Users Group Meeting / Immutech Workshop Thursday, June 18, 2015 - PowerPoint PPT Presentation

IMMUCOR Users Group Meeting / Immutech Workshop Thursday, June 18, 2015 Chronic Transfusion: Indications and Complications Naomi L. C. Luban, M.D. Director, Transfusion Medicine / The Edward J. Miller Donor Center Vice Chair for Academic Affairs, Children's National Medical Center Professor, Pediatrics and Pathology George Washington University School of Medicine

Pathophysiology of Anemia Requiring Chronic Transfusion Beta-Thalassemia major and complex hemaglobinopathies - Dyserythropoiesis Sickle Cell Disease (SS, SB 0 Thal, SC) - Complications of vaso-occlusion and inflammation Myelodysplastic Syndromes / Constitutional Hypoplastic Anemias - Ineffective hematopoiesis Malignancies: ALL, AML, some solid tumors - Hypo/aplasia due to therapy

Thalassemia is a Systemic Disease

Sickle Cell Disease is a Systemic Disease

Sickle Cell Disease – Global Distribution 1/10 African American and 1/1000 Hispanic Americans / Latinos has SCT Found in people of Mid-east, Asian, Indian and Mediterranean descent

“Pathophysiology” of Transfusion Leading to Beneficial Effects In SCD In CHA  Decrease % S by dilution   “Normalize: hemoglobin   Improve oxygen delivery   Inhibit erythropoiesis  Decrease sickle cell adhesion and plasma microenvironment

Justification for Appropriateness of Transfusion Prophylactic perioperative transfusion Acute complications of disease • Acute chest syndrome • Splenic and hepatic sequestration • Stroke • Intra-hepatic cholestasis • Aplastic crisis / symptomatic anemia • Multisystem organ failure Chronic complications of disease • Transcranial Doppler of > 200 cm/sec • Overt stroke

Major Clinical Trials Addressing Transfusion: Evidence Based Chou S.T. ASH Education Book December 6, 2013 vol. 2013 no.1, pgs. 439-446

Complications of Transfusion  Iron overload and further organ damage  Allo / autoantibody formation  DHTRs / Hyperhemolysis  Transfusion-related infections  CVL thrombosis  Immune dysregulation  TRALI  Others yet to be identified - Emerging infections - Pulmonary hypertension

The Problem of RBC Alloimmunization and Chronic Transfusion Occurs in up to 30% of chronically transfused patients - Older studies quote higher rates - Some include pregnant women Causes delayed hemolytic transfusion reactions - Contributes to morbidity Associated with delays in finding blood - Contributes to mortality Likely results in shortened RBC survival and iron overload - Multisystem organ dysfunction

Post-Transfusion Alloimmunization Rates: Selected Studies in SCD Author / Year Group % Alloimmunized Per Unit % Prevalence DHTR Orlina, 1978 Adult SCD 36 Sarnaik, 1986 Pediatric SCD 7 30 † Cox, 1988 Adult SCD 30 3.1 4 Vichinsky, 1990 Adult SCD 34 } 11 Pediatric SCD 24 Pediatric Anemia ‡ 5 Rosse, 1990 Pediatric & 18.6 * Adult SCD Miller , 2013 Pediatric 14 † of those initially sensitized and re -exposed to transfusion. ‡ non -black pts with chronic anemia * exponential rise with more transfusions; usually occurring with >15 txns .

Post-Transfusion Alloimmunization Rates: Selected Studies in Thalassemia Author / Year Number % Alloimmunized Location Thompson, 2011 697 16.5 US Pahuja, 2010 227 3.87 India Sadeghian, 2009 313 2.8 Iran, north Karimi, 2007 711 5.3 Iran, south Bhatti, 2004 161 6.8 Pakistan Spanes, 1992 1135 22.6 Greece

Some Interventions for RBC Alloimmunization Risk Reduction: Mixed Success Phenotypically match donors and recipients Reduction from 3.0 to 0.5% per unit transfused in 63 children Vichinsky. Transfusion. 2001;41:1068 Recruit African-American donors Castro. Transfusion. 2002;42:684 More fully phenotypically match donors and recipients Reduction from 28 to 7% in 99 adults LaSalle. Transfusion. 2011;51:1732 Limit donor exposure through “Buddy” programs and iron overload Luban and others. Immunohematology. 2012;28:13

Strategies to Prevent Alloimmunization C, E, K or more substantive phenotyping and matching O’Suoji et al. Pediatric Blood Cancer. 2013;60 (9):1487 Identification of “immune” responders Tatari-Calderone et al. Clin Dev Immunol. 2013;2013:937846 Fasano RM et al. Br J Haematol. 2014 Sep 26. [Epub ahead of print] Molecular RBC blood group typing Chou et al. Blood. 2013 Aug 8;122(6):1062-71 Pathobiology and mechanistic studies in mouse / animal models Zimring et al. Transfus Clin Biol. 2012:19(3):125 Major topic of NHLBI supported State of the Science, March 25-26, 2015

