Impact of Modification of Immunosuppressive Therapy Following Diagnosis of Transplant-Associated Thrombotic Microangiopathy in Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience

Background Calcineurin inhibitors (CNI) and sirolimus are often implicated in transplant-associated thrombotic microangiopathy (TA-TMA). There is lack of consensus regarding how to modify these immunosuppressive therapies (IST) following a diagnosis of TA-TMA due to the inherent risk of worsening or precipitating acute graft versus host disease (aGVHD). Objective We aim to compare outcomes of aGVHD between patients with different IST strategies adopted at TA-TMA diagnosis [discontinuation (Group A) vs tapering (Group B) vs continuation (Group C)]. Methods This was an institutional review board (IRB) approved retrospective, single center study. All allogeneic HCT recipients (2014-2023) who were diagnosed with TA-TMA and received GVHD prophylaxis with CNI or sirolimus were included. Descriptive statistics were used to analyze aGVHD outcomes. Results Twenty-five patients were identified; majority male (n=17, 68%) and Caucasian (n=16, 64%); 15 with malignant and 10 with non-malignant diagnosis. All but two Group C patients had severe TA-TMA post allogeneic hematopoietic stem cell transplant (HCT). The median age at HCT was 2.87 years (range: 0.21 - 25.1 years). TA-TMA was diagnosed at median of 69 days (range: 17-140 days) from HCT. Pre-TA-TMA, GVHD prophylaxis was either CNI (n=24) or sirolimus (n=1). In the patients not on IST taper (n=23) prior to TA-TMA diagnosis, 65% (n=15) had supratherapeutic levels. In majority of patients (84%; n=21) IST was modified with TA-TMA onset; 16 in Group A stopped IST abruptly or within a week (Group A) and 5 in Group B tapered IST over 2-7.5 weeks. Amongst Group A, 14 were started on alternative IST including steroids (n=5), mycophenolate (MMF) (n=3), MMF + steroids (n=3), ruxolitinib (n=1), abatacept (n=1), and abatacept+ steroid (n=1). In the remaining 2 patients, 1 continued systemic steroid for diffuse alveolar hemorrhage and 1 received no further IST. In Group B, 1 received MMF and 4 continued the taper with no additional IST. In 4 Group C patients IST was unchanged. The median time to TA-TMA resolution amongst the three groups (A vs B vs C) was 157 (38-412) days vs 49 (12-256) days vs 31 (7-56) days. Outcomes of aGVHD amongst the three groups are shown in Figure 1. Worsening of aGVHD (increase in grade or new onset) was seen in 56% (n=9/16) of group A vs 0% (n=0/5) of group B vs 50% (n=2/4) of Group C patients (p=0.10). At 1-year post-HCT, mortality was 25% in Group A (infection:2, relapse: 2), 40% in Group B [relapse:1, multi-organ dysfunction (MOD):1] and 25% in Group C (MOD+GVHD:1) (p=0.82). Conclusion In our limited cohort, irrespective of IST strategy we observed similar rates of worsening/new onset GVHD amongst the three groups. Prospective, multicenter studies are needed to guide the optimal IST approach in this setting.