Sinusoidal Obstruction Syndrome in Adult Patients with B-Cell Acute Lymphoblastic Leukemia Treated with Inotuzumab Prior to Hematopoietic Stem Cell Transplantation

Abstract

BACKGROUND: Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a potentially life-threatening toxicity observed post allo-HCT, with the reported incidence estimated to be 10-15% and mortality as high as 80% based on the severity (Coppell et al. BBMT 2010). Current management of SOS focusses on minimizing transplant- and patient-related factors. Inotuzumab ozogamicin (InO) is a humanized monoclonal antibody-drug conjugate targeting the CD22 antigen and has proven to be more efficacious than conventional chemotherapy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the INO-VATE ALL phase 3 trial. However, liver-adverse events were more frequently encountered in the InO group with SOS occurring in 22.8% (n=18) of patients who proceeded to allo-HCT (Kantarjian et al. NEJM 2016). Given the effectiveness of InO as salvage therapy pre-HCT, we aimed to investigate incidence and outcomes of SOS in adult patients with R/R ALL that received InO and proceeded to consolidation with HCT. METHODS: We retrospectively studied adult patients (pts) with R/R B-ALL that received InO as salvage therapy and underwent consolidation with allo-HCT at City of Hope from 2014 to 2022. Graft source was peripheral blood for all patients. All pts. received prophylactic therapy with ursodiol and heparin was added to pts receiving myeloablative conditioning. Diagnosis and severity grading for SOS was in accordance with the revised EBMT criteria (Mohty et al. Bone Marrow Transplantation 2016). All pts. with SOS were treated with defibrotide. Fischer's exact test was used to complete the case-control analysis of patients with SOS vs. those without, and univariable analysis was completed using Cox regression. RESULTS: We identified 47 patients in our study, with 12 pts (25.5%) developing SOS post-HCT. Median time to diagnosis of SOS was 11 days (range: 3-41) and grade was very severe in 50% (n=6), severe in 25% (n=3), and mild in 25% (n=3). All pts. received treatment with defibrotide for median 20.5 days (range: 3-34), with resolution of SOS in 66.7% (n=8) of patients. Mortality from SOS was 33.3% (n=4) within a median of 10 days from diagnosis (range: 3-31), with pts. being graded as very severe (n=3, 75%) or severe (n=1, 25%). The group of pts with SOS compared to those without SOS did not have any significant difference in median duration between last dose of InO and HCT (46 vs. 53 days, P=0.37), myeloablative conditioning regimen (42% vs. 49%, P=0.75), TBI-based preparative regimen (50% vs. 57%, P=0.74), or disease status at transplant >CR1 (83% vs. 68%, P=0.83). There was no significant difference between the groups in lines of therapy prior to InO (P=0.79). Both groups received median 2 cycles of InO (P=0.14) and received InO as last therapy prior to HCT in 67% of patients with SOS and 66% in those patients without SOS (P=1.0). Sirolimus-based GVHD prophylaxis was more common in the SOS group (75% vs. 29%, P<0.01), but there was no difference in peak sirolimus level (P=0.81) or median time to peak sirolimus level (7 vs. 3.5 days, P=0.39) between the two subgroups. On univariable analysis, the use of sirolimus as GVHD prophylaxis was the only variable significant for SOS development, HR=7.50 [95% CI:1.7-33.6, P<0.01]. In the SOS group, the 100-day mortality rate was 33.3% (n=4) with median overall survival (OS) post-SOS of 4.3 months (range: 0.2 - 57.2). In the group without SOS, the 100-day mortality rate was 14.2% (n=5) and median OS post-HCT was 10.7 months (range: 0.52 - 39.6). CONCLUSION: To our knowledge, this is the largest single-center retrospective analysis of R/R ALL patients that received InO as salvage therapy pre-HCT. The incidence of SOS was high, and prompt initiation of defibrotide demonstrated efficacy in treating SOS. Despite the effectiveness of Ino as salvage therapy, the risk of SOS can potentially be mitigated by minimizing risk factors, especially the use of sirolimus-based GVHD prophylaxis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal