SHOT Data. Why are SCT Patients a Special Group? Transfusion Problems in Stem Cell Transplant (SCT) Patients. BMT Patients are not a Special Group

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1 Transfusion Problems in Stem Cell Transplant (SCT) Patients Derwood Pamphilon Clinical Director Stem Cells NHS Blood and Transplant Bristol, UK Why are SCT Patients a Special Group? Severely immunocompromised Highly prone to infections viral, bacterial, fungal Susceptible to Graft v Host Disease (GVHD) Change of blood groups BMT Patients are not a Special Group SHOT Data Total ICBT ATR DTR PTP TA-GVHD TRALI TTI Administration of wrong blood (ICBT) Acute/delayed transfusion reactions Alloimmunisation to HLA and subsequent platelet transfusion refractoriness Transmission of infection TA-GVHD Febrile reactions (FNHTR) TRALI Death Major Total

2 Regulations the EU Directive on Blood and Blood Components Regulations the EU Directive on Blood and Blood Components The EU Directive 2002/98/EC sets standards for the collection, testing, processing, storage and distribution of human blood and blood components The fate of each unit of all blood components should be recorded and this record kept for 30 years. i.e. vein-tovein traceability Robust Quality Systems should be in place It requires that Blood Establishments should be licensed and this is of importance for both Blood Centres in EU countries that undertake these activities as well as hospitals that collect and issue e.g. granulocytes for transfusion The processing of blood and blood components should be undertaken by licensed blood establishments Training should be provided for hospital transfusion laboratory staff Haemovigilance systems should be established to include the reporting of adverse events Components For Transfusion Platelet Transfusion Key Questions Red Cells - correction of anaemia Platelets - correction of thrombocytopenia/abnormal platelet function with bleeding Need to consider: Dose given Frequency Threshold for use What are the correct transfusion thresholds? Should prophylactic transfusions be given? Is there evidence to support current practice? FFP - management of bleeding with abnormal coagulation Co-administration of other products Granulocytes - prophylaxis/ therapy of infection Assessment of efficacy 2

3 Prospective RCTs of platelet transfusion Cochrane Systematic Review Platelet Transfusion Thresholds in SCT Zumberg et al 8 reports reviewed 3 older studies prophylactic v therapeutic 3 contemporary studies compared 10 v 20 thresholds. No differences in mortality, remission rates, severe bleeding, red cell transfusion requirements 3 investigated the effect of different platelet dose schedules insufficient data to make clinically relevant conclusions No reasons to change practice Consider adequately powered studies of prophylaxis v therapeutic transfusion Prospective RCT included 159 SCT patients 10 v 20 threshold for prophylaxis 2 groups matched patient and SCT characteristics Major bleeding 14% v 17% CNS bleeds 2 v 1 Bleeding deaths - none Bleeding days in both Platelet transfusions v 10.2 No significant differences Stanworth et al, Cochrane Database Syst Rev, 2004 Biol Blood Marrow Transplant 2002,8, Mechanisms of Alloantibody formation Leucocyte Depleted Blood Components DC in transfused blood components interact with recipient T cells Leads to HLA antibody formation DC removal by filtration or inactivation using UVB irradiation minimizes alloimmunisation Reduce HLA - alloimmunisation and platelet transfusion refractoriness Lessen graft rejection in SAA patients Reduce occurrence of FNHTR Minimize CMV transmission Do not prevent TA-GVHD - however only 2 SHOT reports since LD 3

4 Are Leucocyte Depleted Components still indicated in Aplastic Anaemia (AA)? Trial to Reduce Alloimmunisation to Platelets (TRAP) Study Historically transfusion associated with higher rates of graft rejection in AA patients (mha sensitisation) Impact of LD in the modern era where buffy coat transfusions rarely given and supportive care delivered to a higher standard? Study of 24 transfused AA patients: 16 no HLA antibodies 8 had HLA T6379 Txs given to 533 patients Response better: splenectomy, increasing age Response worse: 2+ pregnancies, Male, splenomegaly, bleeding, fever Infection, DIC, presence of HLA antibodies, more transfusions, heparin, amphotericin 2/16 formed HLA antibodies at 9(1-15) months but not refractory 3/8 HLA antibodies disappeared using HLA matched LD components; controls 50% HLA antibody + Suggests that patients with AA should receive LD components from diagnosis Killick et al, Br J Haematol, 1997 TRAP Study Group, NEJM,1997,337, TRAP Study Cytomegalovirus (CMV) Highly cell associated; persists in latent state Transmitted by transfusion Seroprevalence: varies 50-98% HLA antibody+ excluded Causes severe infections in BMT patients Slichter s et al, Blood,2005,105, Transmission can be minimized by serological testing or LD 4

