Age, Gvhd Prophylaxis, and Timing Matter in Thrombotic Microangiopathy after Hematopoietic Cell Therapy- a Secondary CIBMTR Analysis

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) is associated with significant morbidity and mortality. Risk factors for developing TA-TMA and impact of TA-TMA on survival were published from a large Center for International Bone Marrow Transplantation Registry (CIBMTR) (Epperla et al, BJH. 2020). We used this published database to investigate whether there were different risk factors for developing TA-TMA in children and adults and identify prognostic factors, including timing of TA-TMA diagnosis.

Methods: All first allogenic HCT recipients with malignant or non-malignant diseases between 2008-2016 were included in this retrospective secondary analysis of an existing CIBMTR dataset. Measures of association were generated using sub-distribution cox proportional hazard models, treating death as a competing risk. Significant risk factors for developing TA-TMA in univariable models were then tested in a multivariable model. SAS 9.4 (Cary, NC) was used for analysis, and statistical significance was set at 0.05.

Results: The incidence of TA-TMA in children and adults was similar, 2.9% (n=138/4818) and 2.8% (n=514/18249) respectively. Significant adjusted risk factors for developing TA-TMA shared in both children and adults included an unrelated donor, and grade 2-4 acute graft versus host disease (aGVHD) (Table 1a). Female sex, black race, peripheral blood and umbilical cord versus bone marrow, and HLA mismatch were risk factors for developing TA-TMA in adults, but not children in a multivariable analysis (Table 1b). AGVHD prophylaxis withpost-transplant cyclophosphamide (PT-CY) compared to calcineurin inhibitor and mycophenolate mofetil (CNI + MMF) was associated with a decreased risk of developing TA-TMA in children, and an adjusted decreased risk in adults. Compared to black adults, black children had a significantly higher proportion of bone marrow as a stem cell source, non-malignant disease as HCT indication, PFS >90, and lower rates of grade 2-4 acute GVHD (p <0.0001).

Among all patients with TA-TMA (n=652), features associated an adjusted increased risk of death included age >18 years old, onset of TA-TMA diagnosis ≤ 6 months post HCT, unrelated donor, peripheral blood stem cell source, grade 3-4 acute GVHD, and a performance score of <90 prior to HCT (Table 1c). The estimated 2-year survival in patients with an early HCT-TMA diagnosis (<6 months post HCT, n= 468) was 34.2 ± 8.8% versus 55.9 ± 15.6% in those with a later diagnosis (n= 171), p<0.0001, Figure 1a). The early HCT-TMA cohort had significantly more black patients, CNI + MTX, performance score <90 (P<0.05), though there were no significant differences in the severity of acute GVHD compared to late HCT-TMA. Children with HCT-TMA had a significantly higher estimated 2-year survival compared to adults (49.85 ±17.5 vs 36.73 ±8.8, p= 0.002, Figure 1b); after adjusting for significant differences in the cohorts, the HR of death remained lower in children than adults (0.73, p=0.045)

Discussion: Our data add to the prior publication that showed the association of moderate and severe aGVHD and TA-TMA by demonstrating that the incidence of TA-TMA is similar between children and adults though outcomes are better in children and the time of onset post HCT impacted survival. Acute GVHD prophylaxis with PT-CY versus CNI+ MMF was associated with a decreased risk of developing TA-TMA in unadjusted and adjusted models in adults. As there were no differences in proportions of severe aGVHD in the prophylaxis cohorts, additional studies are needed to understand this association. Female sex was not a risk factor for TA-TMA in children, but was for adults, and may be related to the impact of hormones on vascular endothelium, though additional studies are needed. Black race was a risk factor for disease in adults and not children and may be due to lower rates of aGVHD in this adults or smaller numbers limiting power. Our data highlight that early onset TA-TMA was associated with significantly lower survival than TA-TMA diagnosed >6 months post HCT, and that pediatric recipients had higher 2-year OS compared to adults. While this study is limited by the lack of consistent screening among centers, the large sample size, diversity in age, race, HCT indication and transplant approaches, support that expedited and novel interventions for TA-TMA should be considered for children and adults with early onset TA-TMA.