Phase I Clinical Trial of Selinexor in Combination with Daunorubicin and Cytarabine in Previously Untreated Poor-Risk Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by a block in myeloid differentiation and aberrant proliferation of immature myeloid progenitors. An inherent feature of these self-renewing leukemia-initiating cells is their resistance to chemotherapy, which contributes to disease relapse (1). Nuclear–cytoplasmic protein transport is required to maintain normal intracellular signaling and cell-cycle regulation (2). Exportin 1 (XPO1/CRM1) is the sole nuclear export protein responsible for the cytoplasmic translocation of nearly all tumor suppressor proteins (TSP) and growth regulators, including p53, p21, p27, forkhead box O3 (FOXO3), and nucleophosmin 1 (NPM1). This nuclear export leads to the inactivation of TSPs, allowing malignant cells to evade apoptosis (3). XPO1 is overexpressed in AML cells, and increased levels of XPO1 are inversely correlated with overall survival (OS) in patients with AML (4).

Selective inhibitors of nuclear export (SINE) compounds are orally bioavailable small molecules that function by covalently binding to cysteine 528 in the cargo-binding pocket of the XPO1 protein. This prevents XPO1 from binding to the nuclear export signal of proteins, thereby preventing the loading and nuclear export of cargo proteins. The resulting nuclear retention, accumulation, and activation of TSPs restore the tumor suppressor function, leading to apoptosis and cell-cycle arrest of tumor cells, as well as forced differentiation of myeloid blasts. These effects are seen in bulk tumor cells and leukemia-initiating cells (1, 5–8). Another client of XPO1 is the protein topoisomerase IIα. Cytoplasmic localization of topoisomerase IIα is a well-documented mechanism of chemotherapy resistance in multiple myeloma and AML (9). Selinexor (KPT-330) is a SINE compound that has been extensively studied in laboratories by using AML cell lines, AML patient cells, and mouse models. Selinexor is reported to block XPO1, leading to nuclear retention of cargo proteins, including TSPs, and restore their functions. Selinexor also restores topoisomerase IIα in the nucleus and synergistically sensitizes cells to topoisomerase II inhibitors, such as idarubicin, daunorubicin, etoposide, and mitoxantrone (3, 6, 10). The nuclear retention of topoisomerase IIα causes downregulation of DNA repair proteins, such as Rad51 and Chk1, and results in increased lethal DNA double-strand breaks in the presence of topoisomerase II inhibitors (10). When given sequentially with chemotherapy, selinexor appears to synergize with many DNA-damaging agents (including idarubicin, daunorubicin, mitoxantrone, etoposide, and fludarabine), especially when the selinexor exposure precedes that of the other drugs. Preclinical studies completed at our institution using AML cell lines and AML patient cells indicated strong synergistic interactions between selinexor and daunorubicin, and these data rationalized the development of this clinical trial (Supplementary Figs. S1 and S2; Supplementary Table S1). Several early-phase trials have studied selinexor in AML both as a single agent and in combination with chemotherapy and report encouraging results (6, 11–13).

This phase I study (NCT02403310) was conducted to further assess the role of selinexor in patients with previously untreated, poor-risk AML when administered in combination with cytarabine and daunorubicin. The aim of the study was to identify the MTD and the recommended phase II dose (RP2D) of selinexor and to assess the safety profile and preliminary signals of efficacy with this combination.

Adults newly diagnosed with AML (on the basis of World Health Organization 2008 criteria) were eligible if they were considered poor risk in accordance with the National Comprehensive Cancer Network (NCCN) cytogenetic and molecular risk stratification guidelines (14) or if they were ≥ 60 years of age (15). Key eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, total bilirubin levels within H. Lee Moffitt Cancer Center and Research Institution (MCC) institutional normal limits, aspartate aminotransferase and alanine aminotransferase levels ≤ 2.5 × the institutional upper limit of normal, creatinine levels ≤ 2 mg/dL, and a left ventricular ejection fraction of ≥50%. Patients who had prior AML-directed therapy, with the exception of hydroxyurea, were not included. Patients with an antecedent myelodysplastic syndrome were permitted to have had prior hypomethylating agent therapy. A full list of inclusion/exclusion criteria can be found in the Supplementary Methods The study was approved by the Chesapeake Institutional Review Board (IRB) and conducted in accordance with the Declaration of Helsinki. The study was consistent with the International Conference on Harmonisation Good Clinical Practice guidelines. Written informed consent was obtained from all patients before enrollment.

