ALBERT

Description: Introduction Autoimmune hemolytic anemia (AIHA) is the most commonly reported autoimmune complication following hematopoietic stem cell transplantation (HSCT) with incidence of 2-6%. The risk factors and pathogenesis remain poorly understood. Treatment often requires multiple therapeutic agents with variable efficacy and outcome. However no study to date has shown whether AIHA directly results in increased mortality. In order to better understand the risk factors, mortality and management of post-HSCT AIHA, we carried out a retrospective analysis of 533 allogeneic HSCTs in adult patients performed at King's College Hospital between 2005-2011. Method The median follow-up period after HSCT was 31 months (range 2.9 – 100 months). The primary endpoint was the onset of AIHA, defined by positive direct agglutinin test (DAT) arising after the HSCT, with biochemical markers of hemolysis (raised serum lactate dehydrogenase (LDH), reduced haptoglobin, or spherocytes on the blood film). Hemolysis was considered significant if the drop in hemoglobin was more than 20 g/l. Cases of DAT positivity due to ABO antibodies, as well as those with history of AIHA or positive DAT prior to HSCT were excluded. Potential risk factors for development of AIHA were calculated with univariate followed by multivariate analysis comparisons of incidence of AIHA for each clinical stratum. Kaplan-Meier method was used to compare mortality caused by AIHA against overall mortality (OM), and transplant-related mortality (TRM). AIHA was modelled as a time-dependent variable when estimating mortality. All patients alive at last follow-up who did not develop AIHA were censored. Results We identified 19 cases of AIHA following HSCT (overall incidence 3.6%). The median time to onset from HSCT to AIHA was 202 days. AIHA was associated with HSCT from unrelated donors (p = 0.026; Hazard Ratio = 5.28, 95% CI = 1.22 – 22.9), and concordant sex between HSCT recipients and donors (p = 0.045; Hazard Ratio = 3.52; 95% CI = 1.03 – 12.1). No significant association was observed between AIHA and the following eight factors: recipient gender; primary hematological disease; source of hematopoietic stem cells; conditioning regimen (alemtuzumab/ATG versus non-alemtuzumab/ATG, and reduced intensity versus myeloablative); HLA mismatch between donor/recipient; ABO mismatch; recipient CMV status; and concurrent chronic GvHD. AIHA patients also exhibited high frequency of simultaneous alloimmunization to Rh antigens coinciding with the onset of AIHA, which was not due to difference in transfusion rates, and not observed in the population who tested negative for DAT. Majority of AIHA patients (14/19; 72%) required multiple agents for treatment, but only 9/19 (47%) cases achieved complete resolution of AIHA (1 with intravenous immunoglobulin; 2 with prednisolone alone; 6 with rituximab in combination with other agents). The median survival from onset of AIHA was 487 days (range 26 – 1977 days). We compared the mortality of the AIHA versus non-AIHA population that survived beyond the median time of onset for AIHA (202 days). Patients with post-transplant AIHA had a higher OM (p = 0.006, Hazard Ratio = 2.37, 95% CI = 1.28 – 4.39), 1-year OM of 22% versus 10% (p = 0.04) and 1-year TRM of 18% versus 4% (p = 0.001), respectively (Figure 1). 36% (4/11 cases) of deaths were attributable to AIHA. Conclusion The overall incidence of AIHA following allogeneic HSCT in our study was 3.6%. The risk factors associated with AIHA were receiving HSCT from unrelated donors, and matched gender between the donor/recipient, which has not been previously reported. We observed an association between allo and autoimmunization in the AIHA patients, suggesting a common immune defect underlying both phenomena. The most effective treatment was a combination regimen of rituximab with prednisolone or other immunosuppressive agents. The overall mortality rate for our AIHA patients was high at 53% (10/19 cases), with AIHA as a cause of death in 36% of deceased patients. We have shown that AIHA following HSCTs indeed leads to increased mortality with over 2 fold higher OM in the patients with AIHA. Figure 1 Figure 1. Disclosures McLornan: Novartis: Research Funding.

Description: Background: Blood transfusion is a key intervention in the management of sickle cell disease (SCD), and is being increasingly used. Nonetheless, transfusion is not without risks; alloimmunisation to red blood cell antigens is a major complication, and can sometimes precipitate a delayed haemolytic transfusion reaction (DHTR), a potentially life-threatening event. Objectives: We describe the prevalence, risk factors and experience of DHTR in a large cohort of adult patients with SCD. Methods: Medical records of the 637 adult patients (all of African descent) regularly attending the SCD specialist clinic at King’s College Hospital, London, were retrospectively reviewed to identify DHTR cases. 362 (57%) were female, with 401 HbSS, 202 HbSC, 29 HbSβ+-thalassaemia (thal), 4 HbSβ0-thal, and 1 HbSSHPFH patients, mean age 36 ± 12 years. Between 1st August 2008 and 31st December 2013, 219 of the 637 patients received red blood cell transfusion, either as simple or exchange transfusion. 123 /219 (56%) of those who received transfusion were female, 84% HbSS genotype. Their Electronic Patient Records were examined, looking for a sharp drop in haemoglobin (Hb) after transfusion. If this was observed, laboratory data were combined with the clinical notes to detect evidence of a DHTR. Results: We identified 25 DHTR episodes (1.2% of all transfusion episodes) in 16 patients (table 1). Six patients had repeat DHTR episodes – 4 twice, one thrice, and one 4 times. Mean age at transfusion was 35.5 ± 14.8 years. Indications for the transfusion that triggered the DHTR, included 20 acute pain episodes (some with acute chest syndrome), 3 pre-operative and 2 chronic exchange program. Mean interval from transfusion to DHTR onset was 11 ± 7 days. Typical presentations of DHTR were fever, pain and hemoglobinuria. Blood results at DHTR diagnosis showed evidence of active haemolysis (mean LDH 1330 IU/L), and Hb drop (mean drop 40.4g/L, range 7 – 88g/L). 84% of episodes showed a severe haemolysis with nadir Hb lower than the pre-transfusion Hb. Mean reticulocyte count at peak haemolysis was 291 x109/L ± 121 x109/L. Eleven of the 25 episodes (44%) resulted in new red cell antibodies; 8 alloantibodies and 3 autoantibodies (table 1). DAT was positive in 16 of 19 (84%) cases where performed. 56% (14/25) of DHTR episodes were not diagnosed during admission, most often they were misdiagnosed as an acute pain crisis. Four of the 11 recognised DHTRs were treated with immunosuppression that included methylprednisolone, immunoglobulin, and, in one case, rituximab. All four of these uneventfully received further blood transfusions. The mean length of hospital stay was 15.9 days. 2/16 patients died, one of stroke, one of multi organ failure, giving a 13% mortality. Discussion: Our data suggest that DHTRs are a severe but uncommon complication of blood transfusion. They are poorly recognised, possibly as their presentation mimics an acute painful crisis. Notably, most of the DHTRs are triggered by RBC transfusions in the acute setting. We recommend a high index of suspicion for DHTR in any SCD patient who has been transfused in the past month and presents acutely to clinicians, as early intervention can be life-saving. Table 1. Table 1. *Exchange Disclosures No relevant conflicts of interest to declare.