Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

Bobillo, Sabela; Carpio, Cecilia; Raheja, Priyanka; Castellví, Josep; Crespo, Marta; Bosch, Francesc

doi:10.3324/haematol.2017.181636

Cited by 20 publications

(14 citation statements)

References 9 publications

(13 reference statements)

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“…The patient received several lines of treatment including autologous stem cell transplantation prior to the relapse, and failed to respond to methotrexate. Treatment with selinexor results in complete remission within 5 months of treatment [ 76 ].…”

Section: Clinical Trials With Nuclear Transport Inhibitorsmentioning

confidence: 99%

Targeting nuclear import and export in hematological malignancies

Nachmias

Schimmer

2020

Leukemia

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The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.

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Section: Clinical Trials With Nuclear Transport Inhibitorsmentioning

confidence: 99%

Targeting nuclear import and export in hematological malignancies

Nachmias

Schimmer

2020

Leukemia

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“…Additionally, based on our pre-clinical experience, we recently used selinexor in a compassionate way for a patient diagnosed with DLBCL who developed an isolated CNS relapse after several lines of treatment. After a month of treatment a partial response was already observed while after 5 months of selinexor the patient remained asymptomatic and the MRI (magnetic resonance imaging) showed a complete resolution of the brain tumors [19]. Ibrutinib is also able to cross the BBB and is active against CNS lymphoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Also, the ability of selinexor to inhibit both the BCR and the NF-κB signaling pathways makes this drug interesting for studies in NHL [16,18]. Recently, in a clinical case study, selinexor was reported to inhibit refractory DLBCL with CNS involvement [19]. In order to provide a pre-clinical rationale for the design of new therapeutic strategies for patients diagnosed with PCNSL, herein we evaluate the role of XPO1 and BTK inhibition in intracerebral xenograft murine models, focusing on malignant cells and the innate immune microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

et al. 2020

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Background Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Methods Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Results Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumorpromoting M2-like macrophages. Conclusions These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide preclinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

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“…The median onset of N/V occurred at day 3, suggesting delayed emesis, which should be properly managed [28,29]. Previous studies have suggested that selinexorinduced N/V is likely mediated through the central nervous system, as selinexor crosses the blood brain barrier and has anticancer activity in the brain [30][31][32]. Prophylactic use of a 5-HT3 RAs (ondansetron or equivalent) in all patients, was mandated on selinexor trials after phase 1 to reduce N/V.…”

Section: Discussionmentioning

confidence: 99%

Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials

et al. 2020

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Selinexor is an oral, small molecule inhibitor of the nuclear export protein exportin 1 with demonstrated activity in hematologic and solid malignancies. Side effects associated with selinexor include nausea, vomiting, fatigue, diarrhea, decreased appetite, weight loss, thrombocytopenia, neutropenia, and hyponatremia. We reviewed 437 patients with multiple myeloma treated with selinexor and assessed the kinetics of adverse events and impact of supportive care measures. Selinexor reduced both platelets and neutrophils over the first cycle of treatment and reached a nadir between 28 and 42 days. Platelet transfusions and thrombopoietin receptor agonists were effective at treating thrombocytopenia, and granulocyte colony stimulating factors were effective at resolving neutropenia. The onset of gastrointestinal side effects (nausea, vomiting, and diarrhea) was most common during the first 1-2 weeks of treatment. Nausea could be mitigated with 5-HT3 antagonists and either neurokinin 1 receptor antagonists, olanzapine, or cannbainoids. Loperamide and bismuth subsalicylate ameliorated diarrhea. The primary constitutional side effects of fatigue and decreased appetite could be managed with methylphenidate, megestrol, cannabinoids or olanzapine, respectively. Hyponatremia was highly responsive to sodium replacement. Selinexor has well-established adverse effects that mainly occur within the first 8 weeks of treatment, are reversible, and respond to supportive care.

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Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

Cited by 20 publications

References 9 publications

Targeting nuclear import and export in hematological malignancies

Targeting nuclear import and export in hematological malignancies

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials

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