5 CMV Infection Risk of transfusing CMV unscreened blood components (BC) to -/- transplants is 32-37% CMV negative products have minimal impact if donor positive Present in CD34+ and CD33+ cells; productive infection via monocytemacrophage lineage Problems interpreting existing studies relate to era, type of process e.g. LD, patient group not all SCT, CMV infection v CMV disease CMV Intervention Studies in SCT patients CMV negative or No. of CMV CMV Ref. LD patients infection disease 1. CMV- 252* 4(1.4%) 0 Bowden 1995 LD 250* 6(2.4%) 6(2.4%) Bowden BOTH 33 3% 0 Ljungman 2004 LD 49 6% 0 Ljungman (a) CMV -/LD CMV (1.7%) 0 Nichols 2003 (b) CMV -/LD CMV+/aph PC (4%) 1 Nichols CMV (0.9%) 0 Foot 1998 Total (1.5%) 7(0.46%) * secondary end point 5

6 THE BOWDEN STUDY The Nichols Study CMV-related deaths only in LD group Patients pre-transplant serostatus not always clear Transfusions not leucocyte depleted prior to storage Bedside LD doesn t work for alloimmunisation* *HLA antibodies in 37.5% NF v 22% F (p=0.07) FNHTRs in 37% NF v 34% F (p=0.71) Blood product support per patient during the first 100 days after transplantation in period 1 and period 2 Blood product Period 1 (±SE) Period 2 (±SE) p Total units 23.7 ± ± Total red blood cell 10.5 ± ± (RBC) units Filtered RBC units from CMV + donor 0.08 ± ± Total platelets (PLT) 13.2 ± ± Filtered pooled PLT donor 0.16 ± ± from CMV + LR apheresis PLT from CMV + donor ± 0.2 (8.2%) <.001 Total filtered products from CMV + donor 0.24 ± 0.05 (1%) 0.41 ± 0.06 (9.88).03 CMV indicates cytomegalovirus; SE, standard error; LR, leukoreduced. * Period 1: April 1994-November 1996, N = 360 patients. Period 2: December 1996-February 2000, N = 447 patients. Table reports units of product (ie, one unit from one donor). For pooled platelets, one "unit" represents pool of 6 random concentrate CMV status of pool is positive if one unit in pool is positive or unknown. RECOMMENDATION - either approach is acceptable *Williamson et al, 1998, Blood Nichols et al, 2003 Nichols et al, 2003 Not a PRCT Probabilities of CMV infection very low 1.7% v 4.0% (p=0.05) Only 1 patient developed CMV disease with monitoring and use of ganciclovir Authors conclude that their report should spur further investigation 6

7 Review and Meta-analysis of CMV negative and LD blood components TA - GVHD 1/3 studies showed benefit for CMV negative v LD components META-ANALYSIS: risk reduction (RR) v control for CMV negative= 93.1%; RR for LD = 92.3% Caused by transfused alloreactive lymphocytes Invariably fatal: 13/13 SHOT reports over 8 years CMV negative v LD gave RR for CMV negative of 58% suggesting that these are more efficacious in preventing acquired CMV infection Problems era, not all SCT patients, methodological issues Vamvakas, Transfus Med Rev, 2005 Prevented by 2500cGy gammairradiation, X-irradiation Also likely to be prevented by photochemical treatment Strategies for Prevention of TA- GVHD Blood Component Irradiation: BCSH Guidelines Gamma-irradiation (min 2500 cgy)is the standard of care Allogeneic HSC recipients from conditioning for 6 months or until L = 1 x 10 9 /L and no a/c GVHD Allogeneic HSC donors but little autologous blood X irradiation shown to be equally effective in leucocyte inactivation and component quality(raycell RS3000 used in Euroipe and US) Autologous HSC recipients for 3 months (6 months if TBI) All donations from HLA matched donors or 1st/2nd degree relatives All granulocyte transfusions Leucodepletion undoubtedly reduces but not totally protective? All patients with Hodgkins disease (not NHL) Patients treated with purine analogues, e.g. fludarabine Patients with congenital immunodeficiency status BCSH Updated Guideline (Draft),

