Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

Future work examining the clinical impact of RBC alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.

Background Red blood cell (RBC) alloimmunization occurs at a much higher rate in patients with sickle cell disease (SCD) compared to other multiply transfused populations. Reasons for this include: altered immunologic responses, frequent transfusions during times of elevated inflammatory states, and disparate donor/recipient RBC antigens. Providing Rh and Kell matched RBCs has been shown to decrease but not eliminate RBC alloimmunization in patients with SCD. Although it has been shown in murine models that recipient inflammatory state at time of transfusion has the ability to regulate alloimmunization, direct clinical evidence for this effect is lacking in SCD patients. Methods With IRB approval, medical records of alloimmunized pediatric SCD patients were retrospectively reviewed to determine the influence of SCD-related complications often considered to be pro-inflammatory, at time of transfusion on RBC alloimmunization. The degree of antigen matching, age, and additive solution of each RBC unit were also assessed. Potential pro-inflammatory states were classified as: acute chest syndrome (ACS), acute stroke, acute febrile illness in the absence of another sickle-co morbidity, splenic sequestration, aplastic crisis, priapism, VOC with and without leukocytosis (WBC count ≥ 20k/μL) and elective surgery. Initial alloantibody detection dates were ascertained from blood bank records. Clinical events at time of transfusion were compared between transfusions resulting in a new alloantibody (AlloAb) and transfusions that did not. Univariable analysis was performed using Wilcoxon rank sum and Pearson’s Chi square test. Logistic regression modeling was used to estimate adjusted effects of stated variables on alloimmunization. Results A total of 3166 prestorage leukoreduced RBC transfusions (mean age 19.3 days) were provided to 52 SCD patients; 128 transfusions resulted in RBC alloantibodies; 3038 transfusions did not. On univariable analysis, 14.1% of transfusions during any inflammatory event resulted in a new AlloAb compared to 1.4% of transfusions in the absence of inflammation (p<.0001); ACS and VOC with elevated WBC count showed the strongest association. Twenty percent and 27% of transfusions during ACS and VOC with elevated WBC resulted in AlloAbs respectively versus 2% and 4% of transfusions in the absence of these events (p<.0001). On multivariable analysis, the presence of an inflammatory event at time of transfusion was associated with increase risk for AlloAbs (OR: 8.9; 95%CI 5.9-13.5; p<.0001) with ACS showing the highest association (OR: 13.2; 95%CI 8.4-20.8; p<.0001). Any degree of antigen matching beyond ABO/Rh was associated with a significant protective effect on AlloAb formation (OR: 0.24; 95%CI: 0.13-0.46). Multivariable analysis for adjusted unit age effect demonstrated that both fresh and older units exhibited a trend toward reduced probability of alloimmunization; however, there was a paucity of units transfused at the shelf life extremes to allow definitive continuous variable analysis. There was no significant association between the additive solution of the units and AlloAb formation. Conclusion We provide clinical evidence in SCD patients that recipient pro-inflammatory state (most notably ACS) at time of transfusion directly impacts RBC alloimmunization. These results offer indirect evidence that different types of inflammatory states within the recipient induce qualitatively different immunologic processes, which may or may not promote alloimmunization, thereby substantiating previously published mouse model findings. Further investigation of the immunologic processes involved in various pro-inflammatory states, especially ACS, is warranted. Additional data are needed to determine if the age of the RBCs influences the likelihood of alloimmunization. Disclosures: Fasano: ApoPharma: Honoraria.

SummarySickle cell disease (SCD) patients are at increased risk of red blood cell (RBC) alloimmunization. Recipient inflammatory state at time of transfusion has been shown to regulate alloimmunization in murine models, but evidence is lacking in SCD patients. We retrospectively studied a cohort of alloimmunized SCD patients to determine the influence of pro-inflammatory SCD-related complications at time of transfusion on alloimmunization. For each transfusion, the presence of pro-inflammatory state, degree of RBC antigen matching, unit age, storage solution and alloantibody detection date were ascertained. Transfusion-associated pro-inflammatory events were compared between transfusions resulting and not resulting in new alloantibodies. Univariate analysis and multivariate logistic regression were performed. Fifty-two patients received 3166 pre-storage leuco-reduced transfusions of which 128 resulted in alloantibodies. Transfusions during inflammatory events were associated with increased alloantibody risk on univariate and multivariate analysis; acute chest syndrome and vaso-occlusive crisis showed strongest associations with alloimmunization. Increased antigen matching demonstrated a protective effect on alloimmunization (univariate and multivariate analysis). Although an association was seen between citrate-phosphate-dextrose (adenine) stored units and alloimmunization on univariate analysis, no effect was found on multivariate analysis. Identifying recipient pro-inflammatory states at time of transfusion that promote alloimmunization can impact RBC unit selection decisions for SCD patients at risk for alloimmunization.

whom HCT-CI appeared to be crucially important was the group of patients at high risk for disease relapse (beyond CR1/CR2 or with high-risk cytogenetics). A high HCT-CI in these patients resulted in uniformly negative outcomes. This group of patients with very poor prognosis should probably not be transplanted. Lastly, the intermediaterisk group could be the group that would benefit the most from posttransplant interventions to decrease relapse rate. This analysis is limited by a relatively small number of patients treated with haploidentical transplants only. Factors included in the risk model were selected from significant factors identified in the multivariable model for PFS without weighting of the prognostic impact of each component. This model needs to be validated in a larger number of patients, including HLA-matched transplants, as it could have major implications in treatment decisions.In conclusion, risk stratification models combining disease and patient characteristics could further refine prognosis for potential ASCT patients, better identify patients who could benefit from maintenance therapies posttransplant, as well as serve as a tool to further compare results among different studies.

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Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non-responders), a crosssectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC alloimmunization was present in 26/90 (29%) patients, with anti-E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non-alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P 5 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P 5 0.020) than non-alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC alloimmunization. Alloimmunized patients had a significantly increased percentage of CD41 T memory cells compared to non-alloimmunized patients (57% vs. 49%, P 5 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent alloimmunization.

We recommend RCE plus chelation as an effective method for reducing iron overload, while maintaining HbS at 30% to 35%.