Incidences and determinants of HLA class I alloimmunization among hematological patients
Intensive myelotoxic treatments in hematology require support of platelet transfusions. Refractoriness to donor platelets may be due to HLA class I alloimmunization and can severely complicate treatment support. Here, we assessed HLA class I alloimmunization incidences, subsequent refractoriness, and its main determinants in thrombocytopenic hematological patients undergoing disease-modifying treatments.
We performed an observational cohort study among all hematological patients who received disease-modifying treatments, including hematopoietic stem cell transplantation (HSCT), and were tested (at least once at a routine base) for the presence of HLA class I antibodies between January 1, 2015, to December 31, 2019, at the Radboudumc Nijmegen. Using Kaplan Meier analysis, we assessed cumulative HLA class I alloimmunization incidences according to (RBC and platelet) transfusion exposure and treatment phase. Furthermore, we quantified the association of various clinical conditions with the development of HLA class I alloantibodies via multivariate logistic regression analyses. Finally, the risk of platelet refractoriness was quantified according to HLA class I alloimmunization.
HLA class I alloantibodies were detected in 45 of 603 (7.5%) treated hematological patients, of which 35 (77.8%) were parous females. Among HLA class I alloimmunized patients, 44.4% (20/45) were diagnosed with platelet refractoriness as compared to 3.2% (18/558) of non-alloimmunized patients.
Female risk was strongly associated to HLA class I alloimmunization (adjusted odds ratio (OR) 10.2, 95% confidence interval (CI) 4.4-23.3), mainly explained by a history of pregnancies and thus, likely, prior primary immunization. Only 1.9% (7/368) of males and 6.3% (3/48) of nulliparous females developed alloantibodies. In general, cumulative HLA class I alloimmunization incidences increased from 4.7% (CI 1.1-12.7) before any platelet unit received up to 25.6% (CI 8.8-45.9) after 40 platelet units received.
Furthermore, the incidence of HLA class I alloimmunization was significantly increased among patients with HLA class II antibodies (OR 15.5; CI 6.7-35.7). In addition, homozygosity in either HLA-A or HLA-B phenotype increased HLA class I alloimmunization risks, culminating to an OR of 6.04 (CI 1.27-28.65) in case of combined homozygosities.
The risk of HLA class I alloimmunization is dominantly determined by prior pregnancies. To a far lesser extent and despite current leukoreduction strategies, cellular blood transfusions also contribute, especially in case of multiply exposure. Consequently, HLA antibody screening at initiation of therapy may potentially merit optimal transfusion support of parous females, but can be safely postponed for males and nulliparous females.
Finally, the risk is increased in HLA class II alloimmunized and HLA class I homozygous individuals. Identification of such predictors may support phsysicians’ consciousness and thereby early identification of immune-mediated platelet refractoriness in hematological patients.