selinexor and Lymphoma--Non-Hodgkin

Non-Hodgkin lymphoma (NHL) is a common lymphoid hematological malignancy, the treatment and prognosis of NHL have always been the focus of clinical attention. Chemotherapy is the main first-line treatment, but there is still no effective treatment for patients with poor response to chemotherapy, recurrence or progression within a short period of time after treatment, and new and effective drugs need to be developed clinically. As the only clinically validated oral selective inhibitor of nuclear export (SINE), Selinexor has been approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma and multiple myeloma, clinical attempts are being made to apply it to the treatment of other hematological malignancies.This article reviews the anti-tumor mechanism of Selinexor and the latest research progress in its application in NHL, and provides ideas for a more diverse, standardized and effective applications of Selinexor in NHL.. Selinexor治疗非霍奇金淋巴瘤的最新研究进展.. 非霍奇金淋巴瘤（NHL）是一种常见的淋巴造血系统恶性肿瘤，NHL的治疗和预后一直是临床关注的重点。其一线治疗以化疗为主，但对化疗反应不佳、治疗后短期内复发或进展的患者尚缺乏有效的治疗手段，临床上需要研发新型有效药物。作为目前唯一一款经过临床验证的口服型选择性核输出抑制剂（selective inhibitor of nuclear export，SINE），Selinexor已获批用于治疗复发性/难治性弥漫性大B细胞淋巴瘤和多发性骨髓瘤，临床正尝试将其应用于治疗其他血液系统恶性肿瘤。现就Selinexor抗肿瘤的作用机制和在 NHL 中应用的最新研究进展作一综述，为Selinexor在 NHL 中更加多样、规范、有效的应用提供思路.

Topics: Active Transport, Cell Nucleus; Antineoplastic Combined Chemotherapy Protocols; Humans; Hydrazines; Lymphoma, Non-Hodgkin; Triazoles

The efficacy of selinexor, the first commercially available exportin inhibitor, has been evaluated in patients with diffuse large B-cell lymphoma (DLBCL) who have received at least 2 lines of therapy. Its role in treatment of DLBCL requires a review of current evidence.. This review describes the pharmacology of selinexor and the clinical trials of the medication for the treatment of patients with DLBCL. To clarify the role of selinexor in the treatment of DLBCL, a PubMed search was performed for articles on currently available treatments for relapsed/refractory (R/R) DLBCL.. Selinexor, which is administered orally, benefits from an advantageous pharmacokinetic profile with toxicity limited to hematological and digestive side effects. It has little or no interaction with other medications and no dose adjustment is required for patients with renal or hepatic impairment. Selinexor has been assessed for treatment of R/R DLBCL in one phase I and one phase II trial. Those studies found a 28% overall response rate, including 12% complete remission, with a median duration of response of 9.3 months. If selinexor's effectiveness as monotherapy is limited, it remains an option when there are no other therapeutic possibilities and can then give long-lasting responses.

Topics: Humans; Hydrazines; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Triazoles

In this review we highlight the most recent studies furthering the clinical development of selinexor, a novel exportin-1 inhibitor, for the treatment of multiple myeloma and non-Hodgkin lymphomas.. Three pivotal trials, the SADAL trial for diffuse large B-cell lymphoma, and the BOSTON and selinexor treatment of refractory myeloma trials for multiple myeloma, have recently led to the regulatory approval of selinexor monotherapy or combination regimens. They are complemented by several earlier phase clinical trials with iterative combinations, adding selinexor to novel therapies and cytotoxic chemotherapy regimens at various stages in the disease courses. In some, selinexor appears synergistic, occasionally overcoming treatment refractoriness, whereas in other situations appears additive. Consistent issues with tolerability are seen across trials, although consensus guidelines on their preemption and management have recently been adopted which may improve treatment success. While comparative data are lacking, the efficacy of selinexor-based regimens does not approach that of contemporaneous cellular and immunotherapies.. Selinexor is a novel and potentially synergistic therapy for lymphoid malignancies, although requires refined supportive measures and strategies to improve its efficacy. Likely, for continued success, it will need to identify niches that complement recent advances, such as bridging to cellular therapies or maintenance thereafter.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hydrazines; Lymphoma, Non-Hodgkin; Multiple Myeloma; Triazoles

Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease.. Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly.. The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%).. Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens.

