Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase I Study.
Clin Cancer Res
; 27(12): 3307-3316, 2021 06 15.
Article
en En
| MEDLINE
| ID: mdl-33785483
ABSTRACT
PURPOSE:
The nuclear exporter protein exportin-1 (XPO1) is overexpressed in non-Hodgkin lymphoma (NHL) and correlates with poor prognosis. We evaluated enhancing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) activity in NHL by targeted inhibition of XPO1 using the selective inhibitor of nuclear export (SINE) compounds. PATIENTS ANDMETHODS:
We evaluated the antitumor activity of SINE compounds in combination with CHO chemotherapy in vitro and in vivo. Newly diagnosed NHL patients in a phase I dose-escalation study received R-CHOP for 6 cycles with weekly selinexor (60, 80, and 100 mg), then selinexor maintenance therapy for one year. RT-PCR, Western blotting, and RNA sequencing were performed on patient blood samples.RESULTS:
SINE compounds synergized with CHO in vitro in NHL cell lines and in vivo in our murine xenograft model. In our phase I study, selinexor was dosed at 60 mg (n = 6) and 80 mg (n = 6). The most common adverse events (AE) among 12 patients were fatigue (67%) and nausea (100%). Grade 3-4 AEs were infrequent. Ten evaluable patients had an overall response rate of 100% and complete remission rate of 90% with sustained remissions (median follow-up 476 days). Maximally tolerated dose was not reached; however, the recommended phase II dose was 60 mg selinexor weekly after evaluating tolerability and discontinuation rates for each dose cohort. Analysis of patient blood samples revealed downregulation of XPO1 and several prosurvival markers.CONCLUSIONS:
SINE compounds enhance the activity of CHO in vitro and in vivo. Selinexor in combination with R-CHOP was generally well tolerated and showed encouraging efficacy in NHL (NCT03147885).
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfoma no Hodgkin
/
Protocolos de Quimioterapia Combinada Antineoplásica
Tipo de estudio:
Observational_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2021
Tipo del documento:
Article