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

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

IMMUCOR Users Group Meeting / Immutech Workshop Thursday, June 18, 2015

Chronic Transfusion: Indications and Complications

Pathophysiology of Anemia Requiring Chronic Transfusion

Beta-Thalassemia major and complex hemaglobinopathies

• Dyserythropoiesis

Sickle Cell Disease (SS, SB0Thal, 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

• f 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

Chou S.T. ASH Education Book December 6, 2013 vol. 2013 no.1, pgs. 439-446

Major Clinical Trials Addressing Transfusion: Evidence Based

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

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 Pediatric SCD Pediatric Anemia ‡ 34 24 5 }11 Rosse, 1990 Pediatric & Adult SCD 18.6

*

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 SCD

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

Post-Transfusion Alloimmunization Rates: Selected Studies in Thalassemia

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

• f 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

19

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

Phenotype-matching protocol n (%)* Patients with SCD whose alloantibodies would have been prevented, if a matching protocol Had been used, n (%)† Donor requirements for phenotype matching Phenotype Phenotype frequency‡ in White donors (%) African- American donors (%) ABO and D, only None (current study) 249 (70.9) ABO and D, only N/A N/A Protocol 1 D, C, c, E, e 51 (37.2) 289 (82.3) D+C−c+E−e+(R0)§ or 3.2 42.3 D−C−c+E−e+(rr)§ 15.0 N/A Protocol 2: D, C, c, E, e, K 73 (53.3) 307 (87.5) D−C−c+E−e+, K− 13.6 41.2 Protocol 3: D, C, c, E, e, K, S 76 (55.5) 310 (88.3) D−C−c+E−e+, K−, S− 6.1 28.4 Protocol 4: D, C, c, E, e, K, S, Fya 86 (62.8) 320 (91.2) D−C−c+E−e+, K−, S−, Fy(a−) 2.1 25.6 Protocol 5: D, C, c, E, e, K, S, Fya, Jkb 97 (70.8) 328 (93.4) D−C−c+E−e+, K−, S−, Fy(a−), Jk(b−) 0.6 14.6 * Percentage of 137 patients with SCD who received transfusions who formed alloantibodies. ‡ Phenotype frequencies were calculated from tables in the Technical Manual12 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

Challenges in Antigen Phenotyping: Estimating the Matching Pool

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 and SCD 19/57 discrepancies 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

Unanswered Questions

• Why has leukodepletion not

stopped the development of alloantibodies

• What is the economic and

supply-based effect of imposing phenotypic and molecular matching and what effect will it have on rapid RBC availability

• How can we protect those

individuals with alloantibodies from inadvertently getting inappropriate RBCs

Unanswered Questions

• What defines the immunologic

predisposition to RBC alloantibody formation? What is the importance

• f T regulatory cells?
• Can molecular typing especially for

Rh variants identify those at risk for alloimmunization?

• What are the long term effects of

RBC autoantibody formation: an epi phenomena or real disorder?

• Is there really a long term beneficial

effect of partial and / or full phenotypic matching? Are we predisposing patients to rare alloantibodies which will further complicate their transfusion needs?