Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase I Study

This article is featured in Highlights of This Issue, p. 3267

The rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen is currently the standard of care for untreated diffuse large B-cell lymphoma (DLBCL), as well as aggressive presentations of indolent lymphomas (1). Although R-CHOP is curative for ∼50% of patients with advanced-stage DLBCL, a subset of high-risk Non–Hodgkin lymphoma (NHL) patients, including those with transformed lymphomas and double-hit lymphomas, have higher rates of relapse after R-CHOP therapy (2). Resistance to R-CHOP is likely multifactorial (3), with potential mechanisms including inhibition of antibody-dependent cellular cytotoxicity (ADCC) by deposition of C3-activating fragments (3), polymorphism of the FcγRIIIa on cytotoxic cells (4), suppressed complement-dependent cytotoxicity (CDC; ref. 5), loss of CD20 expression on the surface of subclones (6), overexpression of prosurvival genes such as c-myc and the BH-3 family members (7), mutations in CD20 (8), and shedding of CD20 rituximab complexes (9). Recent genomic studies have also shown that refractory B-cell lymphomas consistently carry mutations in TP53 and KMT2D, and CD20 encoding MS4A1 (10). The wide spectrum of molecular drivers of lymphomagenesis and the subsequent emergence of additional acquired mutations contribute to chemoresistance in many patients.

High-throughput screening studies have identified recurrent aberrations in several genes with potential therapeutic significance in NHL, including exportin-1 (XPO1) (11). XPO1 is one of eight nuclear protein exporters and a member of the importin-β superfamily (karyopherins); it uniquely recognizes “cargo” proteins with leucine-rich nuclear export signals (NES; ref. 12). This transport system is critical to normal cellular function, differentiation, and development. Tumor suppressor proteins (TSP), which regulate cell division and replication, must localize to the cell nucleus to function properly (13). Overexpression of XPO1 results in enhanced TSP export from the nucleus, leading to their functional inactivation. XPO1 overexpression was confirmed to functionally suppress TSPs, with resultant effects on NHL cell proliferation (14). An association between XPO1 overexpression and poor overall survival and progression-free survival in NHL has also been established (15). Selective inhibitor of nuclear export (SINE) compounds are a novel class of slowly reversible XPO1 inhibitors developed for this purpose (16). CRISPR/Cas9 genome editing studies have confirmed the specificity of these compounds (17). SINE compounds bind to the Cys528 residue in the XPO1 NES binding pocket, thereby inhibiting XPO1 export activity. We previously demonstrated that SINE compounds can induce nuclear localization of TSPs and inhibit NHL cell line proliferation at low nanomolar concentrations, suppress growth of WSU-DLCL2 (diffuse large B-cell lymphoma) subcutaneous tumors, and suppress WSU-FSCCL (follicular small cleaved cell lymphoma) systemic proliferation in murine models (18).

Selinexor is an orally bioavailable SINE that specifically blocks XPO1 (19). In a phase II study involving 127 heavily pretreated DLBCL patients, the SADAL trial, selinexor monotherapy resulted in an overall response rate (ORR) of 29% [including complete remission (CR) in 13%] with durable responses, and demonstrated efficacy in both germinal center B-cell like (GCB) and non-GCB subtypes (20). Patients with responses included a spectrum of high-risk groups including transformed DLBCL and also patients relapsing after prior autologous stem cell transplant (20, 21). This demonstrated efficacy of selinexor monotherapy in relapsed/refractory NHL validates XPO1 as a therapeutic target in NHL. Given its encouraging single-agent activity in lymphoma, we undertook preclinical studies evaluating the potential use of selinexor with standard CHOP therapy, and also designed a phase I study evaluating the safety and preliminary efficacy of the combination of selinexor with R-CHOP in patients with untreated NHL.

Studies were carried out using the follicular NHL cell line (WSU-FSCCL) and the DLBCL cell line (WSU-DLCL2; mut-p53, myc, and bcl double hit) previously developed by our laboratory at Wayne State University (WSU; ref. 22). The cell authentication for WSU-DLCL2 and WSU-FSCCL was done in the core facility of the Applied Genomics Technology Center at WSU on April 12, 2017. The method used for testing was short tandem repeat profiling using the PowerPlex 16 System from Promega. Mycoplasma testing for WSU-DLCL2 and WSU-FSCCL was done on January 9, 2020. The method used for this testing was PCR using the Mycoplasma PCR Detection Kit (Applied Biological Materials Inc). The length of time between thawing and use of the cells was about one to two months and within 10 passages. All cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (HyClone Laboratories) and 1% penicillin–streptomycin (Invitrogen), at 37°C in a humidified incubator with 5% CO₂. Primary antibodies were purchased from Cell Signaling Technology. All secondary antibodies were obtained from Sigma. Cells were exposed to SINE in the presence or absence of CHO and viability was determined by the trypan blue assay as described previously (20). The results were plotted as means ± Standard Deviation of three separate experiments using three determinations per experiment for each experimental condition.

Apoptosis was analyzed using Annexin V FITC assay using apoptosis assay kit (Biovision). Briefly, NHL cells were treated with selinexor and eltanexor at 25 nmol/L for WSU-FSCCL and 50 nmol/L for WSU-DLCL2 along or in combination with CHO given as: (C) cyclophosphamide monophosphate was dosed at 6 pmol/L, (H) doxorubicin at 1.5 pmol/L, and (O) vincristine at 260 pmol/L. Cells were collected 72 hours later and stained with Annexin and propidium iodide according to the manufacturer-described protocol (Biovision). Stained cells (20,000) were analyzed on a FACScan (Becton Dickinson).

Cells (1 × 10⁶) were grown in T75 flasks and exposed to indicated concentrations of SINE compounds (selinexor or eltanexor) in the presence or absence of cyclophosphamide, doxorubicin, and vincristine (CHO) for 72 hours, followed by extraction of nuclear and cytosolic proteins for Western blot analysis using previously described methods (23).

This study was completed under WSU Institutional Animal Care and Use Committee–approved protocol (#18-12-0887) to evaluate the antitumor effect of the SINE compounds (selinexor or eltanexor) with or without concurrent CHOP chemotherapy in a xenograft model of disseminated human follicular lymphoma. Trypan blue confirmed viable WSU-FSCCL (10 × 10⁶) cells were injected via the tail vein of 42 naïve, 5–6-week-old ICR-SCID female mice (Taconic Biosciences). One week later, mice were randomized into six groups of seven mice each. Group 1: untreated; group 2: eltanexor orally at 15 mg/kg twice weekly for 4 weeks; group 3: selinexor orally at 10 mg/kg twice weekly × 4 weeks; group 4: intravenous cyclophosphamide (C; 40 mg/kg), doxorubicin (H; 3.3 mg/kg), and vincristine (O; 0.5 mg/kg) × 1 and oral prednisolone (P) at 0.2 mg/kg for five consecutive days; group 5: eltanexor plus CHOP (at the doses and routes used in groups 2 and 4, respectively); and group 6: selinexor plus CHOP (at the doses and routes used in group 3 and 4, respectively). Mice were followed daily for any signs of drug toxicity and/or disseminated disease. At the end of 160 days after initial NHL cells inoculation, any remaining animals were euthanized and their livers, spleens, lymph nodes, and brains were grossly inspected for assessment of lymphoma burden and treatment response.

This is an open-label, nonrandomized, phase I study of selinexor in combination with standard R-CHOP chemotherapy in patients with NHL. The primary objective was to determine the safety, tolerability, recommended phase II dose (RP2D), and maximum tolerated dose (MTD) of selinexor in combination with R-CHOP. The phase I portion of this study included (i) patients with stage III or IV DLBCL who had no prior therapy, including transformed DLBCL, and (ii) patients with indolent lymphomas (including indolent mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, and Waldenstrom's macroglobulinemia) who had no prior therapy or received one prior therapy not containing an anthracycline. Eligible patients were 18 years or older, must have an Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function and peripheral blood counts. Important exclusion criteria included central nervous system involvement by lymphoma and prior exposure to anthracyclines. This study was conducted in accordance with the Declaration of Helsinki. This study was approved by the WSU Institutional Review Board (IRB) #123416PH1F; protocol #2016-125, and a data safety monitoring committee meeting was conducted monthly. A written informed consent was obtained from the patients.

