The degree of HLA matching determines the incidence of cytokine release syndrome and associated nonrelapse mortality in matched related and unrelated allogeneic stem cell transplantation with post-transplant cyclophosphamide.

Cytokine release syndrome (CRS) occurs frequently after haplo-identical allogeneic stem cell transplantation (alloSCT) with post-transplant cyclophosphamide (PTCy), increasing nonrelapse mortality (NRM) and decreasing survival. Data on CRS in HLA-matched alloSCT are limited and effects of specific HLA-mismatches on CRS development unknown. We hypothesized that in HLA-matched alloSCT increasing degrees of HLA-mismatching influence CRS incidence, NRM and survival. Retrospective analysis of 126 HLA-matched PTCy-alloSCT patients showed that higher degrees of HLA-mismatching significantly increased CRS incidence (26%, 75% and 90% CRS with 12/12, 10/10 and 9/10 matched donors, respectively). Maximum temperature during CRS increased with higher HLA-mismatch. Specific associations between HLA-mismatches and CRS could be determined. Grade 2 CRS and CRS-induced grade 3 fever were associated with significantly increased NRM (p < 0.001 and p = 0.003, respectively) and inferior survival (p < 0.001 and p = 0.005, respectively). NRM was mainly caused by disease conditions that may be considered CRS-induced inflammatory responses (encephalopathy, cryptogenic organizing pneumonia and multi-organ failure).

Treatments for hematologic malignancies in contrast to those for solid cancers are associated with reduced red cell alloimmunization.

Red cell alloimmunization may induce severe hemolytic side effects. Identification of risk-modifying conditions will help tailor preventative strategies. This study aims to quantify the associations of hematologic malignancies and solid cancers with red cell alloimmunization in patients receiving red cell transfusions. We performed a nested multicenter case-control study in a source population of 24,063 patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Cases (n=505), defined as patients developing a first transfusion-induced red cell alloantibody, were each compared with 2 non-alloimmunized controls (n=1010) who received a similar number of red cell units. Using multivariate logistic regression analyses, we evaluated the association of various malignancies and treatment regimens with alloimmunization during a delineated 5-week risk period. The incidence of alloimmunization among patients with acute (myeloid or lymphoid) leukemia and mature (B- or T-cell) lymphoma was significantly reduced compared to patients without these malignancies: adjusted relative risks (RR) with 95% confidence interval (CI) 0.36 (range 0.19-0.68) and 0.30 (range 0.12-0.81). Associations were primarily explained by immunosuppressive treatments [RR for (any type of) chemotherapy combined with immunotherapy 0.27 (95%CI: 0.09-0.83)]. Alloimmunization risks were similarly diminished in allogeneic or autologous stem cell transplanted patients (RR 0.34, 95%CI: 0.16-0.74), at least during the six months post transplant. Alloimmunization risks of patients with other hematologic diseases or solid cancers, and their associated treatment regimens were similar to risks in the general transfused population. Our findings suggest that, in contrast to malignancies in general, hemato-oncological patients treated with dose-intensive regimens have strongly diminished risk of red cell alloimmunization.

Red cell alloimmunisation in patients with different types of infections.

Red cell alloantigen exposure can cause alloantibody-associated morbidity. Murine models have suggested that inflammation modulates red cell alloimmunisation. This study quantifies alloimmunisation risks during infectious episodes in humans. We performed a multicentre case-control study within a source population of patients receiving their first and subsequent red cell transfusions during an 8-year follow-up period. Patients developing a first transfusion-induced red cell alloantibody (N = 505) were each compared with two similarly exposed, but non-alloimmunised controls (N = 1010) during a 5-week 'alloimmunisation risk period' using multivariate logistic regression analysis. Transfusions during 'severe' bacterial (tissue-invasive) infections were associated with increased risks of alloantibody development [adjusted relative risk (RR) 1·34, 95% confidence interval (95% CI) 0·97-1·85], especially when these infections were accompanied with long-standing fever (RR 3·06, 95% CI 1·57-5·96). Disseminated viral disorders demonstrated a trend towards increased risks (RR 2·41, 95% CI 0·89-6·53), in apparent contrast to a possible protection associated with Gram-negative bacteraemia (RR 0·58, 95% CI 0·13-1·14). 'Simple' bacterial infections, Gram-positive bacteraemia, fungal infections, maximum C-reactive protein values and leucocytosis were not associated with red cell alloimmunisation. These findings are consistent with murine models. Confirmatory research is needed before patients likely to develop alloantibodies may be identified based on their infectious conditions at time of transfusion.