Transfusion therapy: what is new with respect tosafety and control of iron loading?

Yesim AYDINOK

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

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YES, I have presented promotional talks for one or more pharmaceutical companies within the past 12 months

*if yes please provide information below.- NOVARTIS- CERUSI 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.)

15-16 September, 2017 Yesim AYDINOK

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 allo-immunization

• 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

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

VirusWP (days)

for serology1

WP (days) for ID-NAT1,2

Risk of transmission in US3

HIV-1 19 (p24; 15) 1.5-5.0 1:2 300 000

HCV 65 3.3 1:1 800 000

HBV 36 11.6 1:352 000

1. Kleinman SH, et.al.Transfusion. 2009;49(11):2454-89. 2. Weusten J, et.al. Transfusion.2011;51(1):203-15. 3. Lindholm PF, et.al. Infect Disord Drug Targets. 2011;11(1):45-56.

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

TTI; transfusion transmitted infection

It is still impossible to know or reliably predict IF & WHEN emerging pathogens will threat the safety of blood supply

DiagnosisMedian RBC

unit exposure (time)

Total RBC

(unit)

Immune suppressed

Aggregate risk per pt. (%)

minimum maximum

SCD24/year

(30 years)720 asplenic 0.22 (1/450) 43.17 (1/2)

Thalassemia15/year

(50 years)750 splenectomy 0.23 (1/430) 45.13 (1/2)

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

Strategies to reduce TTIs; Donor deferral, testing procedures (serology based +NAT) & leukofiltration

Kleinman S & Stassinopoulos A. Transfusion 2015; 55, 2983-3000TTI; transfusion transmitted infection EIA; emergent infectious agents

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-)

Targeting

Docking & Permanent Crosslinking

(Helical regions of DNA & RNA)

Anchor

LinkerEffector

Reaction Degradation

Henschler R, et.al. Transfus Med Hemother 2011;38:33–42

CLI00076: A Randomized Controlled Study to Evaluate Efficacy and Safety of amustaline (S-303) Treated Red Blood Cells in Subjects with Thalassemia Major

CHRONIC ANEMIATransfusion-dependent thalassemia

major patients (n=70)

INTERCEPT

4 txns2txns*

Control

4 txns2

txns*4 txns

2 txns*

4 txns2

txns*

INTERCEPT

Controln=35

n=35

Each patient is on study ~12 monthsSc

reen

, ran

do

miz

e

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 clearanceSecondary 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

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, Fya, Fyb, Jka, Jkb, M, N, S, s, Lea, Leb, 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, 394-404

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, 147–152. Wilkinson K, et.al, Transfusion, 2012, 52, 381–388.

• DAT positivity with reaction score 3 or 4

• Monospecific DAT with C3d positivity

Relevance of positive DAT in Thalassemia• AIHA• CAS• Allo-Ab (recent Tx)

Pre-transfusion DAT in thalassemic patients has limited clinical utility

• 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

RBC Tx within the prior 28 days (IAT negative) +• newly identified positive DAT (IgG) or• increase of the agglutination strength >1+

Elution + IAT

2866 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) 198-199

Elution studies are suggested in patients transfused within the past 21 days with a newly identified positive DAT

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 10 -11 g/dl

﹘1X4 times N in pre-Tx Hb level of 9 -10 g/dl

﹘1X6 times N in pre-Tx Hb level of 8.5 -9 g/dl

• Maintenance of pre-Tx Hb between 9-10 g/dl2

﹘satisfactory suppression of erythropoiesis (2.4 ± 0.9 times normal)

﹘reduced transfusion requirements

﹘eased controlling iron loading

1. Cazzola M, et.all, Br J Haematol. 1995;89(3):473-8. 2. Cazzola M, et.all, Transfusion 1997;37(2):135-40.3. US, 2009. 4. Canada ,2009, 5. TIF ,2014. 6. Italy,2014, 7. UK,2016.

Guidelines for the management of -thalassemia major advisetransfusion to maintain a pretransfusion Hb at 9 to 10.5 g/dl3,4,5,6,7

Tx Non-Txor

Potential hazards of

The steady state hemoglobin levels have limited value in determining which patient needs regular transfusion

1. Gibson BES et al. Br J Haematol 2004;124:433–453. 2. Cappellini MD et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). TIF: 2014. 3. Goss C et al. Transfusion;54:2773-2782.

• Italian cohort (n;300), homozygous thalassemia (DoB; 1966-2016)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

What is new with respect to transfusion trend in thalassemia

1. Origa R, et al, AJH (Epub ahead of print) 2017, Goss, c, et.al, Transfusion 2014, 1773–1781

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.’

variability of transfusion practice in US

Transfusion suppresses erythropoiesis and increases hepcidin in thalassemia major1

• 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: 124-133

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