Age at Hematopoietic Cell Transplantation Is a Risk Factor for Transplant Associated Thrombotic Microangiopathy in Patients with Sickle Cell Disease

Background: Transplant Associated Thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic cell transplantation (HCT). Female sex, prior autologous transplant, primary disease (acute lymphoblastic leukaemia and severe aplastic anaemia), donor type (mismatched or unrelated donor), conditioning intensity (myeloablative), GVHD prophylaxis (sirolimus + calcineurin inhibitor), pre-transplant kidney dysfunction and acute GVHD (time-varying effect) have previously been reported as independent predictive factors for TA-TMA in patients undergoing HCT for malignant or non-malignant diseases (Epperla et al BJH 2020). Patients with sickle cell disease (SCD) have elevated markers of endothelial activation and may be at risk for developing TA-TMA (Schoettler et al Blood Advances 2023). There is a gap in knowledge of pre-HCT characteristics predicting TMA, specifically among patients with SCD undergoing HCT.

Objective: Identify risk factors for TA-TMA in HCT for SCD with a view to aid in early intervention and management.

Methods: Data from 1,881 SCD patients who underwent HCT were analysed using the Centre for International Blood and Marrow Transplant (CIBMTR) HCT for SCD dataset. Of these, 1004 patients with available TA-TMA records were included, of whom 40 had developed TA-TMA. Descriptive statistics were summarized and compared between patients with and without TMA using the chi-squared test for several baseline categorical variables. The relationship between conditioning intensity and age group was also analysed. Univariable and multivariable Cox regression analyses were conducted to examine the association between development of TA-TMA post-HCT and age, with the multivariable analysis also adjusting for conditioning intensity.

Results: Overall, 3.98% of the patients developed TA-TMA, with the highest percentage observed in the 11-17 age group (7.53%), followed by the ≤10 age group (2.86%), and the ≥18 age group (2.21%). The distribution of age groups differed significantly among patients with and without TA-TMA post-HCT (p=0.002). Other baseline characteristics including sex, ethnicity, HCT comorbidity index, transplant type, donor type, graft type, conditioning intensity, and GVHD prophylaxis were not significantly associated with TA-TMA. Age group was significantly associated with conditioning intensity (p<0.001). Specifically, 61.7% of those receiving myeloablative conditioning were in the ≤10 age group, 43.8% of those receiving reduced-intensity conditioning were in the 11-17 age group, and 70.3% of those receiving non-myeloablative conditioning were adults. Univariate Cox regression analysis identified age at HCT as a significant risk factor for developing TA-TMA (p=0.003). This association remained significant after adjusting for conditioning intensity in the multivariable Cox regression analysis (p=0.012). In the multivariable Cox regression model, patients aged 11-17 years were more likely to develop TA-TMA compared to those aged ≤10 years (HR=2.497, 95% CI: 1.205-5.316, p=0.0148). Patients aged ≥18 years did not exhibit a significant difference in TA-TMA risk compared to patients aged ≤10 years (HR=0.775, 95% CI: 0.234-2.206, p=0.6504). Additionally, there was no significant difference in TA-TMA risk between reduced-intensity and myeloablative conditioning (HR=1.250, 95% CI: 0.602-2.533) or between non-myeloablative and myeloablative conditioning (HR=0.508, 95% CI: 0.078-1.890).

Conclusion: These data suggest that age at transplant, particularly the age group between 11-17 years, is a significant risk factor for TA-TMA. Further research is needed to explore mechanisms of increased risk of TA-TMA in patients aged 11-17, as well as to devise preventive strategies and management.