8 TA-GvHD since the introduction of LD Granulocyte Transfusions Key Questions 13 cases of TA-GVHD reported to SHOT 11 non-ld; 2 LD Which products are available? No cases since non-irradiated transfusions to high risk recipients Prophylactic and/or therapeutic use? Included BMT, HD and fludarabine therapy (diagnoses in 62%) and no proven cases of GVHD SHOT data may be an underestimate Shapira et al, BMT, 2005 What are the toxicities? Is there data available to guide decision making? Williamson et al, Transfusion, 2007 Granulocyte Transfusions (GTX) Systematic Reviews of Granulocyte Transfusions (GTX) Pooled buffy coats optimised granulocyte component (OGC) Yield: non-mobilised <1 x mobilised usually >4 x Cochrane review of RCTs comparing GTX v control* 10 trials met criteria; 9/10 random allocation Non-mobilised apheresis granulocytes G-CSF mobilised granulocytes Consider fitness to donate, venous access, ABO, CMV, WBC compatibility Mobilisation steroids - G-CSF Adverse effects on the donor: - G-CSF-related e.g. bone pain - steroid-related e.g. insomnia - apheresis-related e.g. venepuncture All conducted >20 years ago except for 1 where G-CSF was used Relative risk (RR) of mortality 0.94 Excluding 2 studies with doses <1 x RR for mortality and mortality due to infection were 0.69 and 0.36 Suggests that prophylactic GTX may reduce mortality Cochrane Review of GTX as therapy in 8 trials including 310 patients evidence inconclusive due to heterogeneity in studies** Times change antibiotics, better supportive care *Massey et al. Cochrane Database Syst Rev, 2009; **Stanworth et al Cochrane Database Syst Rev,

9 Prophylaxis: Episodes of infection Prophylaxis: Mortality due to infection Therapy: Subgroup analysis of mortality: by dose Granulocyte Transfusions as Prophylaxis 22/16 allograft patients with proven/possible fungal infection Median 4 GTX with mean dose of 5.95 x Mean granulocyte increment 1.5 x 10 9 /L Significant reduction in - neutropenia - incidence/duration of fever - maximal CRP Some patients showed improved pulmonary infiltrates Stanworth et al 2005 Cochrane data base. FURTHER STUDIES ARE NEEDED Kerr et al, Br J Haematol, 2003; Robinson and Marks, BMT,

10 Granulocyte Transfusions as Therapy Transfusion in Sickle Cell Patients who undergo SCT Daily/ twice daily using family, friends and community-based donors 6 studies using G-CSF-mobilised GTX for neutropenic sepsis Most were small, single-centre studies with diverse haematological diagnoses, infections, lack of controls Largest, controlled study showed non-significant trend to worse outcome with GTX (Hubel et al, Transfusion, 2002) Remainder showed improvement Impact of GTX on clinical outcome currently unclear Unique transfusion characteristics including prophylaxis against stroke 27 SCD patients had MSD SCT using myeloablative conditioning between Extended red cell phenotypic matching in 6 alloimmunised patients [C, c, E, e, K, Fy(a), Jk(b)] Limited matching in 14 non-sensitised patients [ C, c, E, e, K] No phenotypic matching in 7 Tx requirements: Red cells 7(3-15); platelets 13.5(4-48) Increased red cell Tx in patients with SCT-related morbidity e.g. VOD Increased phenotypic matching reduced red cell transfusions Robinson and Marks, BMT, 2004 McPherson et al, Transfusion, 2009 Types of ABO incompatible BMT Problems in ABO Incompatible SCT Classified according to whether donor isohaemagglutinins, antigens or both are incompatible with the recipient Major patient has antibodies directed against donor RBC antigens e.g. A donor O recipient Failure of engraftment no Acute HTR when graft given - remove donor RBC or plasma Delayed erythropoiesis e.g. anti-a in recipient Minor donor has antibodies directed against recipient RBC antigens e.g. O donor A recipient Bidirectional e.g. A donor B recipient Delayed haemolysis - passenger lymphocyte syndrome; max d9-16 GITMO survey showed high heterogeneity of practice in testing, methods for dealing with ABO incompatible grafts and post-sct support* *Raimondi R et al, BMT,

