Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis

Abstract

Selinexor is the first oral selective inhibitor of nuclear export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (#NCT03071276, #NCT02343042, #NCT02227251, #NCT03110562, and #NCT02606461). Although selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management. We determined that selinexor causes thrombocytopenia by blocking thrombopoietin (TPO) signaling and therefore differentiation of stem cells into megakaryocytes. We then used both in vitro and in vivo models and patient samples to show that selinexor-induced thrombocytopenia is indeed reversible when TPO agonists are administered in the absence of selinexor (drug holiday). In sum, these data reveal (1) the mechanism of selinexor-induced thrombocytopenia, (2) an effective way to reverse the dose-limiting thrombocytopenia, and (3) a novel role for XPO1 in megakaryopoiesis. The improved selinexor dosing regimen described herein is crucial to help reduce thrombocytopenia in selinexor patients, allowing them to continue their course of chemotherapy and have the best chance of survival. This trial was registered at www.clinicaltrials.gov as #NCT01607905.

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

“…Selinexor-induced thrombocytopenia results from the inhibition of hematopoietic stem-cell maturation to megakaryocytes, without affecting hematopoietic stem-cell survival, platelet activation, mature megakaryocyte survival, or proplatelet formation. 29 In this study, thrombocytopenia was reversible with platelet-stimulating growth factors, and evaluation of two patients with selinexor-induced thrombocytopenia showed normal marrow with maturing trilineage hematopoiesis. Some patients reported dizziness despite adequate volume repletion.…”

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

“…The safety results with SKd were generally consistent with safety outcomes from previous studies of selinexor in RRMM, although the rates and severity of non‐haematological AEs, particularly GI events, were lower than anticipated (Bahlis et al , ; Chen et al , ; Vogl et al , ). In the phase II STORM study ( N = 79 RRMM), the most common grade 3/4 treatment‐related AEs associated with twice‐weekly Sd (80 mg selinexor/20 mg dexamethasone) was thrombocytopenia (59%) (Vogl et al , ), an established toxicity of selinexor because of its inhibition of megakaryocyte maturation (Machlus et al , ). Other grade 3/4 treatment‐related AEs included anaemia (28%), neutropenia (23%) and lymphopenia (11%).…”

Thrombopoietin Metabolically Primes Hematopoietic Stem Cells to Megakaryocyte-Lineage Differentiation

“…Finally, we asked what downstream signals mediate HSC mitochondrial function in response to Thpo. Selinexor (KPT-330) has been used recently to confine phospho-signal transducer and activator of transcription 3 (pSTAT3) to the HSC nucleus by inhibiting exportin 1 (XPO1)-mediated translocation to the cytoplasm and alter Mk differentiation (Machlus et al, 2017). HSCs purified from WT mice were cultured 3 days with or without KPT-330.…”