This study used a standard “3 + 3” dose-escalation design in which patients received six 21-day cycles of R-CHOP [rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² (maximum 2 mg) given by infusion on day 1; prednisone 100 mg orally on days 1 through 5 in a 21-day cycle] and escalating doses of selinexor on days 1, 8, and 15 of each cycle. The dose levels for selinexor weekly were 0: 60 mg, 1: 80 mg, and 2: 100 mg. Weekly selinexor maintenance, at the dose used at the conclusion of chemotherapy, was continued for an additional one year. Dose-limiting toxicity (DLT) in the first cycle of therapy was defined as discontinuation of selinexor due to adverse events (AE), one or more missed doses of selinexor due to an AE, grade 3 or higher fatigue lasting more than 5 days despite optimal supportive medications, grade 3 or higher nausea/vomiting/diarrhea persisting more than 7 days despite optimal supportive meditations, grade 4 hematologic toxicities resulting in a dose delay, grade 3 thrombocytopenia associated with major clinically significant bleeding, and grade 3 or above biochemical abnormalities (including markers of liver and renal function) lasting more than 3 days. Given early recognition of profound neutropenia with the combination, mandatory G-CSF support was implemented. Mandatory antiemetic therapy with ondansetron was used, and the addition of megestrol acetate or olanzapine daily was also strongly recommended based on prior studies (24, 25). The AEs listed above were not considered DLTs if they occurred after cycle one of therapy.

Blood samples were obtained serially on days 0, 3, 8, and 15 of this phase I study. Blood was collected in EDTA blood collection tubes (BD, Biosciences). Within 30 minutes of collection, WBCs were isolated using density gradient centrifugation (Ficoll), followed by RNA isolation for standard RT-PCR and protein isolation for Western blotting.

The total RNAs in blood samples from patients before and after treatment for 3 days were extracted and purified by using EL buffer and miRNease Mini Kit from Qiagen following the manufacturer's manual. RNA sequencing (RNA-seq) was conducted by LC Sciences. In their laboratory, total RNA was subjected to isolation of poly(A) mRNA with poly-T oligo attached magnetic beads (Invitrogen). Following purification, the poly(A)− or poly(A)+ RNA fractions were fragmented into small pieces using divalent cations under elevated temperature. Then the cleaved RNA fragments were reverse-transcribed to create the final cDNA library using the mRNA-Seq Sample Preparation Kit (Illumina). The average insert size for the paired-end libraries was 300 bp. Then the paired-end sequencing was performed on an Illumina Hiseq 4000 following the manufacturer's protocol. Transcripts assembly and different expression mRNAs were conducted and analyzed. Gene set enrichment analysis was conducted using software GSEA and Molecular Signatures Database (Broad Institute).

Student t test was used to compare statistically significant differences. Wherever suitable, the experiments were performed three times. The data were also subjected to unpaired two-tailed Student t test wherever appropriate and P < 0.05 was considered statistically significant.

We first tested the activity of single-agent selinexor or eltanexor against two established cell lines. Exposure of WSU-DLCL2 or WSU-FSCCL cell lines to increasing concentrations of either selinexor or eltanexor resulted in statistically significant inhibition of growth over 72 hours compared with untreated cells (Fig. 1A–D). Levels of selinexor used in these studies are achievable in humans with recommended 60 mg dosing (21). We further analyzed the impact of combining SINE compounds with CHO chemotherapy (used at IC₅₀ concentration). Compared with single-agent SINE treatment, both selinexor-CHO and eltanexor-CHO showed enhanced antiproliferative effects against WSU-DLCL2 and WSU-FSCCL cells (Supplementary Fig. S1A–S1C). The combination enhanced apoptosis compared with single-agent treatment (Fig. 1E and F). Furthermore, combination therapy was associated with reduced expression of XPO1 and increased PARP cleavage, indicating induction of apoptosis (Supplementary Fig. S1D).

We evaluated the impact of SINE treatment on ERK and CD20 using Western blotting and RT-PCR. Exposure to 50 nmol/L of selinexor caused upregulation of p-ERK and CD20 in WSU-DLCL2 and WSU-FSCCL cell lines (Fig. 2A). RT-PCR confirmed the Western blotting data (Fig. 2B). We were also able to validate the finding that selinexor enhances CD20 expression using patient-derived samples (Fig. 2C).