Topics: Humans; Hydrazines; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Triazoles

Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).. In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.. Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1-14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9-16.1] and 2.7 (95% CI, 0.7-5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1-89.2) and 27.8% (95% CI, 10.1-48.9) for patients with CLL and NHL, respectively.. The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

Topics: Adenine; Adult; Humans; Hydrazines; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Piperidines; Pyrazoles; Pyrimidines; Triazoles

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.. We evaluated the antitumor activity of SINE compounds in combination with CHO chemotherapy. SINE compounds synergized with CHO. SINE compounds enhance the activity of CHO

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Humans; Hydrazines; Lymphoma, Non-Hodgkin; Mice; Prednisone; Rituximab; Triazoles; Vincristine

Selinexor is a first-in-class, oral therapy that selectively inhibits nuclear export. The drug is active with an overall response rate (ORR) of approximately 30% in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL). Long-term patient follow-up has not been reported. Thirty-one NHL patients were treated between July 2012 and July 2018; 22 were evaluated for response. ORR was 32% (7/22). Two patients achieved complete remission (CR) and were alive and lymphoma-free at the end of follow-up. Fifteen patients (68%) progressed during treatment, most of them died within 3-10 months. The most common grade 3/4 adverse events were gastrointestinal and hematological. Median follow up was 50 months. Overall survival for the entire cohort was 16%. Selinexor monotherapy for r/r NHL is an active therapy with the potential for long-term disease control. It may serve as a 'bridge' to subsequent therapy. Additional studies are needed to identify predictive biomarkers and to evaluate combination approaches.

Topics: Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; Hydrazines; Lymphoma, Non-Hodgkin; Retrospective Studies; Triazoles

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Choline; DNA Repair; DNA Replication; DNA, Neoplasm; Drug Combinations; Drug Synergism; Exportin 1 Protein; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Phthalazines; Piperazines; Random Allocation; Receptors, Cytoplasmic and Nuclear; S Phase Cell Cycle Checkpoints; Salicylates; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Characterize the population PK and exposure-response (ER) relationships of selinexor in patients with diffuse large B-cell lymphoma (DLBCL) (efficacy endpoints) or other non-Hodgkin's lymphoma (NHL) patients (safety endpoints) to determine the optimal dose in patients with DLBCL.. This work included patients from seven clinical studies, with 800 patients for PK, 175 patients for efficacy and 322 patients for safety analyses. Logistic regression models and Cox-regression models were used for binary and time-to-event endpoints, respectively. Model-based simulations were performed to justify dose based on balance between efficacy and safety outcome.. Selinexor pharmacokinetics were well-described by a two-compartment model with body weight as a significant covariate on clearance and central volume of distribution and gender on clearance. Overall response rate (ORR) in patients with DLBCL increased with day 1 C. Simulations of the safety and efficacy ER models suggested that, compared to a starting dose of 60 mg twice weekly (BIW), a 40 mg BIW regimen resulted in an absolute decrease in AE probabilities between 1.9 and 5.3%, with a clinically significant absolute efficacy decrease of 4.7% in ORR. The modeling results support that 60 mg BIW is the optimal dose in patients with DLBCL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Clinical Studies as Topic; Female; Humans; Hydrazines; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Middle Aged; Treatment Outcome; Triazoles; Young Adult

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.. 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.. 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 tumor-promoting M2-like macrophages.. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Central Nervous System Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Female; Humans; Hydrazines; Karyopherins; Lymphoma, Non-Hodgkin; Macrophages; Mice; Mice, Nude; Piperidines; Receptors, Cytoplasmic and Nuclear; Survival Rate; Triazoles; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL. Combination of selinexor with DEX or EVER resulted in enhanced cytotoxicity in WSU-DLCL2 and WSU-FSCCL cells which was consistent with enhanced apoptosis. Molecular analysis showed enhancement in the activation of apoptotic signaling and down-regulation of XPO1. This enhancement is consistent with the mechanism of action of these drugs in that both selinexor and DEX antagonize NF-κB (p65) and mTOR (EVER target) is an XPO1 cargo protein. SINE compounds, KPT-251 and KPT-276, showed activities similar to CHOP (cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone) regimen in subcutaneous and disseminated NHL xenograft models in vivo. In both animal models the anti-lymphoma activity of selinexor is enhanced through combination with DEX or EVER. The in vivo activity of selinexor and related SINE compounds relative to 'standard of care' treatment is consistent with the objective responses observed in Phase I NHL patients treated with selinexor. Our pre-clinical data provide a rational basis for testing these combinations in Phase II NHL trials.

Topics: Acrylamides; Active Transport, Cell Nucleus; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Cyclophosphamide; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Everolimus; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Lymphoma, Non-Hodgkin; Mice, Inbred ICR; Mice, SCID; Oxadiazoles; Prednisone; Protein Kinase Inhibitors; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Thiazoles; Time Factors; TOR Serine-Threonine Kinases; Transcription Factor RelA; Triazoles; Tumor Burden; Vincristine; Xenograft Model Antitumor Assays