Apheresis red cell exchange and transfusion therapy for management of sickle cell disease. Dr Paul Telfer

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1 Apheresis red cell exchange and transfusion therapy for management of sickle cell disease Dr Paul Telfer

2 OVERVIEW Pathophysiology and epidemiology Physiological and clinical considerations prior to transfusion Exchange transfusion Indications for transfusion including recent trials Conclusions

3 PATHOPHYSIOLOGY Polymerization and RBC/vascular interactions NO depletion

4 CLINICAL COMPLICATIONS Acute Infection (e.g. pneumococcal) Dactylitis Acute pain crisis (APC) Acute chest syndrome (ACS) Aplastic crises: Parvovirus B19 Acute splenic sequestration Stroke (ischaemic and haemorrhagic) Bilary tract disease Visual loss-retinopathy Priapism Multi-organ failure Chronic Ischaemic brain damage Avascular necrosis Lower limb ulceration Cardiopulmonary- chronic sickle lung syndrome, pulmonary hypertension, myocardial ischaemia Renal impairment Chronic pain Psychological and psychiatric disorders

5 Newborn screening significant conditions Rates of significant conditions* per 1000 screened babies: April 2008 to March 2009 London South Central East of England West Midlands Unknown North West South East Coast East Midlands Yorkshire and The North East South West * Significant condition comprise FS, FSC, FS other, and FE In addition there were 23 F only results but these are not included Source: NHS Sickle Cell and Thalassaemia Screening Programme sct.screening.nhs.uk 5

6 Geographical distribution of patients with SCD: England London North Middlesex Leeds Manchester Newcastle Hillingdon Central Middlesex Ealing St Mary s University College Whittington Royal Free Great Ormond St Whipps Cross Royal London Newham Guy s & St. Thomas s King s College BHR River Thames QE Hospital, Woolwich Liverpool Birmingham Nottingham Milton Keynes Bristol Oxford Southampton Sheffield Reading Leicester Northampton & Kettering London Portsmouth Luton Cambridge Basildon and Essex Medway Maritime Hosp University Hospital, Lewisham St George St Helier Mayday University Hospital Number children with sickle cell disease > Plymouth <21 Unknown Source: Sickle Cell Anaemia Survey (May, 2008)

7 RATIONALE FOR TRANSFUSION Increase total Hb Dilute with HbAA RBC s Suppress endogenous HbS production Improve blood flow Improve tissue oxygen delivery Inhibit vaso-occlusion Prevent vasculopathy Prevent tissue damage

8 BASIC PRINCIPLES Swerdlow P. ASH Education session 2006 Pouseuille equation v= πpr 4 /8lη p = pressure r= radius l = length η = viscosity: Strongly determined by haematocrit and intracellular HbS HbS <30%

9 STEADY STATE Hb LEVELS Haemoglobin levels in 6 yr olds with HbSS in E London Cohort >11 Hb g/dl

10 TRANSFUSION TARGETS Hb 11 g/dl HbS 30% Clinical judgement

11 TRANSFUSION OPTIONS Acute transfusion Chronic transfusion programme Simple or exchange transfusion Exchange Partial or full volume Manual or automated

12 Automated versus Partial Manual RBCX Automated Effective at reducing and maintaining Hb S < 30% More blood Apheresis nurse and equipment Central venous access Anticoagulation for CVC Partial Manual Less blood exposure (2 3 U prbc) Can be achieved with peripheral veins Time intensive for nursing Risk of hypotension and symptomatic anemia during phlebotomy Both methods can maintain iron balance

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14 Erythrocytapheresis therapy to reduce iron overload Kim et al, Blood 1994

15 Options for venous access for apheresis Peripheral veins (often inadequate) Temporary central (femoral) line High flow double lumen port-a-cath AV fistula

16 NHS costs of manual and automated exchange transfusion Type Consumables Nursing Blood Total Manual (3 units) 537 Automated (6 units) 933 Current NHS tariff for exchange transfusion: 422 for adult 603 for child There is no tariff for automated exchange Blood is included in the tariff.

17 SEROLOGICAL ISSUES RBC antigenic disparity between African patients and caucasian blood donors eg ABO; Rhesus, Duffy, Kell Allo-immunization in >50% of chronically transfused in USA Reduced to 1 per 200 units by prospective RBC phenotype matching (Vichinsky et al, Transfusion 2001) Post-transfusion hyperhaemolysis in 1-2 %

18 INDICATIONS Acute complications Simple top-up Acute splenic sequestration Aplastic crisis Moderate Acute Chest Syndrome Usually requires exchange Severe acute chest syndrome Ischaemic stroke Fulminant priapism Multi-organ failure Acute painful crisis is not an indication for transfusion

19 ACUTE CHEST SYNDROME Mild: may not require transfusion Moderate: top-up transfusion or partial exchange: Hb should not rise beyond 11g/dl Severe: Exchange transfusion, HbS <30% Vichinsky et al, NEJM 2000 Swerdlow P. ASH Edu 2006

20 INDICATIONS Prevention of ischaemic brain damage Primary stroke prevention (Grade A, Adams et al 1998) Secondary stroke prevention (Grade B, Pegelow et al 1995)?Prevention of progression of silent cerebral ischaemia (SITT trial, reporting 2013)