In our murine model of disseminated NHL, animals in the untreated group all died or had to be culled between days 50 and 69 with day 62 as a median day of death (solid squares in Fig. 3A and B). Animals treated with single-agent eltanexor and selinexor had a median survival of 65 days (range, 57–90 and 57–160, respectively; inverted colored triangles, Fig. 3A and B). Whereas the CHOP-treated group had a modest increase in survival compared with the single-agent SINE groups (median 77 days; range, 57–160 days; yellow circles, Fig. 3A and B), the results in mice treated with CHOP–SINE combination therapy were markedly better. Median survival following CHOP with low-dose eltanexor was 101 days (range, 50–160 days, with 2 out of 7 animals alive without detectable disease at 160 days after inoculation; colored triangles, Fig. 3A and B). The median survival of mice treated with CHOP plus low-dose selinexor was longer: 126 days (range, 96–160 days), with 3 out of 7 animals without detectable disease at 160 days; colored triangles, Fig. 3A and B). Thus, the median survival of mice cotreated with eltanexor or selinexor plus CHOP was 31.1% and 63.6% longer than that of mice treated with CHOP alone.

There were 12 patients enrolled in the phase I trial of R-CHOP plus selinexor. All were evaluable for safety and 10 were evaluable for efficacy. Ten patients had DLBCL, including four who had transformed DLBCL following a prior history of follicular lymphoma. Two patients had follicular lymphoma only. Additional baseline patient characteristics are described in Table 1.

Six patients received selinexor 60 mg weekly + R-CHOP and six patients received selinexor 80 mg weekly + R-CHOP. For reasons described below, no patients were treated with selinexor 100 mg weekly + R-CHOP.

Among the first three patients dosed at selinexor 60 mg daily, there was one episode of grade 3 supraventricular tachycardia (SVT) in a patient with a prior history of SVT and in the context of an upper respiratory infection. One episode of grade 3 syncope occurred in another patient in the absence of arrhythmia. These two patients continued selinexor after a brief hold, and no further arrhythmia or syncopal events occurred. Given these events in the 60-mg cohort, we expanded this dose level by three additional patients. No further serious cardiac events were appreciated after expansion and for the remainder of the phase I study.

Among the first three patients of the 80-mg weekly cohort, one DLT occurred with grade 3 nausea/vomiting, and this cohort was expanded by three additional patients. There were notably more discontinuations and dose reductions in combination with R-CHOP therapy within the 80-mg cohort as compared with the 60-mg cohort. Selinexor treatment was discontinued in 9 of 12 patients before completion of the 12 months of maintenance therapy: 4 patients at 60 mg and 5 patients at 80 mg (Fig. 4A). There were no discontinuations due to progressive disease. Reasons for treatment discontinuation included AEs due to selinexor (fatigue only n = 2, nausea only n = 1, nausea and fatigue n = 1, nausea and vomiting n = 1), noncompliance (n = 2), and patient preference (n = 2). Dose reductions occurred in three patients, all due to fatigue. Of the patients who discontinued selinexor after therapy-related AEs, one patient was taking selinexor 60 mg weekly, and four patients were taking selinexor 80 mg weekly. All patients taking selinexor 60 mg weekly (with the exception of one patient due to noncompliance) were able to complete selinexor through six cycles of R-CHOP into maintenance therapy, and two of these patients completed a year of maintenance therapy. Only three of six patients on the 80 mg weekly dose completed six cycles of selinexor with R-CHOP therapy; two of these patients required dose reductions and eventually discontinued selinexor, and one completed maintenance therapy. The MTD (as defined in the protocol) was not technically reached. However, because the higher frequency of selinexor discontinuations and dose reductions in the 80-mg weekly cohort, we recommended selinexor 60 mg weekly + R-CHOP as our final RP2D. A swimmers' plot demonstrating time on R-CHOP + selinexor, time on selinexor maintenance, and reasons for discontinuation is shown in Fig. 4A.

