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Patients with acute leukemia who undergo allogenic hematopoietic cell transplantation with active disease have high rates of relapse and poor overall survival (OS) post-transplant compared to patients undergoing HCT in remission. Here, we report the long-term outcomes in 32 patients who received a high-intensity conditioning regimen comprising fractionated total body irradiation (FTBI; 1200 cGy) with pharmacokinetic (PK) dosing of intravenous Busulfan (IV BU) targeted to first dose area under curve (AUC) of 700–900 µM/min and etoposide (30 mg/kg) in a prospective phase 2 clinical trial. The median age of the patients at the time of HCT was 37 years (range: 18–50) presenting with high-risk (n = 6) and relapsed/refractory(r/r) acute leukemias (n = 26). All but one patient underwent HCT using peripheral blood stem cells from matched sibling donors. At a median follow-up of 17.3 years (range 14.4–19.0), 11 patients remained alive. The disease-free survival and OS at 15 years was 34% (versus 40% at 5-years post-HCT). The 15-year cumulative incidence of relapse was 26% and non-relapse mortality (NRM) was 38% (95% CI: 21–54%) and the cumulative incidence of chronic GVHD at 15 years was 33% using a prophylactic regimen of cyclosporine A and mycophenolate mofetil. The most common life-threatening late effects were secondary malignancies, metabolic, or cardiac complications with a cumulative incidence of 6.6%, 6.6%, and 13.3%, respectively. No unusual late effects or patterns of relapse were noted on longer followed on patients treated with intensified myeloablative condition regimen. Results from this study supports continued development of intensive conditioning regimens in patients with r/r acute leukemias to improve leukemia free (LFS) and OS in this high-risk population. [ABSTRACT FROM AUTHOR]

Background: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease–positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19– disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. Methods: This study retrospectively reviewed the outcomes of adult patients with B‐cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013‐2021) and analyzed factors associated with treatment response and EMD failure. Results: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P =.049) and no history of previous EMD (P =.019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P =.005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P =.012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. Conclusions: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. Lay Summary: Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia.A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites.Most extramedullary failure cases retain CD19 expression. Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. [ABSTRACT FROM AUTHOR]