KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells.

Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML.

Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.

Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.

The outcome of targeting community mental health services: evidence from the West Lambeth schizophrenia cohort.

OBJECTIVES: To report outcome of targeting community mental health services to people with schizophrenia in an inner London district who had been shown, one year after discharge, to have high levels of psychotic symptomatology and social disability but very low levels of supported housing and structured day activity. DESIGN: Repeat interview survey of symptoms, disability, and receipt of care four years after index discharge. SETTING: Inner London health district with considerable social deprivation and a mental hospital in the process of closure. SUBJECTS: 51 patients originally aged 20-65 years who satisfied the research diagnostic criteria for schizophrenia. MAIN OUTCOME MEASURES: Contact with services during the three months before interview, levels of symptoms (from present state examination), global social disability rating. RESULTS: 65% (33/51) of the study group had been readmitted at least once in the three years between surveys. Recent contacts with community psychiatric nurses and rates of hospital admission increased (8 at one year v 24 at four years, p < 0.01; 5 v 13, p < 0.06). Conversely, fewer patients were in contact with social workers (17 v 7, p < 0.03). Proportions in supported housing, day care, or sheltered work did not change. Unemployment rates remained very high. A considerable reduction (almost a halving) in psychiatric symptoms was observed, but there was no significant change in mean levels of social disability. CONCLUSIONS: The policy of targeting the long term mentally ill resulted in significant increases in professional psychiatric input to the cohort but failed to improve access to social workers or suitable accommodation. Improvements in social functioning did not follow from reductions in the proportions of patients with psychotic mental states. Social interventions are likely to be crucial to achieving the Health of the Nation target of improving social functioning for the seriously mentally ill, as improving mental state seems in itself to be insufficient.