Treatment of Delayed Hemolytic Transfusion Reactions in Sickle Cell Disease Patients By an Anti-C5 Antibody
Authors: Floch Aline , Morel Alexandre , Zanchetta-Balint Fabian , Cordonnier-Jourdin Catherine , Allali Slimane , Grall Maximilien , Ithier Ghislaine , Carpentier Benjamin , Pakdaman Sadaf , Merle Jean-Claude , Goulabchand Radjiv , Khalifeh Tackwa , Berceanu Ana , Chantalat-Auger Christelle , Frémeaux-Bacchi Véronique , Michel Marc , Mekontso-Dessap Armand , Habibi Anoosha , Pirenne France , Bartolucci Pablo 
Published: November 2019

Background:
Delayed hemolytic transfusion reaction (DHTR) is an unpredictable and severe complication of transfusion, especially in Sickle Cell Disease (SCD) patients (Habibi Am J Hematol 2016). The clinical presentation is a vaso occlusive crisis (VOC), often associated with one or more organ failures, after packed red blood cell transfusion (pRBC). The hypothesis of complement activation through the classical pathway by alloantibodies and/or the alternative pathway by free heme (released by hemolysis) suggests that an inhibitor of complement activation may be a treatment option for DHTR.
Methods:
This retrospective study focuses on the SCD patients who received anti-C5 monoclonal antibody during DHTR treatment after consulting with our French SCD referral center between 2013 and 2018.
DHTR diagnosis associated VOC signs occurring 5 to 20 days after pRBC transfusion, with no other cause for intravascular hemolysis, and one or more of the following:
- rapid decrease in, or unexpectedly low, hemoglobin A (HbA) concentration
- hemoglobinuria defined by dark urines
- direct antiglobulin test (DAT) positivity or new antibody formation.
The treatment efficacy was evaluated through patients' clinical and biological data.
Findings:
Sixteen patients received anti-C5 for a DHTR defined by a VOC 5 to 20 days after a transfusion and the following criteria: 12 had low HbA or rapid decrease of HbA, 10 had hemoglobinuria, and 10 had positive DAT or antibody formation. One patient received anti-C5 for hyperhemolysis without being able to discriminate DHTR from hemolysis under Extracorporeal Membrane Oxygenation and was excluded from the analysis.
The 16 patients included in the analysis had severe DHTR at diagnosis, with one or more organ failures (N=7), median hemoglobin concentration 57 g/L [30-97], LDH 2807 UI/L [510-12500], total bilirubin 92 mmol/L [15-730]. Two additional patients had organ failures during the follow-up. Lowest hemoglobin concentration was 32 g/L [19-58] and highest LDH 4238 UI/L [510-24000].
One to 3 anti-C5 doses were given at 1 week intervals, associated with symptomatic treatment (hydration, oxygen, analgesia; N=16), erythropoietin (N=15), pRBC transfusions (N=12), immunoglobulins (N=8), plasma exchange (N=4), steroids (N=1). The outcome was favorable for 13 patients. The number of pRBC transfused were limited as much as possible.
Three patients died. All three had acute liver failure that required emergency liver transplant. Two patients improved after anti-C5 and could be grafted, but died of infectious complications unrelated to anti-C5: Klebsiella pneumoniae pulmonary infection 11 days after transplant for one, and digestive and urinary infection 47 days after transplant for the other. For the third patient, no compatible organ could be found.
Conclusion:
In association with other therapies (EPO, plasma exchange, limiting pRBC transfusions), anti-C5 can be a treatment option for severe DHTR despite its high cost, in the absence of effective alternatives.

Disclosures
Michel: Amgen: Consultancy; Rigel: Consultancy; Novartis: Consultancy. Bartolucci:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Anti-C5 is currently used to treat paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).