All AEs reported over the course of the trial are described in Table 2. The majority of AEs were grade 1 or 2, with the most common ones being nausea (100%), fatigue (67%), skin/nail changes (58%), vomiting (42%), dizziness (42%), sinus congestion (42%), and constipation (42%). Of note, some previously documented side effects of selinexor were infrequent or not reported, including anorexia (8%), thrombocytopenia (0%), and hyponatremia (0%). Maximal grade of neutropenia experienced was grade 3–4 in three patients. There were more grade 3 events of nausea and vomiting in the 80-mg cohort compared with the 60-mg cohort. All patients completed six cycles of R-CHOP chemotherapy, regardless of whether selinexor had to be discontinued.

Preliminary efficacy of selinexor + R-CHOP is described in Table 3. Ten of 12 patients were evaluable for treatment response; two patients in the 80-mg cohort were not evaluable for response: one who did not continue selinexor through cycle 1 of R-CHOP due to a DLT, and one patient due to noncompliance with visits/social issues. The ORR among these 10 patients was 100%, with 9 patients achieving a CR by end of induction therapy, and 1 patient who achieved a radiographic partial response (PR) after cycle 4 of R-CHOP therapy before subsequently coming off study due to transportation issues. All of the nine patients who achieved a CR remain in CR after a median follow-up of 476 days. In Fig. 4B, CT scans showing response in a patient with transformed DLBCL are presented.

Blood samples were obtained from patients on selinexor–R-CHOP regimen on days 0, 3, 8, and 15. RNA was isolated followed by RT-PCR to evaluate the expression of several targets or downstream effectors, including XPO1, ABCG2, AKT, Bcl-2, Bax, and ERK. The findings were consistent with our preclinical studies, and we observed that ERK and CD20 mRNA expression was enhanced post combination treatment in patient samples (Fig. 5A and G). Of note, KCI-7 was a patient who had initially received CHOP + selinexor on day 1 of cycle 1 and rituximab on day 4 of therapy. More significantly, results of Western blot corroborated RT-PCR analysis with markedly increased expression of p-ERK (indicative of ERK activation) and CD20 at day 3 after treatment (Fig. 5H). We also observed downregulation of Bcl-2 (Fig. 5B). We have previously shown in patient biopsies from different trials that selinexor administration transiently induces XPO1 mRNA expression at early time points (20, 26). In line with these published observations, we observed consistent enhancement of XPO1 expression at day 3 across all patient blood samples (Fig. 5C). We observed upregulation of proapoptotic Bax (Fig. 5D) and downregulation of Akt and the multidrug transporter ABCG2 (Fig. 5E and F). We also performed RNA-seq analysis in two patients pre- and posttreatment. In these limited samples and at early time points, we observed upregulation in transcripts of XPO1, MAPK1/ERK1, MCL-1, BCL-2, BAX, and BCL2A1 and downregulation of MS4A14, ABCG2, and AKT (Supplementary Table S1).

In this series of preclinical in vitro and in vivo investigations, we established a strong rationale for combining selinexor plus CHOP-based chemotherapy for NHL. The phase I clinical study of selinexor plus R-CHOP in patients with NHL demonstrates the combination is feasible for clinical use, with favorable safety and general tolerability observed.

Earlier studies showed that aberrant XPO1 expression and/or function could have prognostic relevance in NHL (27). It has been clearly demonstrated that XPO1-mediated nuclear-to-cytoplasm translocation of TSPs has an effect on NHL cell proliferation (28). Additionally, comprehensive genomic profiling in DLBCL reveals a recurrent gain-of-function mutation in XPO1 (E571K), suggesting XPO1 may contribute to disease pathogenesis (29). We previously demonstrated that SINE compounds alone can suppress NHL proliferation in lymphoma cell lines and in vivo murine models (18). SINE compounds effectively suppress XPO1 function and B-cell NHL cellular proliferation even in cells with E571K mutation (30). Our current study demonstrates synergistic activity of combining SINE compounds with CHOP in both lymphoma cells and murine models. In preliminary studies, we also observed that SINE compounds inhibit proliferation of “double hit” (Bcl-2, Myc mutation–positive) lymphoma cell lines (WSU-DLCL2 and DOHH2), with enhancement of the antilymphoma activity of CHOP (data not shown)—suggesting potential utility versus high-risk NHL. It would be important to validate these early findings in future studies both preclinically and through our clinical trial.