Selinexor was supplied by Karyopharm Therapeutics, Inc. Induction therapy was given in the inpatient setting. All patients received daunorubicin (60 mg/m²/day) intravenously on days 1 through 3 and cytarabine (100 mg/m²/day) as a continuous intravenous infusion on days 1 through 7 (7+3 regimen). Dose escalation was used for selinexor only. Dose cohorts 1 and 2 received 60 mg and 80 mg of selinexor orally, respectively, during induction on days 1, 3, 8, 10, 15, and 17. Selinexor was given 2 hours before daunorubicin on days 1 and 3 on the basis of preclinical studies, suggesting that selinexor sensitizes leukemic blasts to chemotherapy (3). During the dose escalation phase, patients who did not receive at least 5 doses of selinexor, in the absence of a dose-limiting toxicity (DLT), were replaced.

Reinduction was permitted for patients with residual leukemia seen on a day 21 bone marrow biopsy, provided a ≥50% reduction in the total blast count from baseline was observed. Reinduction consisted of administration of daunorubicin (45 mg/m²/day) on days 1 and 2 and cytarabine (100 mg/m²/day) as a continuous intravenous infusion on days 1 through 5 (5+2 regimen). Selinexor was given at the same dose as induction on days 1, 3, 8, and 10. On day 1, selinexor was given 2 hours before daunorubicin administration.

Patients who achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) were allowed to receive up to 2 cycles of consolidation therapy, consisting of 5+2 with selinexor given at the same dose as induction on days 1, 3, 8, and 10.

Patients were permitted to discontinue their participation in the study and proceed to allogeneic hematopoietic stem cell transplant (HSCT) at any time after achieving CR/CRi. Patients who did not undergo HSCT could subsequently receive maintenance therapy consisting of selinexor at the same dose as induction on days 1 and 8 of a 21 day cycle for up to 17 cycles (12 months).

Supportive care measures were established to manage side-effects. These included the use of prophylactic antibiotics, antifungal agents, and antivirals. Nausea was managed with antiemetics as needed and, for some patients, nausea management consisted of empiric treatment with olanzapine (5 mg) taken orally at bedtime beginning 24 to 48 hours before day 1 of induction. Diarrhea was managed with loperamide or tincture of opium as needed, and hyponatremia was managed with intravenous infusions of sodium chloride and/or salt tabs.

The MTD was defined as the dose at which 0 out of 3 or ≤1 out of 6 patients experienced a DLT. If DLTs did not occur in either dose cohort, then 80 mg of selinexor taken orally twice weekly was to be deemed the RP2D. Treatment-emergent adverse events (TEAE) were assessed using the National Cancer Institute Common Terminology Criteria of Adverse Events v4.3. The observation period for a DLT was a minimum of 28 days. Hematologic DLTs were defined as grade 3/4 neutropenia and/or thrombocytopenia due to bone marrow hypoplasia, without residual leukemic burden, that did not recover to grade ≤ 2 by day 56.

Nonhematologic DLTs were defined as any grade 3/4 drug-related toxicity, with the exception of nausea, vomiting, dehydration, or diarrhea that was adequately controlled with antiemetics or antidiarrheals; infection or febrile neutropenia adequately controlled with antibiotics; liver function abnormalities (without clinical symptoms) that recovered to baseline or grade ≤ 1 within 7 days; electrolyte or metabolic laboratory abnormalities that were not considered clinically significant by the treating physician and recovered to baseline or grade ≤ 1 within 7 days; and alopecia and dysgeusia.

