Characterization and risk factors of transplantation-associated thrombotic microangiopathy (TA-TMA): Increased incidence associated to post-transplant cyclophosphamide (PTCy) prophylaxis.

Abstract

Abstract Introduction Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially severe post-transplant complication of allogeneic stem cell transplant (AlloSCT) resulting from endothelial damage. It has multifactorial origin and can increase morbimortality due to microvascular thrombosis that eventually progress to multi-organ dysfunction. Its incidence varies across reported series. We aim to characterize TA-TMA and identify eventual risk factors in the setting of new AlloSCT platforms with posttransplant cyclophosphamide (PTCy).Methods We designed an unicentric retrospective study of patients >14 years old receiving an AlloSCT from 2017 to 2024, with an initial identification of potential cases from clinical histories, and a second revision to confirm the diagnosis applying “TMA harmonization committee” criteria. Organ involvement was defined as the presence of hypertension, proteinuria, or evidence of renal, gastrointestinal, central nervous system, or cardiopulmonary damage.Statistical analysis was performed with R (version 4.4.0; R Foundation for Statistical Computing, Vienna, Austria). Fisher's exact test and Wilcoxon rank-sum tests were used to compare categorical and continuous variable respectively. Survival and cumulative incidence (CI) analysis were performed using Fine & Gray and cause-specific Cox regression with the cmprsk package (version 2.2-12), considering death as a competing event.Results We included 609 AlloSCT with median follow-up of 17.4 months (5.9–48.3), with 32% of unrelated and 60% of HLA-identical donors. GVHD prophylaxis consisted of Tacrolimus-MTX in HLA-identical donor transplants with myeloablative conditioning regimen (27%), PTCy-based prophylaxis in haploidentical and other mismatched donor transplant with myeloablative conditionings (36%) and Tacrolimus-Sirolimus +/- mofetil mycophenolate in reduced-intensity conditioning regimen (36%). We identified 116 potential cases with 86 (14.1%) confirmed as TA-TMA, 24 of them (27.6%) retrospectively identified without a prior documented diagnosis. Estimated CI of TA-TMA was 11.3% at 100 days and 14% at 1 year, and those patients with TA-TMA MAT had significantly increased transplant-related mortality (HR 2.83, 95% CI 1.91-4.18, p<0.001). The median time to onset was 56 days (9–349), with 69% appearing between 30 and 100 days posttransplant. Organ involvement was observed in 46% of cases, including renal (n=23, 58%), hypertension (16, 40%), gastrointestinal (12, 30%), central nervous system in 12 (30%), and cardiopulmonary in 4 (10%). AlloSCT from unrelated donors (OR 3.7; 95% CI: 1.45–9.41; p=0.013) and presence of grade 3–4 acute GVHD (OR 3.12; 95% CI: 1.08–8.92; p=0.034) were associated with organ involvement. Overall, 80.4% of cases (n=70) resolved after a median of 7 weeks (range 1–35), with a higher resolution rate in cases with isolated analytical abnormalities compared to those with organ involvement (89.5% vs. 70%; p=0.02). The presence of organ involvement was associated to lower OS (24% vs 57% at 36 months; p=0.02). When analyzing risk factors by Fine-Gray test univariate analysis, presence of HLA mismatch (p<0.01), GVHD prophylaxis regimen with PTCy (p<0.01), prior hemorrhagic cystitis due to BK/JC virus (p<0.05), and previous acute GVHD (p<0.05) were significantly associated with TA-TMA. In the setting of PTCy, TA-TMA incidence was higher in patients with BK/JC cystitis (31.8% vs 11%, p<0.001) and acute GVHD (23.3% vs 9%, p=0.022). In multivariate Fine & Gray competing risks analysis, GVHD prophylaxis with PTCy was the only independent significant factor associated with higher incidence of TA-TMA. [HR 2.03 (1.11-3.71); p=0.021]. Considering individual risk associated with risk factors detected in reduced Cox model, we could define a risk-score prediction for TA-TMA after AlloSCT: TA-TMA estimated incidence would be 6% for patients with GVHD prophylaxis other than PTCy, 8% for those with PTCy prophylaxis, 17% for PTCy + one of acute GVHD or BK/JC cystitis and 25% for those presenting all three risk factors. Conclusion: TA-TMA is associated with impaired OS, especially in those with organ involvement. PTCy is significant and independently linked to increased risk of TA-TMA, and co-occurrence of BK/JC cystitis or acute GVHD increased risk in these patients, suggesting that a closer monitorization should be implemented for them.