11 Haemolysis in ABO Incompatible BMT Management of Graft in ABO Mismatched BMT The immediate risk of major ABO mismatch is haemolysis - high for bone marrow since volume of RBC is high (25-35% of component volume) - low for peripheral blood stem cells (PBSC) since volume of RBC is low (2-5% of component volume) Risk reduced by RBC removal from the graft Depends on isoagglutinin titre Risk of minor ABO mismatch is delayed haemolysis Major depends on graft volume and recipient anti-a,b titres If titres less than 1:32 infuse unmodified Small amounts of mismatched RBC are removed rapidly after infusion causing the titre to fall Higher titres remove red cells by sedimentation or using cell separators - deplete isoagglutinins in recipient by immunoabsorption or plasma exchange (where cell dose critical) Minor deplete plasma from the graft by centrifugation according to volume/titre Management of the Patient in ABO Incompatible BMT Management in ABO Incompatible BMT Pre-transplant blood group, antibody screen and isoagglutinin titres Patient must be well hydrated and carefully observed Watch for signs of immediate and delayed haemolysis Rowley SD, Bone Marrow Transplantation,

12 ABH Isoagglutinin Persistence after BMT Pure Red Cell Aplasia after BMT Slower in ABO mismatched v compatible BMT Slower if Reduced Intensity Conditioning (RIC) used Risk Factors include (i) the use of cyclosporin A (CSA) to prevent GvHD (ii) High initial or persistently elevated recipient anti-donor isohaemagglutinin titre (iii) RBC incompatibilty involving the A antigen Recipient haemopoiesis erradicated by conditioning and inhibition of donor red cells by persisting anti-donor isohaemagglutinin Rowley SD, Bone Marrow Transplantation, 2001 Glycophorin stain Reduced Intensity Conditioning (RIC) delayed donor red cell chimerism Delayed Donor Red Cell Chimerism - PRCA Comparison of RIC v MAT BMT where major ABO mismatch RIC MAT Total BMT ABO MM Evaluable PRCA occurred in 4 RIC patients These patients showed rapid donor chimerism in T cell and myeloid cells (mean 14 and 30 days) RIC fludarabine + cyclophosphamide MAT TBI + cyclophosphamide Outcome donor red cell chimerism delayed in RIC - delay correlated with host anti-donor isoagglutinin titres - titres decreased more slowly in RIC - PRCA in 4/14 RIC v 0/12 MAT Anti-donor isoagglutinins >1+ : 166 days ( ) Red cell chimerism delayed for 181 days ( ) PRCA resolved with CSA discontinuation 3/4 + PEX in1/4 Patients failed to respond to EPO Bolan et al, Blood, 2001 Bolan et al, Blood,

13 RIC v MAT: Red Cell Usage Passenger Lymphocyte Syndrome (PLS) Haemolysis of patients red cells after BMT by graft produced isoagglutinins Passenger B lymphocytes in the graft are restimulated by host AB delayed and sometimes massive haemolysis May be fatal; occurs maximally d 9-16 Rarely seen where BM grafts T cell depleted with alemtuzumab (anti B cell effect) Mijovic et al, Br J Haematol, 2008 Post graft methotraxate and mycophenelate mofetil (MMF) may reduce RIC More Haemolysis in ABO minor mismatched BMT? Effects of ABO Incompatibility on BMT Outcome RIC associated with reduced overall red cell and platelet transfusion requirements ABO mismatched RIC associated with higher transfusion requirements, more haemolysis and cases of PRCA (as in myeloablative SCT) Worel et al* suggested that PLS might be worse in the setting of RIC 32 patients RIC allogeneic PBSCT; 10/30 had minor mismatch; 5/10 had severe haemolysis and 3 died Introduced prophylactic red cell exchange in next 20 patients 1/20 showed signs of mild haemolysis *Worel et al,transfusion, 2007 Red cell antigens are not major histocompatibility antigens Most reports show no difference in overall survival (OS), treatment-related mortality(trm), graft rejection or GvHD e.g. Seebach et al 3103 patients: 2108 identical minor major bidirectional JMDP ABO mismatch reduced OS, increased TRM, delayed trilineage engraftment and increase severe GvHD (Kimura F, Haematologica, 2008) 13

14 ABO Incompatible SCT - Blood Groups to Transfuse Outcome after ABO mismatched BMT Seebach et al, Biol Blood Marrow Transplant, 2005 Need to consider donor and patient ABO groups Depends on whether red cells, platelets or FFP Check for disappearance of antidonor ABO antibodies, the antiglobulin test and disappearance of recipient type red cells ABO Incompatible SCT Transfusion Support Summary and Future Directions SCT patients are highly immunocompromised Susceptible to all complications of transfusion Particular challenges include changing blood groups, prevention and management of infection, need for irradiated blood components Clear policies for transfusion and regular audit of outcome are essential 14

15 Thank You 15