. 2011;117:745-46.

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