Transfusion therapy: what is new with respect to safety and control of iron loading? Yesim AYDINOK

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1 Transfusion therapy: what is new with respect to safety and control of iron loading? Yesim AYDINOK

2 Following the Policy of the National Regulation 3.3, page 17, on CME disclosures, dated 5 November 2009, and on behalf of the Provider, - Collage S.p.A.- n. 309 I ( YESIM AYDINOK) HERE DECLARE DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS NO, have no relevant personal financial relationship in the medical/health field. DISCLOSURE OF PROMOTIONAL TALKS YES, I have presented promotional talks for one or more pharmaceutical companies within the past 12 months *if yes please provide information below. - NOVARTIS - CERUS I understand that continuing education accreditation guidelines prohibit me from accepting any reimbursement (financial, gifts or in-kind exchange) for this presentation from any source other than the accredited CME provider ( Collage S.p.A.) September, 2017 Yesim AYDINOK

3 Agenda Progress in safety of prbc therapy in thalassemia Prevention of transfusion transmitted infections Potential impact of Pathogen Inactivation Technologies on transfusion safety RBC antigen matching strategies and prevention of alloimmunization Molecular blood group antigen typing to enhance RBC matching Relevance of positive DAT with respect to detection of a delayed hemolytic transfusion reaction Changing trend on standard-of-care for transfusion in thalassemia What is new with respect to transfusion trend in thalassemia Potential clinical role of new indices (stfr, EPO, GDF-15, hepcidin) as indicators of erythropoiesis

4 Transmission for traditional transfusion-associated viruses Nucleic acid testing (NAT) has not completely eliminated window period for transfusion-associated viruses and residual risk of transmission Virus WP (days) for serology 1 WP (days) for ID-NAT 1,2 Risk of transmission in US 3 HIV-1 19 (p24; 15) : HCV : HBV : FDA licensed methods for infectious disease screening; Serology tests; HBsAg, anti-hbc, anti-hiv1/2, anti-hcv and HTLV-I/II NAT tests; HCV-RNA, HIV-RNA and WNV-RNA It is still impossible to know or reliably predict IF & WHEN emerging pathogens will threat the safety of blood supply TTI; transfusion transmitted infection 1. Kleinman SH, et.al.transfusion. 2009;49(11): Weusten J, et.al. Transfusion. 2011;51(1): Lindholm PF, et.al. Infect Disord Drug Targets. 2011;11(1):45-56.

5 Strategies to reduce TTIs; Donor deferral, testing procedures (serology based +NAT) & leukofiltration FDA licensed donor testing protocols for infectious disease screening; Serology tests; HBsAg, anti-hbc, anti-hiv1/2, anti-hcv and HTLV-I/II NAT tests; HCV-RNA, HIV-RNA and WNV-RNA Minimum risk category; HIV, HCV, HBV Bacteria Babesia-nonendemic area Maximum risk category; HIV, HCV, HBV Bacteria Babesia-endemic area New chronic EIA Diagnosis SCD Thalassemia Median RBC unit exposure (time) 24/year (30 years) 15/year (50 years) Total RBC (unit) Immune suppressed Aggregate risk per pt. (%) minimum maximum 720 asplenic 0.22 (1/450) (1/2) 750 splenectomy 0.23 (1/430) (1/2) TTI; transfusion transmitted infection EIA; emergent infectious agents Kleinman S & Stassinopoulos A. Transfusion 2015; 55,

6 Strategies to reduce TTIs; Pathogen inactivation Pathogen inactivation may imply a proactive, more generalized approach against new and (re-) emerging pathogens Mirasol system (Terumo BCT): photochemical inactivation (Riboflavin, UV light+uv illuminator) INTERCEPT Blood System (CERUS): chemical inactivation (amustalin - S303-, glutathion GSH-) Linker Effector Reaction Degradation Anchor Targeting Docking & Permanent Crosslinking (Helical regions of DNA & RNA) Henschler R, et.al. Transfus Med Hemother 2011;38:33 42

7 Screen, randomize CLI00076: A Randomized Controlled Study to Evaluate Efficacy and Safety of amustaline (S-303) Treated Red Blood Cells in Subjects with Thalassemia Major CHRONIC ANEMIA Transfusion-dependent thalassemia major patients (n=70) n=35 n=35 INTERCEPT 2 txns* 2 txns* 4 txns Control 4 txns Control 2 txns* 2 txns* 4 txns 4 txns INTERCEPT Each patient is on study ~12 months Primary efficacy endpoint: Hemoglobin consumption during each efficacy evaluation Primary safety endpoint: Incidence of a treatment-emergent antibody with confirmed specificity to S-303 treated RBC associated with clinically significant accelerated RBC clearance Secondary safety endpoints: Adverse events, transfusion reactions within 24 hours of a study transfusion, frequency of allo-immunization to RBC antigens *Patients receive 2 wash-in transfusions followed by 4 transfusions of INTERCEPT or control

