ALBERT

Description: Sperm parameters are known to be impaired in men with sickle cell disease (SCD). Although treatment with hydroxyurea (HU) impacts sperm quality, sperm preservation is impossible before puberty. The present study's primary objective was to analyze and compare sperm parameters in male SCD patients exposed (or not) to HU before puberty. Twenty-six sperm samples from 15 patients (median (range) age: 17 (16-23)) treated with HU during childhood were compared with 46 samples from 23 HU-naïve patients (median (range) age: 20 (16-24)). The median (range) age at HU initiation was 6 years (1-14), the median duration of HU treatment was 4 years (0.5-10) and the mean ± standard deviation dose of HU was 22.4 ± 3.7 mg/kg/day. Although we observed substantial quantitative and qualitative semen abnormalities in all patients, there were no significant differences in semen volume, sperm concentration, total sperm count, and spermatozoa motility, morphology and vitality between the HU-exposed and HU-naïve groups. At the time of the semen analysis, respectively 100% and 52% of the patients in the HU-exposed and HU-naïve groups were on transfusion therapy. Hydroxyurea's specific effect on spermatogenesis in very young infants and the putative value of transfusion for reversing HU's toxicity warrant further investigation.

Description: 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).

Description: Background: Sperm parameters alteration is documented in untreated men with sickle cell disease (SCD). An aggravating effect of hydroxyurea (HU) on sperm parameters is also well established: HU, at current doses, causes significant, rapid, and unpredictable impairment of spermatogenesis. Reversal of its effect when treatment is stopped has also been documented, albeit in patients given very low doses of treatment (10 mg/kg/d). In France, sperm banking is free of charge and recommended whenever possible before initiation of HU treatment. While recent guidelines have broadened the indication of HU for asymptomatic infantssuch banking is impossible in younger boys before puberty. In addition, little is known on the effect of HU on sperm parameters when given at this specific period. Objectives and Methods: The main objective of this study was to compare sperm parameters after treatment resolution in young males treated by HU prior to puberty with sperm parameters of untreated males. Secondary objective was to analyze longitudinally sperm parameters during HU washout in those treated prior to puberty.Data regarding indication of HU, dosage, date of initiation and stop, clinical profile including vaso occlusive events (VOE) transfusion episodes and date of puberty was collected. Alternative treatment before or during semen analysis was also documented. A period of 3 months of HU wash out was required prior to semen analysis in treated patients. Results: A total of 26 patients (43 semen samples) were studied, with 16 patients treated with HU prior to puberty (HU-PP) and 10 untreated (HU-naive). Characteristics of patients are presented in Table 1. Indication of HU was cerebral vasculopathy (n=3), VOE (n=5), severe anemia (n=1) or combined (n= 7). The median stopping of the HU before CECOS is 4.5 years [0.5-11.0]. An alternative treatment based on a transfusion program was initiated in 14 patients (87.5%) at the time of sperm analysis in the HU-PP group versus 5 patients (50%) in the HU-naive group. Duration of transfusion program was 126 months [3-188] in HU-PP versus 13 [7-100] in the HU naive group. We compared the fraction of abnormal values in semen samples in both groups (25 samples in the HU-PP group and 18 in the HU-naive). No significant difference was observed regarding volume of ejaculate, spermatozoid concentration, total sperm count, spermatozoid motility, morphology and vitality, and sexual abstinence before sampling in both groups (Table 1). In the HU-PP group, there was a trend in improvement of sperm parameters with the duration of transfusion program. In addition, a kinetic analysis of sperm parameters during the period of HU wash out was performed in 3 patients exposed to HU prior to puberty, demonstrating reversibility of HU toxicity in all. All 26 patients were offered semen cryopreservation. For 22 of them, semen parameters after thawing indicated a possible use for assisted reproductive technologies, mostly in vitro fertilization with intracytoplasmic sperm injection. In the remaining 4 (3 in HU-PP group and 1 in HU naïve), there was serious concern about the possible use because of a very low initial sperm concentration and the absence of motile spermatozoids after thawing. Discussion/Conclusion: Toxicity of HU upon spermatogenesis has been well documented in animal studies and in adult males. In many settings, such issues may be a drawback for parents and/or caregivers to treat young boys before semen banking can be performed, given the lack of robust information on reversibility after treatment resolution. Abnormalities of sperm count are also common in non-treated males so that demonstrating the specific effect of HU may be complex. Oseggbe et al. and Berthaud et al. showed that 91% of untreated SCD males have at least one abnormal sperm parameter. Here, we show that after treatment resolution, there are no differences in sperm parameters in patients exposed to HU before puberty compared to untreated males. Because a majority of patients benefitted from transfusion therapy at the time of analysis, we were however unable to demonstrate whether reversal of toxicity occurs spontaneously or requires transfusion. Notwithstanding possible limitations due to small sample size, this study shows that in boys with severe disease requiring HU treatment before puberty, toxicity of HU on sperm parameters should not be a major drawback. Disclosures Bernaudin: AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Consultancy. De Montalembert:Novartis: Consultancy, Honoraria; Addmedica: Consultancy, Honoraria; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Brousse:bluebird bio: Consultancy; Add medica: Consultancy.