Pilot experience with opebacan/rBPI21 in myeloablative hematopoietic cell transplantation

Abstract

Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT). Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI), a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities. Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI 21, generic name opebacan) might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0) and continued for 72 hours. The trial was to have included escalation of rBPI 21 dose and duration but was stopped prematurely due to lack of further drug availability. Therefore, to better understand the clinical course of opebacan-treated patients (n=6), we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35). Opebacan-treated participants had earlier platelet engraftment (p=0.005), mirroring beneficial effects of rBPI 21 previously observed in irradiated mice, fewer documented infections (p=0.03) and appeared less likely to experience significant regimen-related toxicities (p=0.05). This small pilot experience supports the potential utility of rBPI 21 in ameliorating HCT-related morbidity and merits further exploration.

rBPI21 (opebacan) promotes rapid trilineage hematopoietic recovery in a murine model of high‐dose total body irradiation

“…In this report, at TBI doses where D30 survival was 42%-75% without intervention, we nonetheless observed profound persistent recovery and substantially fewer infections and Grade 3-5 toxicities in the first 35 days post-transplant than that observed in protocol-eligible cotemporaneous controls. 51 In aggregate, these data support the hypothesis that rBPI 21 could impact transfusion requirements, pancytopenia-related complications including infections, and associated material, personnel and hospitalization utilization postirradiation.…”

“…Notably, a different N‐terminal BPI construct was recently shown to promote HSC, progenitor and myeloid cell recovery postirradiation in a perfused murine BM‐on‐a‐chip model of AHS (RBC, megakaryocyte and PLT production were not quantitated) . In addition, in a small phase I/II study we conducted in patients receiving myeloablative chemoradiotherapy conditioning for allogeneic hematopoietic cell transplantation, a 72‐hour rBPI 21 infusion was well‐tolerated and associated with considerably more rapid PLT recovery and substantially fewer infections and Grade 3–5 toxicities in the first 35 days post‐transplant than that observed in protocol‐eligible cotemporaneous controls . In aggregate, these data support the hypothesis that rBPI 21 could impact transfusion requirements, pancytopenia‐related complications including infections, and associated material, personnel and hospitalization utilization postirradiation.…”