Why Do Some But Not All Patients Become Alloimmunized? Genetic Underpinnings of the Problem Age at first transfusion:? number of transfusions Antigen disparity between donors of European ancestry and recipients of African and Afro-Caribbean ancestry Immune responder vs. non-responder phenotype • TRIM 21 • SNPs in CD81 gene • HLA-B235; HLA – Cw4 • Toll-like receptor gene Future large scale GWAS using Afro-centric SNPs may help with better identification

Why Not Provide Fully Phenotypically Matched Transfusions for All Hemoglobinopathy Patients Access to appropriate donor pool Logistical issues, especially during emergencies - Patients use multiple ERs, hospitals - No centralized patient registries of phenotype or antibodies Lack of consensus on when to initiate matching - No study has evaluated phenotypic matching, from first transfusion to confirm efficacy Need to use “older” RBC products - ?More microparticles, more alloimmunization? - “Fresh blood” requests Cost to the Transfusion Service vs. reimbursement from insurers 19

Challenges in Antigen Phenotyping: Estimating the Matching Pool Patients with SCD Donor requirements for phenotype matching whose alloantibodies would have been Phenotype frequency‡ in prevented, if a matching protocol African- Had been used, White donors American donors Phenotype-matching protocol n (%)* n (%)† Phenotype (%) (%) ABO and D, only None 249 (70.9) ABO and D, only N/A N/A (current study) Protocol 1 51 (37.2) 289 (82.3) D+C−c+E−e+(R 0 )§ or 3.2 42.3 D, C, c, E, e D−C−c+E−e+(rr) § 15.0 N/A Protocol 2: 73 (53.3) 307 (87.5) D−C−c+E−e+, K− 13.6 41.2 D, C, c, E, e, K Protocol 3: 76 (55.5) 310 (88.3) D−C−c+E−e+, K−, S− 6.1 28.4 D, C, c, E, e, K, S Protocol 4: 86 (62.8) 320 (91.2) D−C−c+E−e+, K−, 2.1 25.6 D, C, c, E, e, K, S, Fy a S−, Fy(a−) Protocol 5: 97 (70.8) 328 (93.4) D−C−c+E−e+, K−, 0.6 14.6 D, C, c, E, e, K, S, Fy a , Jk b S−, Fy(a−), Jk(b−) * Percentage of 137 patients with SCD who received transfusions who formed alloantibodies. ‡ Phenotype frequencies were calculated from tables in the Technical Manual 12 and from D− frequency in unselected plateletpheresis donors. † The number of all patients who received transfusions (351) is used as the denominator. § Most transfusion services select D−(rr) RBC units for D+ recipients who require C−E− RBCs. Castro. Transfusion. 2002;42:684

Donor Recruitment and Provision of Rh, K Antigen Negative RBC Units “Buddy Programs”

Discrepancies Between Molecular and Serological Testing The Argument for Molecular Matching Year Author Patient Diagnosis Comment 2013 Bakanay Beta-thalassemia 19/57 discrepancies and SCD In 12, potential alloimmunization 2013 La Costa SCD 21/35 discrepancies 8 Rh alloimmunized with Rh variants 2014 Rampersad MDS 3/15 discrepancies Used buccal swabs successfully in over 90 cases 2014 Rujirojindakul Beta-thalassemia 7/10 discrepancies Serological discrepancies also noted in 32/100 assays 2015 Casas J SCD 71 typing discrepancies 2015 Guelsin MDS 17/43 discrepancies Rh, K matching alone would meet needs

Preparing for Arguments Against Molecular Matching Molecular phenotyping is a “prediction” - Will fail if allele carries an unexpected inactivating mutation not tested for Everyone has access to and knowledge of serological methods and their pitfalls - Molecular testing requires specialized equipment and technical expertise Molecular testing is time consuming, especially if using a reference lab - Substantive delay in blood product provision Cost Wagner F. Blood Transfusion. 2014;12:1 Kacker S. Transfusion. 2014;54:86 and 54:2034

Preparing for Arguments For More Substantive Molecular Matching High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors Study design: 15 year retrospective review of 182 SCD patients transfused with units serologically matched for D,C,E and K from African American donors Bottom line: Variant Rh alleles in 87% of patients Chou ST. Blood 2013;122:1062

Rationale for Recruiting Donors Specifically for Patients with Hemoglobinopathies Transfusion of C, E, K and more fully phenotyped RBCs a major mainstay of current therapy - Molecularly type all repeat “Buddy” donors Diverse donor populations required to fill current and future needs - More diverse phenotypes Donor recruitment will mandate younger donors, many of whom are of mixed race and of child bearing age