After induction/reinduction, bone marrow aspirations and biopsies were performed between days 28 and 72 to assess response. The International Working Group criteria were used to define a CR or CRi (16). Patients who did not achieve CR or CRi with up to 2 induction courses were considered treatment failures. Patients who voluntarily withdrew consent before completing all of the prescribed study treatment for reasons unrelated to toxicity were not considered evaluable for response.

G-banding cytogenetic analyses were performed on the bone marrow aspirate samples of each patient at the time of diagnosis and, for most patients, at time of response assessment. Next-generation sequencing was performed at MCC (Tampa, FL) using the TruSight Myeloid-54 gene panel to assess for the presence of common myeloid mutations.

Pharmacokinetic analyses of selinexor were performed on plasma samples from patients at hours 0, 1, 2, 4, and 8 after dose administration on days 1 and 15 of induction. At each time point, 2 mL of blood was collected in an ethylenediaminetetraacetic acid tube, and plasma samples were stored at −20°C or below until further analysis.

The samples were assayed using a validated LC/MS-MS by AIT Biosciences. The measurement range was 1 to 100 ng/mL. The overall accuracy and precision of the quality control samples were both within 15% of the measurement.

Pharmacokinetic parameters were calculated using a standard noncompartmental analysis approach. Protocol nominal sampling time was used to calculate and summarize pharmacokinetic data. Plasma samples that were below the lower limit of quantification before the first quantifiable concentration (i.e., predose samples) were set to zero to conduct pharmacokinetic analyses (17).

Baseline ex vivo sensitivity to selinexor both alone and in combination with daunorubicin and cytarabine was assayed by flow cytometry on gated CD34⁺ cells for apoptosis (active caspase-3). An additional 20 mL of bone marrow aspirate and 20 mL of blood were collected from the screening bone marrow biopsies and aspirations for exploratory studies. The bone marrow aspirates were processed by MCC Translational Research Core, and the blood samples were processed by MCC Tissue Core to obtain plasma and buffy coats; the samples were then biobanked (3 or more aliquots each). The bone marrow aspirate samples were enriched for mononuclear cells (MNCs) using a Ficoll density gradient to evaluate the predictive value of baseline ex vivo sensitivity testing with selinexor alone and in combination with daunorubicin and cytarabine. For this assay, the bone marrow MNCs were incubated for 20 hours in the presence of selinexor with or without daunorubicin or cytarabine.

A cytospin centrifuge was used to deposit 1.0 × 10⁵ paraformaldehyde-fixed CD34⁺ cells onto Shandon Double Cytoslides (Thermo Fisher Scientific) to perform immunofluorescent microscopy. Rabbit polyclonal antibodies (Novus Biologicals, NBP2-38322) were used to detect CD34; mouse monoclonal CRM1antibodies (C-1; Santa Cruz Biotechnology, SC74454) were used to detect XPO1; and mouse monoclonal Ki-S1 antibodies (Millipore, MAB4197) were used to detect topoisomerase IIα. The fluorescent secondary antibodies used were anti-rabbit Alexa Fluor 488 and anti-mouse Alexa Fluor 594 (Invitrogen). Proteins within the nucleus and cytoplasm of the CD34⁺ cells were analyzed using the Definiens Tissue Studio v4.4.2 software suite (Definiens). See Supplementary Methods for more details regarding the methods used.

Twenty-one patients were enrolled between June 2015 and 2016. Patient characteristics are shown in Table 1. The median age was 69 years (range, 37–77). Fourteen patients (67%) were male and 7 (33%) were female. Nineteen (90%) patients had an ECOG performance status of 0 or 1 and 2 (10%) had an ECOG performance status of 2. On the basis of NCCN cytogenetic and molecular risk stratification, 17 (81%) patients were found to have poor-risk disease, and the remaining 4 (19%) patients were determined to have intermediate-risk disease. These patients were eligible for enrollment as they were ≥60 years of age or because they had secondary AML with diploid cytogenetics. Thirteen patients (62%) had secondary AML, 8 (62%) of whom had received a hypomethylating agent before AML progression. Patients did not receive any AML-directed therapy (with the exception of hydroxyurea) before enrollment. All 21 patients received at least 1 dose of selinexor and were included in the safety evaluations and survival analyses.