Selinexor showed broad single-agent activity in a phase I study of various types of heavily pretreated NHL (19). Based on that study, it was evaluated in the phase IIb SADAL clinical trial in patients with relapsed or refractory DLBCL who had received a minimum of at least two prior multiagent therapies and who were ineligible for transplantation (18). In SADAL, 127 patients with relapsed or refractory DLBCL were treated with a fixed 60 mg oral dose of selinexor twice weekly for a four-week cycle. Single-agent selinexor demonstrated a clinically meaningful ORR of 29%, including a CR of 13%, in patients with relapsed or refractory DLBCL (18). Importantly, some patient responses were durable with an overall median duration of response (DOR) of 9.3 months. For patients attaining a CR, the median DOR was 23 months (20). Based on these results, the FDA approved selinexor for the treatment of adult patients with relapsed or refractory DLBCL, including DLBCL arising from follicular lymphoma in June 2020. Selinexor is also currently FDA approved for use as treatment for multiple myeloma refractory to two prior therapies and as second-line therapy in combination with bortezomib. For both relapsed DLBCL and relapsed multiple myeloma, selinexor was approved on the basis of trials using twice-weekly schedules, at higher doses than what was used in the study reported herein. The reported results of other trials have suggested better tolerance at weekly dosing (31, 32), and the results of this phase I study further support this. It is apparent that there were selinexor discontinuations due to toxicities, even during maintenance therapy, and more discontinuations in the 80-mg cohort (Fig. 4A). This underscores the widely observed clinical experience that lower-grade toxicities can still be intolerable in the long term. However, in comparison with toxicity experienced with twice-weekly selinexor, the combination had relatively better tolerability, and most patients completed selinexor along with six cycles of R-CHOP without interruption. This makes it a promising combination for higher risk patients, and this is being studied further with our phase II study. Fatigue and nausea were the most common AEs observed in this trial, with the majority being grade 1–2, and usually lasting only 1–2 days after each dose of selinexor. The severity of other gastrointestinal symptoms, including anorexia, vomiting, and diarrhea, was much lower than previously reported in trials where patients received higher doses of selinexor twice weekly (20, 32, 33). Further, nausea during therapy was generally easily controlled with the prophylactic and routine use of multiagent antiemetic regimens such as olanzapine and ondansetron. Overall, nonhematologic grade 3 and 4 toxicities were infrequent. Neutropenia of grade 3–4 severity was seen in three patients, but febrile neutropenia was uncommon. Severe thrombocytopenia was not reported. The MTD was not reached after enrolling six patients to each of the first two dosing cohorts. Still, based on the higher eventual discontinuation rate of selinexor when dosed at 80 mg weekly, selinexor 60 mg weekly was deemed the RP2D when given together with R-CHOP.

The high overall response rate observed is consistent with our prior in vitro work demonstrating potent activity of selinexor against DLBCL cells harboring MYC and BCL2/6 mutations (“double hit”) as well as follicular NHL. The small number of patients treated in this trial preclude being able to reach any conclusions as to whether all subtypes of DLBCL would respond equally well to selinexor plus R-CHOP, or whether the combination will overcome inherent chemoresistance imparted by high-risk cytogenetic and molecular features. Studies have shown that the loss of CD20 expression occurs in >30% of refractory and/or relapsed cases treated with R-CHOP (3, 4). Significantly, chemically induced ERK hyperphosphorylation can cause reexpression of CD20 that restores sensitivity of DLBCL to R-CHOP (5). Therefore, strategies that can activate CD20 can certainly prime B-NHL patients to R-CHOP for better therapeutic outcomes. Our results show that selinexor can activate CD20 in WSU-DLCL2 cell lines and in patient blood samples from the phase I. Additionally, XPO1 activation at early time points has been captured using RT-PCR in other selinexor trials in hematologic malignancies (20, 26). In line with those findings, we also observed XPO1 activation at day 3 followed by progressive decline in the expression over time. However, these are limited studies and warrant further evaluation. Ultimately, the completion of larger phase studies will demonstrate whether the combination has better efficacy than R-CHOP alone in DLBCL, which is an ongoing challenge. The broad single-agent activity of selinexor in relapsed/refractory DLBCL suggests that it could contribute to antitumor activity across many molecular subtypes of DLBCL (18).