21 Cerebral artery stenosis/occlusion on MRA No signal from L MCA

22 Acute ischaemic stroke R Middle Cerebral Artery occlusion

23 Silent cerebral infarction Official Report-Normal Official Report No- Change

24 SECONDARY STROKE PREVENTION No transfusion recurrence rate 30-70% Long-term transfusion HbS 30% recurrence 14-23% episodes per 100 patient years Pegelow et al, J Pediatr 1995 Scothorn et al, J Pediatr 2002

25 Stroke recurrence in SWiTCH Ware et al, Blood e-pub Feb 2012 All patients enrolled, 78% of pt years achieved 7 episodes of ischaemic stroke in Hydroxyurea/venesection (10%, 5.6 per 100 pt yrs) None in transfusion/chelation arm Still within margin of non- inferiority

26 No difference in LIC between two arms at first interim analysis at 30 months Study terminated on grounds of futility for composite primary end point Based on the SWiTCH trial results, transfusion and chelation remain the better way to manage children with SCA, stroke and iron overload..

27 Transcranial Doppler Scanning in children with SCD: Risk classification From Adams et al, Blood 2004; 103: 3689

28 Primary prevention of ischaemic stroke in children with abnormal TCD scan STOP Study. Adams et al, N Engl J Med randomised, 63 transfusions, 67 standard care 11 CVA (10 ischaemic) in standard care, 1 (1 ischaemic) in transfusion arm 92% difference in stroke risk Early termination of trial Recommendation of TCD screening and transfusion of children with abnormal TCD

29 Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease: STOP 2 N Eng J Med 2005; 353: 2769 Children with abnormal TCD, on transfusions >30 months with normalization of TCD and no severe stenotic lesion on Cerebral MRA Composite primary end-point of stroke or reversion to abnormal TCD 71 out of planned 100 enrolled 41 stop, 38 continue 14 reverted to abnormal TCD, 2 had CVA vs none in transfusion arm Early termination of trial Transfusions cannot be safely stopped even in children considered at low risk

30 Management of cases with abnormal TCD E London and Essex network. Telfer et al, BSH % 5% 3% 3% Transfusion Transfusion - hydroxyurea Transfusion-BMT Hydroxyurea Aspirin 86%

31 Results with implementation of TCD screening programme Setting Time period Number pts/pt yrs fu Rate of abnormal TCD Rate of Stroke per 100 pt yrs (95%CI) Bernaudin et al, Blood, e- pub 2010 Paris, regional centre / % 0.19 ( ) Enninful- Eghan et al, Journal of Pediatrics 2010 Philadelphia, regional centre / % 0.06 ( ) Telfer et al, 2011 E. London and Essex, Regional centre / % 0.13 ( )

32 Silent Cerebral Infarct Transfusion Trial: Multi-Center Clinical Trial Primary Hypothesis: Prophylactic blood transfusion therapy in children with silent cerebral infarcts will result in at least 86% reduction in the proportion of patients with clinically evident strokes, new or progressive silent cerebral infarcts

33 Other indications for regular transfusion Prevention of acute painful crisis and ACS (Grade B) Severe anaemia and renal dysfunction (Grade C) Maintenance of transplant renal function postallograft (Grade C) Recurrent lower limb ulceration (Grade C) Recurrent priapism (Grade C) Avascular necrosis of hips in childhood (Grade C)

34 Pre-Operative Transfusion Reduces Serious Adverse Events in Patients with Sickle Cell Disease (SCD) Results from the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) Randomised Controlled Multicentre Clinical Trial Jo Howard, Moira Malfroy, Charlotte Llewelyn, Louise Choo, David Rees, Isabeau Walker, Tony Johnson, Louise Tillyer, Karin Fijnvandraat, Melanie Kirby-Allen, Renate Hodge, Shilpi Purohit, Sally C Davies, Lorna M Williamson On behalf of the TAPS Principal Investigators With thanks to: NHSBT for sponsorship and funding, UK NIHR MCRN & CRN, Dutch MCRN and UK Sickle Cell Society

35 Primary Outcome and Serious Adverse Events (SAEs) Arm A Arm B Trial Arm No Pre-operative Pre-operative Overall blood transfusion blood transfusion Patients Recruited Patients with significant complications 13 (39.3%) 5 (14.7%) 18 (26.9%) OR 3.8 (CI ) p Patients with SAEs 10 (30.3%) 1 (2.9%) 11 (16.4%) 27.4% difference (CI ) P Patients with Acute Chest Syndrome 9 (27.3%) 1 (2.9%) 10 (14.9%)

36 Blood usage/patient year Drasar E et al. Br J Haematol. 2011;152: Increasing use of blood transfusions in adult patients. Kings College Hospital Total blood usage Blood usage: Acute Blood usage: Planned Blood usage: Exchange Blood usage: Top-up % of all patients received 1 unit blood in 10 years Significant increase in blood usage both for planned and acute sickle-related complications More indications : renal failure, ulcers, lung disease, priapism

37 CONCLUSIONS There are limited treatment options for SCD Transfusions are beneficial for acute and chronic complications There are increasing indications for chronic transfusion and a significant trend for increasing blood usage in UK for management of SCD Automated exchange transfusion is method of choice for maintenance of low Hbs% and avoiding iron overload Automated exchange is labour intensive, expensive, and technically challenging if venous access is poor To expand use of automated red cell exchange in the UK, a health economic assessment and national commissioning of specialised centres in UK is probably needed

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