Three patients were removed from the study before the first response assessment. Two patients withdrew consent before completing the planned study treatment (days 3 and 14, respectively), and 1 patient died from an adverse reaction to antibiotics on day 24. The 2 patients who voluntarily withdrew consent for reasons other than toxicity, before completing the study treatment, were not considered evaluable for response. Therefore, 19 patients were evaluable for response.

Nineteen patients received a full course of induction therapy. Six patients required reinduction with selinexor plus 5+2, and 6 patients completed at least 1 cycle of consolidation. Only 1 patient entered the maintenance phase and completed 5 cycles of maintenance therapy. Six patients underwent allogeneic stem cell transplants.

Four patients were enrolled in cohort 1. One patient was replaced after consent withdrawal prior to completion of 5 doses of selinexor. Four patients were also enrolled in cohort 2, with one being replaced due to unrelated toxicity prior to completing the DLT period.

DLTs did not occur in either dose-escalation cohort and the MTD was not established. Further dose escalations did not occur because of concerns of cerebellar toxicity observed at higher doses in concurrent selinexor trials at other institutions (6). An additional 13 patients received 80 mg of selinexor in a safety expansion phase to better understand the safety profile of this drug combination. The RP2D was 80 mg of selinexor taken orally twice weekly.

All 21 patients were included in the adverse event (AE) assessment. Every patient experienced at least 1 TEAEs during the induction period, and 20 (95%) had at least one grade 3/4 AEs. Table 2 lists all the nonhematologic TEAEs observed in ≥ 10% of patients. The most common nonhematologic TEAEs (all grades) were diarrhea (81%), hyponatremia (81%), which typically occurred between days 8 and 21 of induction, nausea (71%), and febrile neutropenia (71%). The most common grade 3/4 nonhematologic TEAEs that occurred in ≥10% of patients included febrile neutropenia (67%), diarrhea (29%), hyponatremia (29%), and sepsis (14%). Diarrhea was managed with antidiarrheal medications; nausea was controlled with antiemetics (including prophylactic olanzapine in some cases); and hyponatremia was managed with high-salt diets, salt tablets, and intravenous fluids. No patients experienced symptoms associated with hyponatremia. There were no cases of cardiac events, heart failure, decreased ejection fraction, or arrhythmias.

One patient (4.8%) died within 30 days of beginning the study treatment from antibiotic-related (vancomycin and piperacillin/tazobactam) acute tubular necrosis in the setting of febrile neutropenia. No other deaths occurred within 60 days of beginning induction. Thirteen (62%) patients died during the treatment or follow-up phases of the study. The majority of deaths were related to relapsed or refractory AML. There were no deaths related to selinexor.

The median number of days in the hospital for all 21 patients was 37 (range, 3–82). Among the 10 patients who achieved CR/CRi, the median time to a platelet count ≥ 50,000 was 35 days (range, 25–77) and the median time to absolute neutrophil count (ANC) ≥ 500 was 26 days (range, 18–45).

None of the 6 patients who completed at least 1 cycle of consolidation experienced diarrhea or hyponatremia during this phase of treatment. The only grade 3/4 AEs during consolidation were dyspnea (17%) and headache (17%). For the 1 patient who received maintenance therapy, the only grade 3 AE was fatigue, which prompted the patient to voluntarily withdraw from the study while in remission.

All 21 patients were evaluated for survival. The 2 patients who withdrew consent did not undergo a formal response assessment and were, therefore, not included in the efficacy analysis. At a median follow-up of 28.9 months for all 21 patients, 8 (38%) patients were alive, and the median OS was 10.3 months [95% confidence interval (CI), 3.74–NR; Fig. 1A].

