Red Cell Alloimmunisation Is Associated with Development of Autoantibodies and Increased Red Cell Transfusion Requirements in Myelodysplastic Syndromes (MDS)

Introduction: Up to 90% of MDS patients require red blood cell (RBC) transfusions and 30-45% become RBC transfusion dependent (RBC-TD). However, literature addressing RBC alloimmunisation in MDS is limited. This study evaluates the incidence and clinical impact of RBC alloimmunisation in 817 adult MDS (or related disorders) patients enrolled in the South Australian-MDS registry.

Methods: Demographic, clinical, laboratory and treatment (including transfusions) details of patients with at least 6-month follow up were analysed. RBC-TD was defined as >1unit of RBC transfusion every 8 weeks over a period of 4 months. Azacitidine, intensive chemotherapy or allogeneic stem cell transplantation were denoted as disease modifying therapies (DMT).

Results: Median age at diagnosis was 73 years and 66% were male. During the study, 695 (85%) patients received >1 RBC unit, and 98 developed 175 alloantibodies. Of these, 11 patients developed alloantibodies following MDS-unrelated RBC transfusion well before the MDS diagnosis, and seven developed antibodies before their first documented RBC transfusion. Remaining 80 patients developed alloantibodies following MDS-related RBC transfusion. The cumulative incidence of RBC alloimmunisation with death as competing risk was 11% at 50 months following the first MDS-related RBC transfusion (Fig. 1A). Importantly, 73% and 50% of allo-immunised patients developed alloantibodies during first 20 RBC transfusions and within 6 months of commencement of RBC transfusion, respectively. Of the 98 allo-immunised patients, 50 (51%) developed one alloantibody, while 48 (49%) developed multiple alloantibodies. Rh (93/175; 54%) and Kell (41; 24%) alloantibodies were most frequent followed by Kidd (13, 7.5%) and Lutheran (10, 5.7%). Within Rh system anti-E, anti-C and anti-D were the most frequent.

Autoantibodies were detected in significantly more alloimmunised than in non-alloimmunised patients (65% vs. 18%, p<0.0001; Fig 1B) and >85% autoantibodies occurred within 5 months of alloimmunisation. Though 73% of alloimmunised patients developed alloantibody during their first 20 RBC units, total RBC units transfused were significantly higher in alloimmunised compared to non-alloimmunised patients (90±100 vs. 30±52; p<0.0001) (Fig. 1C). In alloimmunised patients, total RBC transfused after alloimmunisation were significantly higher than before alloimmunisation (p<0.0001, Fig. 1D). In MDS patients, multiple other factors such as disease progression, infection, bleeding and treatment can influence RBC-transfusion intensity. Hence, we evaluated RBC-transfusion intensity in 33 patients meeting strict inclusion criteria (Fig. 2A). In these patients, RBC-transfusion intensity substantially increased after alloimmunisation (p=0.002; Fig. 2B-C).

We then evaluated risk factors for alloimmunisation using RSF and R-PART analysis. RBC units transfused before alloantibody formation was the most important predictor of alloimmunisation, followed by RBC-TD status, treatment type and age. A classification tree using RPART suggested that 46% patients who were RBC-TD developed an alloantibody within first 20 units of RBC transfused. Landmark analyses using CRR model both at baseline (using age, sex, WHO subtype, IPSS-R risk groups and type of treatment) and at six months (baseline factors plus number of RBCs transfused within 6 months and RBC-TD status at 6 months) following the start of RBC transfusions were performed. At both time-points, alloimmunisation risk was significantly lower in DMT treated patients (HR -3.04; p=0.0023) and appears unrelated to number of RBC transfusions as patients managed with DMT received significantly more RBC units than patients treated with supportive care (p<0.0001).

Conclusion: This study characterises alloimmunisation in a large statewide cohort of MDS patients and demonstrates a significant increase in RBC transfusion requirements following alloimmunisation, most probably due to development of additional alloantibodies and autoantibodies, resulting in subclinical/clinical haemolysis. Use of DMT is associated with lower alloimmunisation risk. Strategies mitigating alloimmunisation risk are critical for optimising RBC-transfusion management.

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