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9 RBC antigen matching strategies and prevention of allo-immunization Current Status RBC alloimmunization remains as a significant clinical challenge may be associated with DHTR increase the complexity of compatibility testing may delay or prevent the receipt of compatible blood Prevention is the key reducing the burden of alloimmunization An extended RBC phenotype should be performed using an un-transfused specimen (ABO, D, C, c, E, e, K, Fy a, Fy b, Jk a, Jk b, M, N, S, s, Le a, Le b, P1) guide the serological workup of new RBC Ab findings serve minimizing the risk of alloimmunization by implementation of phenotype-matched RBCs Phenotype-matched RBCs (D, C, c, E, e, K) Extended phenotype-matched RBCs (D, C, c, E, e, K + duffy, kidd, lewis, MNS) Chou ST, et.al. BJH 2012, 159,

10 RBC antigen matching strategies and prevention of allo-immunization Future Considerations Molecular blood group antigen typing (Rh, Kell, Kidd, Duffy, Diego, Dombrack, Colton, Lutheran, Scianna, MNS) Blood suppliers are adapting this novel technology to screen donor RBCs Genotyping of patients can identify the clinically significant minor antigens that put the patient at risk for alloimmunization Mass-scale genotyping of blood donors can facilitate to provide extended antigen matched RBCs to the patients The implementation of RBC genotyping may definitely decrease alloimunization and improve transfusion therapy Ribeiro KR, et.al, Vox Sanguinis 2009, 97, Wilkinson K, et.al, Transfusion, 2012, 52,

11 Relevance of positive DAT in Thalassemia DAT positivity with reaction score 3 or 4 Monospecific DAT with C3d positivity AIHA CAS Allo-Ab (recent Tx) DAT positivity with reaction score 1 or 2 Only IgG IAT negative Nonspecific reaction Hyper gamma globulinemia Prior HCV infection Sialic acid abnormalities in RBC Elution Pre-transfusion studies are suggested DAT in thalassemic in patients transfused patients within the past 21 days has with limited a newly clinical identified utility positive DAT RBC Tx within the prior 28 days (IAT negative) + Elution + IAT newly identified positive DAT (IgG) or increase of the agglutination strength > samples were tested: Novel Allo-Ab was detected in 40 patients (%1.4) IgG agglutination strength was 1 or 2 in 98% Geisen C, et.al, Vox Sanguis 2017, 112 (Suppl 1)

12 1. Cazzola M, et.all, Br J Haematol. 1995;89(3): Cazzola M, et.all, Transfusion 1997;37(2): US, Canada,2009, 5. TIF, Italy,2014, 7. UK,2016. Standard-of-care for transfusion in thalassemia Transfusion regimen and suppression of erythropoiesis Erythroid proliferation (stfr) 1 1x2 times N in pre-tx Hb level of g/dl 1X4 times N in pre-tx Hb level of 9-10 g/dl 1X6 times N in pre-tx Hb level of g/dl Maintenance of pre-tx Hb between 9-10 g/dl 2 satisfactory suppression of erythropoiesis (2.4 ± 0.9 times normal) reduced transfusion requirements eased controlling iron loading Guidelines for the management of -thalassemia major advise transfusion to maintain a pretransfusion Hb at 9 to 10.5 g/dl 3,4,5,6,7

13 1. Gibson BES et al. Br J Haematol 2004;124: Cappellini MD et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). TIF: Goss C et al. Transfusion;54: Potential hazards of Tx or Non-Tx The steady state hemoglobin levels have limited value in determining which patient needs regular transfusion

14 What is new with respect to transfusion trend in thalassemia Italian cohort (n;300), homozygous thalassemia (DoB; ) 1 The mean age at the 1st Tx was lower whereas the mean Hb was higher in more recent births The % of children receiving the 1st Tx at Hb<7g/dl progressively decreased since 2005 (the last decade) Only 22% of thalassemic children started Tx simply on the basis of Hb The 78% of children started Tx on the basis of clinical criteria variability of transfusion practice in US Proposal of evidence based guidelines (2014) institute a hypertransfusion regimen (maintaining a trough Hb of 10 g/dl) at diagnosis and continue it until growth and development is completed in the second decade of life. 1. Origa R, et al, AJH (Epub ahead of print) 2017, Goss, c, et.al, Transfusion 2014,

15 Transfusion suppresses erythropoiesis and increases hepcidin in thalassemia major 1 Mean pre-tx Hb 10.2 g/dl & relative erythroid activity 2.1XN (based on stfr) Pre-Tx hepcidin was within the normal range, hepcidin:ferritin<1.0 indicating suppression of hepcidin out of proportion with the degree of IOL. Post-Tx (d6), Hb & hepcidin increased, EPO & GDF15 fell stfr unchanged Hepcidin: ferritin ratio rose but remained<1 Monitoring of stfr, EPO and GDF-15 may have a role in optimizing Tx dosing, hepcidin may become a useful indicator of erythropoiesis & iron kinetics in complex cases. 1. Pasricha S, et.al, Blood 2013, 122:

16 Conclusions PI technologies shifts the blood safety standard from reactive to proactive and provides insurance against the new EIAs The implementation of RBC genotyping may definitely decrease alloimunization and improve transfusion therapy Despite improvements in safety of transfusion and controlling IOL, a regular transfusion regimen is still a significant burden and monitoring patients over a period of time may prevent unnecessarily given transfusion decisions Transfusion decision given on the basis of clinical criteria may be tapered or withdrawn when clinical goals have been met in patients who otherwise are not reliant to transfusion for survival. Longitudinal studies for clarifying clinical role of indicators of erythropoiesis (stfr, EPO, GDF-15, hepcidin) may help optimizing transfusion regimen