Eight patients (42%) achieved CR and 2 (11%) achieved CRi, resulting in an overall response rate of 53%. The median time to confirmation of CR/CRi for these 10 patients was 42 days (range, 31–77). Nine patients (47%) were considered treatment failures due to refractory AML (Table 3). Of the 6 patients who received a second induction, 1 (17%) achieved CRi. Among the 19 patients evaluable for response, the median follow-up time was 26.9 months, with a median OS of 10.3 months. At 12 months, 47.4% of evaluable patients were alive (Fig. 1B). Response rates were less encouraging among those patients who had previously received a hypomethylating agent for an antecedent hematologic disorder, with only 13% of those patients achieving CR/CRi. Among the 17 patients who were considered poor-risk on the basis of NCCN criteria, one was not eligible for response. Of the 16 response eligible patients in this subgroup, 8 (50%) achieved CR/CRi and 8 (50%) were treatment failures. Among the 4 patients who were eligible for this study on the basis of being ≥60 years of age or because they had secondary AML with diploid cytogenetics, 3 were eligible for response. Of those 3 patients, 2 (67%) achieved CR/CRi and 1 (33%) was a treatment failure.

Among the 10 responding patients, the median OS was not reached, and 6 of these patients were alive at the time of this report (September 2018; median follow-up 28.9 months). Six patients proceeded to undergo an allogeneic stem cell transplant in first remission, 5 of whom remain in remission. Among the 5 patients who relapsed, the median time to relapse was 9.2 months. The characteristics of the responding patients are detailed in Table 4.

A total of 16 patients evaluable for efficacy were treated at the RP2D of selinexor, 8 (50%) of whom achieved CR/CRi. None of the 16 patients required a dose reduction of selinexor.

Oral selinexor was absorbed at a moderate rate on day 1, with a median T_max of 2.0 hours at both 60 mg and 80 mg. For the 4 patients treated with 60 mg of selinexor, the mean C_max was 457 ng/mL (1.0316 μmol/L) and AUC_0–8h was 1,853 ng/h/mL. For the 17 patients who received 80 mg of selinexor, the mean C_max was 601 ng/mL (1.3567 μmol/L) and AUC_0–8h was 2,590 ng/h/mL (Table 5). The pharmacokinetics of selinexor exhibited moderate to high variability (Table 5).

Considering the relatively high intersubject variability, exposure (based on AUC) appeared to be similar on days 1 and 15. On day 15, a delay was observed in the absorption of selinexor (mean T_max of 4 hours); as a result, the day 15 C_max values were lower than those on day 1 (Table 5).

Flow cytometry was performed on bone marrow aspirates obtained from 10 patients to conduct ex vivo treatment studies. Of these, 2 samples were eliminated from the analysis. One sample had low viability and the other had low representation CD34⁺ cells (<5%). For the 8 remaining samples, the MNCs were plated at a concentration of 3 million cells per mL. The cells were then treated with titrated concentrations of selinexor in combination with either 40 μmol/L of cytarabine or 1 μmol/L of daunorubicin. Selinexor concentrations > 6.25 μmol/L had an increased active caspase-3 compared with the untreated controls. Adding cytarabine or daunorubicin to the titrated selinexor resulted in increased apoptosis, above the levels observed in individual drug-treated cells. Contrary to preclinical observations, the effects of the combination appeared to be additive, and no synergy was noted between selinexor and daunorubicin.

Immunofluorescent microscopy was used to evaluate topoisomerase IIα and XPO1 relative protein amounts and locations in 8 patients. These data were used to compare patients who had a complete response and those determined to be treatment failures, with 4 patients in each group. No significant difference was found between the complete response and treatment failure groups when comparing topoisomerase IIα protein concentrations (mean fluorescence; P = 0.425) or nuclear/cytoplasmic ratios (P = 0.444). Similarly, no significant difference was found between the XPO1 amount (P = 0.303) and nuclear/cytoplasmic ratios (P = 0.330; refer to Supplementary Fig. S3). Lack of significance may be due to the small sample size.

These ex vivo results did not provide data predictive of response to this treatment combination.

