Veno-Occlusive Disease Risk and Other Outcomes in Patients With B-Cell Precursor Acute Lymphoblastic Leukemia Receiving Inotuzumab Ozogamicin and Proceeding to Hematopoietic Stem Cell Transplantation

Objectives: Inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate indicated for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL), is associated with hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), particularly after post-hematopoietic stem cell transplantation (HSCT). In this sttudy, we evaluate HSCT outcomes in patients (pts) who received InO before HSCT. Materials and methods: This observational, post-authorization safety study included pts (>=18y) in the US with B-cell precursor ALL and R/R ALL who received InO and proceeded to first allogeneic HSCT. Post-HSCT outcomes included overall survival (OS), non-relapse mortality (NRM), relapse, and adverse events (AEs). Multivariate analysis examined prognostic factors for NRM and VOD. This final analysis is based om 5-y data. Results: 261 pts (median age 39y, 58% male) were evaluated: 36% in first complete remission (CR1), 46% in CR2, 11% in CR>=3, 4% in first relapse, 1% in >= third relapse, and 2% with primary induction failure. Prior to HSCT, 32%, 47%, 14%, 5% and <1%received 1,2,3,4, and 5 InO cycles respectively: 120 pts received InO monotherapy and 112 received InO with systemic therapy (data unavailable for 29 pts). CR/CRi and MRD negativity was achieved in 80% and 64% of pts respectively after InO> Median time from last InO dose to HSCT was 2.5 mo. Post-HSCT 18-mo OS was 54% and 50% and 18-mo NRM was 22% and 25% for pts with ALL and R/R ALL respectively; most common causes of NRM were VOD (26%, 24%) and graft-versus-host disease (GVHD: 22%, 19%). AEs<=100d post-HSCT occuring in >=30% of pts with ALL and R/R ALL respectively were bacterial infection (51%, 56%), viral infection (44%, 44%) and acute GVHD (grades II-IV; 43%, 41%). 35 pts with ALL developed VOD: 15 cases were mild, 20 were severe and 22 died <= 18 mo post-HSCT; 8/35 pts received prophylactic defibrotide (22/244 of all pts). Transplant sources for the 15 mild and 20 severe cases of VOD, respectively, were peripheral blood stem cells (n+10,12), bone marrow (n+4,8) and umbilical cord blood (n = 1,0). VOD incidence <=100d post-HSCT was, respectively: 20%, 17%, 10% and 16% in pts with cumulative InO doses of <1,8, 1.8-2.7, 2.8-3.2, and >= 3.3 mg/m2; and 15%, 2%, 17% and 14% in pts with time from las InO dose to HSCT of 1, 1.1-1.6, 1.7-4, and >=3 mo. 204 pts with ALL were included in multivariate analyses; Karnofsky score <90 or unknown (vs 90-100) and dual alkylators (compared by MAC/no dual alkylators and RIC/non-MAC) were significant negative prognostic factors for NRM at 18 mo. Dual alkylators were the only significant negative prognostic factor for VOD at 100d (compared by MAC/no dual alkylators and RIC/non-MAC). Discussion: In this real-world population of adults withh ALL who received InO before HSCT, including heavily pretreated pts, 18-mo OS was 54% and 18-mo NRM was 22%. Common AEs post-HSCT were bacterial infection, viral infection, and acute GVHD. Conclusions: VOD incidence was consistent with previous reports and dual alkylators should be avoided, when possible, in this subset of pts. Pts receiving these regimens should be considered for clinical trials testing novel prophylactic treatments for post-HSCT endothelal dysfunction syndromes, such as VOD.