Management of Sickle Cell Disease

Transcription

1 Management of Sickle Cell Disease A.Ferster HUDERF-ULB 29 th BHS meeting Friday 31 January 2014

2 Introduction > affected births each year 2000 births in US 15 births/y in Belgium Pts in US >> 600 pts in Belgium

3 Pathophysiology Stuart et al. Lancet Rees et al. Lancet. 2010

4 Pathophysiology Endothelial dysfunction Reducued NO bioavailability Enhance adhesion of PMN and reticulocytes Proinflammatory State Activation of the coagulation system

5 Clinical symptoms, complications and survival

6 Complications of SCD: childhood and adulthood Kanter J. Blood Reviews

7 Clinical symptoms, complications and survival 95% of children survive to adulthood Death rate in children ~ 0.5/100 pts-year Death rate is adults ~ 5/100 pts-year Transition period at risk ++++ Quinn et al. Blood Lanzkron et al. Public Health Rep Yanni et al. J Pediatr Blinder et al. Pediatr Blood Cancer Seth et al. Haematology. 2013

8 Trends in age-specific death rates from SCD Mean age at death: 36 y in women 33 y in men Hamideh et al. Ped Blood Cancer.2013 Lanzkron et al Yanni et al. Journal of Pediatrics. 2009

9 Management Prevention education Treatment of acute events Treatment of complications Disease modifying therapy Hydroxyurea Chronic transfusion (or exchange) Hematopoietic stem cell transplantation

10 Management: Prevention Education and information Good lifestyle and avoidance of hypoxia, dehydratation, cold exposure, Recognize an acute complication Folic acid Prevention of infection Prophlyactic antibiotics Vaccination Streptococcus pneumonia, Haemophilus influenzae, Flu Emipiric antibiotherapy Prevention of stroke Treatment of asthma

11 Prevention of stroke Cerebral vasculopathy Stroke (Ischemic or hemorragic) Seizures Silent infarcts Cognitive impairement Switzer 2006 Stenosis or occlusion of the internal carotid arteries (ICA), the anterior (ACA) and middle cerebral arteries (MCA)

12 Transcranial doppler Measure of the time averaged maximal velocity (TAMX) in the cerebral arteries (ICA,MCA and ACA) using a 2 MHz pulsed doppler. Correlation between the stroke risk and the velocity in the internal carotid and middle cerebral arteries Adams < 170 cm/sec cm/sec : RR x cm/sec : RR x 40

13 Prevention of Stroke Children with elevated cerebral flow velocity are at risk of stroke Risk stroke prevented by chronic transfusion Evaluation of stroke risk by TC Doppler STOP Study Adams et al. N Engl J Med.1998

14 Treatment of acute events PAIN Vaso-occlusive crisis Rapid and aggressive pain management Hydratation Transfusion Not the treatment of isolated pain crisis! Risks: Iron overload (>20 TF) Infection Allo-immunisation Benefit Transfusions: Simple TF Exchange TF ( manual or automated)

15 Transfusion in SCD: Indications Acute: Acute exacerbation of anemia (splenic sequestration, aplasic crisis) Acute chest syndrome if oxygenation compromised Stroke (EXT) to HbS < 30% and progression of cerebral ischiemia Chronic: Primary and secondary stroke prevention (EXT) (STOP Study TwiTCH Study) duration? Recurrent ACS severe crisis despite HU (EXT) Repeated acute splenic sequestration Prevention of progressive organ damage (??) Smith-Whitley et al. Peditr Blood Cancer Adams et al. N Engl J Med Vichinsky et al. N Engl J Med Miller. Blood Brousse et al. Br J Haematol Hb level < 11g/dl

16 Transfusion in SCD: Complications Iron overload Prevented by partial exchange (manual or erythrocytapheresis) RBC allo-immunisation, mainly Rh, Kell, Jk, Duffy ( if extended phenotype C, E, K buit still high) Multifactorial Discrepancy between D and R antigen expression Genetic heterogeneity of the Rh system Extended phenotype - Molecular blood group antigen typing Delayed Hemolytic Transfusion Reaction (DHTR) might be life-threatening!!! and worsens with further transfusions Chou et al. Br J Haematol Chou et al. Blood De Montalembert et al. Haematologica. 2011

17 Management Prevention education Treatment of acute events Treatment of acute events Disease modifying therapy Hydroxyurea Chronic transfusion (or exchange) Hematopoietic stem cell transplantation

18 Effects of hydroxyurea Hydroxycarbamide : inhibitor of ribonucleotide reductase Dosage: mg/ kg up to tolerated maximal dose, once a day CBC every 3 months recommanded (useful??) Steinberg. N Engl J Med. 1999

19 Hydroxyurea in SCD MSH study RDZ patients: 299 Trial prematurely stopped CVO, ACS and TF Charache et al, NEJM 1995 Tolerance Well tolerated Low hematological toxicity Skin rash Hyperpigmentation Nausea

20 Baby-HUG study Randomized Study (HU versus placebo) to assess the effect of HU on organ dysfunction and clinical complications Wang et al, Lancet Baby-HUG study Age at randomization: 9 to 18 months (n=193) BABY-HUG Study Hydroxyurea Placebo p splenic function 27% 38% ns glomerular filtration 18% 17% ns Howell Jolly bodies 106% 197% 0,04 Pain episods ,004 Acute chest syndrom ,02 Transfusions ,03 Cerebral velocities (cm/sec) ,0002

21 Summary of indications of HU therapy Probable indications > 2 VOC / year > 2 Acute Chest Syndrome Multiple osteonecrosis Hemoglobin level < 7g/dL Stroke Micro-albuminuria or evidence of renal disease Chronic pain TRV >2.5 m/sec or evidence of PHT Moderate Sickle Cell lung disease Chronic hypoxemia Stroke prevention? (SWiTCH and TWiTCH studies) Rees. Haematologica Ware. Blood Ware. Blood. 2012

22 Safety of HU Genotoxicity?

23 The effect of hydroxcarbamide therapy on survival of adults with SCD Voskaridou E, Christoulas D, Bilalis A, 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. 2010;115(12): Hydroxyurea improves survival across SCD phenotypes (40) Legend: (A) Patients with HbS/β 0 thalassemia and hydroxyurea exposure had improved 10-year overall survival (OS) compared to patients without hydroxyurea exposure (87% vs. 54%, p=0.001); (B) HbSS patients receiving hydroxyurea had a 10-year OS of 100% compared to 10% in those without hydroxyurea exposure (p<0.01).

24 The effect of hydroxcarbamide therapy on survival of adults with SCD MSH study: efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia Steinberg. Am J Hematol 2010 FU (17Y) during which they could start or stop HU Mortality: 43.1%; 4.4 per 100 person-years 87.1% occurred in patients who never took HU or took it for < 5 years

25 The effect of hydroxcarbamide therapy on survival of children with SCD Lopes de Castro Lobo. Br J Haematol children / 267 on HU Data on mortality collected 9y after the start of Paediatric Hydroxycarbamide Program 38 deaths

26 The effect of hydroxcarbamide therapy on survival of children and adults with SCD Lê. ASH abs Belgian Registry: 470 patients prospectively followed 6 centers Median age at entry: 0.7 y Mean FU: 8.1 y 3810 pts-years 181 pts on HU 91 pts transplanted

27 HSCT in Sickle Cell Disease Trans Am Clin Climatol Assoc 1990 BONE MARROW TRANSPLANTATION IN FIVE CHILDREN WITH SICKLE CELL ANAEMIA C. Vermylen, J. Ninane, E. Fernandez Robles and G. Cornu The Lancet. 1988

28 Benefits/risks after HSCT for SCD No more vaso-occlusive crises/ SCD related events Correction of anaemia Improved quality of life Stable cerebrovascular disease Stable or improved sickle lung disease Recovery of splenic function Normal growth BUT: cgvh Impaired fertility

29 HSCT in Sickle Cell Disease Indications for genoidentical Tx: Stroke Elevated TCD velocity Recurrent acute chest syndrome* Recurrent VOC* Silent stroke with cognitive impairment Pulmonary HT Sickle lung disease with hypoxemia Sickle nephropathy Multiple osteonecrosis RBC alloimmunisation Recurrent priapism Walters. NEJM Shenoy. Hematology Locatelli. Pediatr Blood Cancer Gluckman. Hematology.2013 Hsieh. Blood * On hydroxyurea at MTD?

30 HLA identical sibling HSCT in SCD Vermylen (BMT 1998) Walters (Blood 2000) Bernaudin (Blood 2007) Panepinto (BMT 2005) Dedeken (Br J Haematol 2014) Pts (N) Conditioning BuCY BuCy BuCy BuCy BuCy EFS 82% 84% 91%* 85% 86 97% OS 95% 94% 96%* 96% 94 97% * Since the addition of ATG

31 Incidence of rejection in patients conditioned with and without antithymocyte globulin (ATG)-at 5 years 2.9% with ATG versus 22.6% without (P =.002) Bernaudin et al (Blood 2007)

32 Are results better in younger patients?

33 HSCT in Sickle Cell Disease 1238 patients transplanted worldwide (EBMT Eurocord IBMTR) Gluckman E. Hematology. 2013

34 HSCT with alternative conditioning Ianone BBMT 2003 Hsieh (NEJM 2009) Bolanes-Mead (Blood 2012) Pts (N) Age Children Adults Adults Donor HLA-Id Sib HLA-Id Sib Haplo-Id. Stem cell source BM/PBSC PBSC BM (+ G-CSF) Conditioning Flu-TBI 2Gy-ATG TBI 3Gy Alemtuzumab GVHD prophylaxis Tacro MMF or CsA - MMF Sirolimus ATG CPM Flu TBI 2Gy MMF Sirolimus CPM post Tx EFS OS

35 HSCT with alternative donors Unrelated Cord Blood - registries survey 16 pts UCB EFS: 50% Higher engraftment rate if TNC > /kg Ruggieri et al. Biol Blood Marrow Transplant 2011 SCURT Study (Sickle Cell Unrelated donor Transplant trial) Alemtuzumab Fludarabine Melphalan 3/8 alive w/o graft failure STOP Kamani. Biol Blood Marrow Transplant Other.. Bu Flu - Alemtuzumab: 8 pts EFS: 50% and OS: 62.5% Radhakishnan. Biol Blood Marrow Transplant. 2013

36 HSCT in Sickle Cell Disease Gluckman. Hematology.2013

37 HSCT in Sickle Cell Disease Bernaudin and Kuentz. Blood.2012

38 Future directions North South partnership Development of new drugs targeting inflammation, NO metabolism, coagulation, endothelial adhesion,. Expansion of HSCT possibilities MAC in children and adolescent («standard practice») Less toxic conditioning in adults with major organ impairement (in experimental setting only) Reduction of rejection risk if alternative donors pool (unrelated, haplo) (in experimental setting only) Gene therapy

39 Thank you!