In this trial, oral selinexor was safely combined with a standard 7+3 daunorubicin and cytarabine regimen for treatment of patients with newly diagnosed, poor-risk AML, resulting in an overall response rate of 53%. The median OS was 10.3 months, and the 12-month OS was 47.4%. Of note, the responses were durable, with 60% of responders being alive at a median follow-up of 28.9 months. The MTD was not reached, and the RP2D of selinexor in combination with daunorubicin and cytarabine was 80 mg twice weekly. Furthermore, induction therapy with selinexor plus 7+3 for patients with previously untreated, poor-risk AML appears to be safe and tolerable.

Several studies have been conducted using selinexor either as a single agent or in combination with chemotherapy to treat patients with AML. Garzon and colleagues (13) recently published data from a phase I dose-escalation trial of single-agent selinexor for patients with advanced hematologic malignancies. This trial enrolled 95 patients with AML with a median age of 70 years. Of the 81 patients evaluable for response, 14% achieved a CR/CRi. The most common AEs included fatigue, nausea, vomiting, anorexia, thrombocytopenia, and hyponatremia.

Given the molecular complexity of AML, the efficacy of selinexor may be greater when it is used in combination with other therapies. As such, many investigator-initiated trials have been designed combining selinexor with cytotoxic chemotherapy. In another phase I trial, 18 pediatric patients with relapsed or refractory acute leukemia were treated with a combination of selinexor plus fludarabine and cytarabine. Fifteen of these patients were evaluable for response after combination therapy, 47% of whom achieved CR/CRi, and 5 patients tested negative for measurable residual disease (6). A larger, phase II trial of 42 adults with relapsed or refractory AML (many of whom relapsed after a HSCT) combined selinexor (40 mg/m², twice weekly) with idarubicin (10 mg/m², days 1, 3, and 5) and cytarabine (100 mg/m², days 1–7; ref. 12). Two selinexor dose cohorts were studied, and the CR/CRi rate ranged from 45% to 55%. The side-effect profile of our trial and theirs demonstrated strong similarities.

The CR/CRi rate of 53% observed in our cohort of older poor-risk patients was encouraging. The CR/CRi rate (13%) was lowest among the 8 patients who had previously been treated with hypomethylating agents for an antecedent hematologic disorder. Sixteen (84%) of the 19 patients who were evaluable for response after induction therapy had NCCN-defined poor-risk AML. Although 3 of the evaluable intermediate-risk patients had a clinical diagnosis of secondary AML, they were classified as intermediate-risk per NCCN criteria.

The CR/CRi rates with 7+3 alone that have been reported in other trials with patient populations similar to ours range from 30% to 50% (18–20). A TP53 mutation was detected in 7 evaluable patients at the time of diagnosis; this mutation typically correlates with a low CR rate and an overall poor prognosis (18). Six of these patients also had a complex karyotype. In our study, the CR/CRi rate among this very high-risk subset of patients was 43% with 7+3 plus selinexor.

Encouragingly, the early death rate observed in our phase I study was low, comparing favorably with expected mortality rates among similar patient populations (20). The side-effect profile observed was consistent with the well-established side effect profile, including gastrointestinal toxicity, fatigue, hyponatremia, and cytopenias (13). Neither new safety events nor major organ toxicities were noted. The most frequently observed TEAEs were diarrhea and hyponatremia. Diarrhea was controlled with antidiarrheal medications. Hyponatremia is a well-documented side effect of selinexor, with an unclear etiology (13). It can be managed with sodium supplementation in the form of salt tabs or intravenous infusions of 0.9% sodium chloride. Nausea, vomiting, and anorexia were also commonly reported. In most cases, these AEs were grade 1/2 and were successfully managed with supportive measures, including the use of prophylactic olanzapine for some patients.

The noncompartmental analysis for pharmacokinetic studies indicated that the plasma concentration of selinexor was similar to plasma concentrations observed in previous studies (unpublished data). The moderate intersubject variability (approximately 50%–70% CV) in exposure parameters (AUC, C_max) is probably due to the limited sampling schedule and differences in actual sampling time among patients. No correlation was identified between the plasma concentration of selinexor and overall response.

The responses to selinexor and 7+3 appeared durable in many cases, as evidenced by the fact that 5 of 10 responding patients remained in CR/CRi at a median follow-up time of over 2 years; all 5 of these patients underwent allogeneic stem cell transplant in first remission.

In addition to demonstrating single-agent activity, selinexor has been shown to demonstrate promising activity in combination with chemotherapy. CPX-351 (liposomal daunorubicin plus cytarabine) has emerged as frontline therapy for secondary AML, with reported response rates similar to those reported in our current trial, among a similar group of patients (20). Therefore, a future trial of selinexor in combination with CPX-351 is likely warranted (20). Further emerging novel therapies (including venetoclax and other targeted agents) could warrant novel combinations.

In summary, SINE compounds offer a unique mechanism to increase lethal DNA damage by retaining topoisomerase IIα in the nucleus in proximity to its DNA substrate and by localizing and activating TSPs in the nucleus. Although selinexor is reported to have modest single-agent activity in AML, available data suggest that selinexor in combination with other cytotoxic chemotherapy agents leads to improved efficacy (6, 11–13). Our preclinical data suggest strong synergy between selinexor and daunorubicin. However, our correlative studies, which were conducted using bone marrow samples from enrolled patients, could not reproduce these results. Furthermore, neither the baseline levels of topoisomerase IIα nor the nuclear/cytoplasmic ratios of topoisomerase IIα or XPO1 appeared to correlate with response to treatment. However, this analysis was limited to 8 patient samples.

Our data indicate that 80 mg of selinexor can safely be given in combination with a 7+3 induction regimen in older adults with newly diagnosed poor-risk AML. Future randomized studies are needed to definitively identify the benefit of selinexor as a component of induction therapy in AML.

K. Sweet reports receiving other commercial research support from Karyopharm Therapeutics. R. Komrokji is an employee/paid consultant for DSI, Pfizer, JAZZ, Celgene, Novartis and Agios, and reports receiving commercial research grants from Celgene, and reports receiving speakers bureau honoraria from Jazz Pharmaceutical and Novartis. D.M. Sullivan reports receiving commercial research grants from Karyopharm Therapeutics. B.D. Shah reports receiving commercial research grants from Incyte and Jazz Pharma, and is an advisory board member/unpaid consultant for Kite/Gilead, Celgene/Juno, Novartis, Adaptive, AstraZeneca, Pharmacyclics, and Spectrum/Acrotech. J.E. Lancet is an employee/paid consultant for Jazz Pharmaceuticals, Daiichi Sankyo, Agios Pharmaceuticals, and Pfizer. No potential conflicts of interest were disclosed by the other authors.

Conception and design: K. Sweet, R. Komrokji, D.M. Sullivan, J.E. Lancet

Development of methodology: K. Sweet, C.L. Cubitt, J.G. Turner

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): K. Sweet, R. Komrokji, E. Padron, C.L. Cubitt, J.G. Turner, J.L. Dawson, J. Chavez, B.D. Shah, J.E. Lancet

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K. Sweet, C.L. Cubitt, J.G. Turner, J. Zhou, A.F. List, D.M. Sullivan

Writing, review, and/or revision of the manuscript: K. Sweet, R. Komrokji, C.L. Cubitt, A.F. List, D.A. Sallman, J.L. Dawson, D.M. Sullivan, B.D. Shah, J.E. Lancet

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): K. Sweet

Study supervision: K. Sweet

We thank Paul Fletcher and Daley Drucker (H. Lee Moffitt Cancer Center and Research Institution) for editorial assistance. They were not compensated beyond their regular salaries. This work has been supported in part by the Analytic Microscopy Core Facility at the H. Lee Moffitt Cancer Center and Research Institute; an NCI-designated Comprehensive Cancer Center (P30-CA076292). The clinical trial was funded by Karyopharm.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.