In summary, in vitro and in vivo preclinical models demonstrating that inhibition of XPO1-mediated prosurvival signaling is associated with decreased NHL cell proliferation provide a strong rationale for combining SINE compounds with CHOP-based therapy in B-cell NHL. Coadministration of R-CHOP with weekly selinexor at a dose of 60 mg showed both durable efficacy and an acceptable long-term tolerable safety profile. Previously described selinexor-related toxicities including cytopenias were generally milder than seen in past clinical trials. Gastrointestinal side effects, in particular, were easily managed, and there was no anorexia reported in the 60-mg cohort (RP2D). Importantly, no new safety signals were seen, even with dosing in combination with six cycles of R-CHOP and continued selinexor maintenance for an additional year. The results of correlative studies performed over the course of the phase I clinical trial were consistent with our preclinical findings. Given the results of this phase I trial, as well as the previously reported efficacy of single-agent selinexor against B-cell NHL, selinexor/chemotherapy combinations should be explored. We are currently conducting a multisite phase II study evaluating R-CHOP + selinexor as first-line treatment of DLBCL. In this phase II trial, we will be evaluating efficacy among both de novo and transformed DLBCL. Patients with double-hit lymphomas are also eligible, and the study also has an additional arm to specifically evaluate the efficacy of this combination in newly diagnosed Richter's transformation in untreated or previously treated CLL (NCT03147885).

E.K. Seymour reports other from Karyopharm Therapeutics Inc during the conduct of the study, as well as other from Roche outside the submitted work and equity in Roche. Y. Li reports other from Karyopharm Therapeutics Inc during the conduct of the study. R. Ramchandren reports personal fees from Seattle Genetics, BMS, and Celgene; grants from Pharmacyclics and Merck; and non-financial support from Trillium outside the submitted work. C. Houde reports other from Curis Inc outside the submitted work. Y. Landesman reports personal fees from Karyopharm Therapeutics during the conduct of the study. J. Shah reports other from Karyopharm Therapeutics during the conduct of the study. M. Kauffman reports personal fees from Karyopharm Therapeutics during the conduct of the study and personal fees from Karyopharm Therapeutics outside the submitted work. S. Shacham reports other from Karyopharm Therapeutics outside the submitted work; in addition, S. Shacham has a patent for composition of matter selinexor issued. A.S. Azmi reports personal fees from Karyopharm Therapeutics Inc. during the conduct of the study. A.S. Azmi also reports personal fees from Guidepoint and GLG outside the submitted work, funding from Janssen and Rhizen, and is a consultant for GLG and Guidepoint. J.A. Zonder reports grants from Celgene and BMS during the conduct of the study and personal fees from Regeneron, Amgen, Takeda, Oncopeptide, Janssen, Caelum, Intellia, and Alnylam outside the submitted work. No disclosures were reported by the other authors.

E.K. Seymour: Conceptualization, data curation, formal analysis, investigation, writing–original draft, writing–review and editing, project administration. H.Y. Khan: Data curation, methodology, writing–original draft. Y. Li: Data curation, writing–review and editing. M. Chaker: Data curation. I. Muqbil: Data curation, writing–review and editing. A. Aboukameel: Data curation, methodology, writing–original draft. R. Ramchandren: Investigation, writing–review and editing. C. Houde: Resources, project administration, data curation. G. Sterbis: Project administration. J. Yang: Investigation, project administration. D. Bhutani: Conceptualization, investigation, writing–review and editing. S. Pregja: Methodology, project administration. K Reichel: Project administration. A. Huddlestun: Project administration. C. Neveux: Project administration. K. Corona: Resources. Y. Landesman: Resources. J. Shah: Resources. M. Kauffman: Resources. S. Shacham: Resources. R.M. Mohammad: Resources, supervision, writing–original draft, writing–review and editing. A.S. Azmi: Conceptualization, data curation, software, funding acquisition, writing–original draft, project administration. J.A. Zonder: Conceptualization, resources, formal analysis, supervision, writing–original draft, project administration, writing–review and editing.

Work in the lab of A.S. Azmi is supported by NIH R37 grant 1R37CA215427. The phase Ib/II study is partly supported by Karyopharm Therapeutics Inc.

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