15-PGDH Inhibition Mitigates Aplastic Anemia Severity

Acquired aplastic anemia (AA) is a primary bone marrow (BM) failure syndrome in which hematopoietic stem cells (HSC) are depleted in an immune-mediated fashion. AA is rare, with an estimated 900 new cases per year in the U.S., and onset is typically in childhood or adolescence. AA is fatal if untreated and poses a high burden of frequent, long-term transfusions and associated complications. The current standard of care for severe AA is allogeneic stem cell transplantation for young patients who have a matched related donor or immunosuppressive therapy (IST) for those who do not. Among other toxicities, prolonged neutropenia, immune suppression and the resulting risk of severe infections remain challenges in managing even AA patients responding to standard therapies. These challenges are more critical in severe AA patients refractory to front line therapy. Importantly, this disorder is also associated with clonal evolution of myeloid progenitor cells, and the development of myelodysplastic syndrome and acute myeloid leukemia in 10-20% of cases (Yoshizato, N Engl J Med, 2015). Therefore, additional therapies to either block immune-mediated BM destruction, or to accelerate hematologic recovery in patients receiving IST, are needed.

Inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) using the small molecule SW033291 (PGDHi) in mice was recently shown by Zhang et al. to increase BM prostaglandin E2 (PGE2) levels, expand HSC numbers, accelerate hematologic reconstitution following BM transplantation, and synergize with G-CSF for neutrophil recovery (Zhang, Science, 2015). To determine whether PGDHi is capable of improving hematopoiesis in acquired AA, we induced immune-mediated BM failure in mice (Chen, Blood, 2004) and treated with SW033291 starting at day 4 post-induction. PGDHi mitigated both neutropenia and thrombocytopenia, increased phenotypic and functional BM HSC and progenitor cells, and significantly extended survival compared to vehicle-treated mice in the same cohort. Analysis of peripheral blood serum revealed no impact of PGDHi on circulating IFNγ levels, however. These data suggest that PGDHi protects hematopoietic stem cell function in acquired AA. There was an observed trend for lower CD8⁺ FasL⁺ T cells in the BM of PGDHi treated mice. Experiments are underway to determine if PGDHi reproducibly impairs T cell activation and modulates the inflammatory cytokine milieu in the BM. A comparison of PGDHi and Cyclosporine (CsA), the backbone of IST in AA, is also underway to examine if PGDHi can augment IST efficacy using lower, better tolerated cyclosporine dosing. In this murine model, low dose (10mg/kg) CsA, unlike standard dose (50mg/kg) CsA, did not cause kidney or liver toxicity as assessed in peripheral blood serum, but failed to protect against neutropenia and thrombocytopenia. Preliminary results demonstrate that dual PGDHi and low dose Cyclosporine administration significantly enhances neutrophil and platelet recovery, achieving responses similar to that of standard dose IST, thus suggesting that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.