A phase I trial of selinexor plus FLAG-Ida for the treatment of refractory/relapsed adult acute myeloid leukemia patients

Sánchez, María Pilar; Megías‐Vericat, Juan Eduardo; Rodríguez‐Veiga, Rebeca; Vives, Susana; Bergua, Juan; Torrent, Anna; Suárez-Varela, Sara; Boluda, Blanca; Martínez‐López, Joaquín; Cano-Ferri, Isabel; Acuña‐Cruz, Evelyn; Torres-Miñana, Laura; Martín-Herreros, Beatriz; Serrano, Alfons; Sempere, Amparo; Barragán, Eva; Sargas, Claudia; Sanz, Miguel Á.; Martínez‐Cuadrón, David; Montesinos, Pau

doi:10.1007/s00277-021-04542-8

Cited by 10 publications

(8 citation statements)

References 26 publications

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“…In contrast, allo-HSCT in patients with active leukemia at the time of transplant have poor outcomes with long-term survival rates of only about 20% (Jabbour et al, 2014;Othus et al, 2015). In our study, four patients received an allo-HSCT after achieving CR, one patient received an allo-HSCT after achieving PR and our transplantation rate was 50.0%, which was similar to that seen with selinexor in combination with standard and intensive chemotherapy regimens (Fiedler et al, 2020;Martinez Sanchez et al, 2021).…”

Section: Discussionsupporting

confidence: 82%

“…Studies of selinexor alone or in combination with other chemotherapy drugs have shown good efficacy in the treatment of R/R AML. Selinexor 100 mg/weekly with FLAG-IDA in the treatment of R/R AML achieved a CR/CRi rate of 66.7% (Martinez Sanchez et al, 2021); Selinexor 60 mg on days 1,5,10,12 based on CLAG achieved a CR/CRi rate of 45% in 40 R/R AML patients (Abboud et al, 2020); Selinexor in combination with fludarabine and cytarabine in pediatric R/R AML achieved the CR/CRi rate of 47% in 15 patients (Alexander et al, 2016) and selinexor plus cytarabine and idarubicin in patients with R/R AML achieved a CR/CRi rate of 47.6% (Fiedler et al, 2020). In this study, we proposed chemotherapy-free or low-dose chemotherapy regimens containing selinexor for the treatment of R/R AML and myeloid sarcoma.…”

Section: Discussionmentioning

confidence: 97%

“…Patients with R/R AML received 4, 8, or 10 doses of selinexor in a 21-or 28-day cycle, and 14% of the 81 evaluable patients achieved an objective response and 31% showed ≥50% decrease in bone marrow blasts from baseline (Garzon et al, 2017). There are also other R/R AML trials combining selinexor with intensive chemotherapy (Abboud et al, 2020;Bhatnagar et al, 2020;Fiedler et al, 2020;Martinez Sanchez et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma

Tong

Jin

et al. 2023

Front. Pharmacol.

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Introduction: Treatment of relapsed or refractory acute myeloid leukemia (R/R AML) and myeloid sarcoma (MS) has presented challenges for decades. Studies on selinexor in combination with various standard or intensive chemotherapy regimens for the treatment of R/R AML have demonstrated promising results. This study aimed to evaluate the efficacy and safety of chemotherapy-free or low-dose chemotherapy regimens with selinexor for R/R AML and MS patients.Methods: Ten patients with R/R AML or MS who received chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor at Tongji Hospital from October 2021 to August 2022 were included in this study. The primary endpoint was overall response rate (ORR) and secondary endpoints included complete remission (CR), CR with incomplete hematological recovery (CRi), partial remission (PR), transplantation rate, and safety.Results: All patients were evaluable for response, achieving CR in four (40.0%) patients and CRi in two (20.0%) patients for a total CR/CRi of 60.0%. The ORR was 80.0% when patients with PR were included. Five (50.0%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after treatment with selinexor-containing regimens. At the end of the follow-up, seven (70.0%) patients were alive, and three patients died of transplant-related complications or disease progression. The most frequently reported nonhematologic adverse events (AEs) in patients were grade 1 or 2 asymptomatic hyponatremia.Conclusion: The chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor for R/R AML are feasible and tolerable and provide an opportunity for patients to receive transplantation.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma

Tong

Jin

et al. 2023

Front. Pharmacol.

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“…Five of 12 (42%) patients demonstrated a CR or CRi and the median OS was 6.0 (range 0.9–19.3) months. Notably, 3 out of 14 patients (21.4%) had fatal AEs [83].…”

Section: Experimental Non-immunotherapeutic Approaches For R/r Amlmentioning

confidence: 99%

Non-Immunotherapy Approaches for Relapsed or Refractory AML: An Update for 2024

Buchrits,

Wolach

2023

Acta Haematol

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Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) is a challenging, high-risk, clinical scenario with a dismal outcome. Recent insights on the genetic, epigenetic, and metabolic events that drive clonal progression and the advent of novel therapies resulted in the incorporation of several new targeted therapies, alone or in combination, in the R/R setting with the aim of improving response rates and survival. Herein we review current challenges and future opportunities with non-immunotherapeutic approaches to treat R/R AML. Summary: Inhibitors of FLT3 and IDH 1/2 are now FDA-approved for patients with R/R disease and corresponding mutations. These agents are also used in combination with intensive and low-intensity platforms in an attempt to improve response and survival. Several targeted agents are currently being tested alone or in combination in early-phase trials. These include drugs that target apoptotic pathways, drugs that interfere with key survival pathways of the R/R leukemic cell as well as therapies aimed towards the leukemia marrow microenvironment. Menin inhibitors are a promising class of active drugs in NPM1 and KMT2A-rearranged AML. Key-messages: Several new targeted therapies, immunologic and non-immunologic are being studied and are moving through pre-clinical and clinical pipelines. Significant remaining challenges include the development of synergistic combination therapies tailored to the specific biology and clinical context of the patient, and re-defining the role and timing of allogeneic transplantation in patients with R/R disease.

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“…Selinexor (KPT-330) is a new XPO1 inhibitor and is an effective small-molecule drug with promising antitumor effects in various human tumors, including AML in vitro and in vivo [ 23 , 25 , 26 , 27 ]. Several studies indicated that selinexor monotherapy [ 28 , 29 ] or combination therapy shows promising clinical activity and safety for the elderly and relapsed or refractory (R/R) AML patients [ 30 , 31 , 32 ]. Due to its effectiveness, novel combinations of KPT-330 with AZA (NCT05736965, NCT05736978) were under clinical investigation.…”

Section: Introductionmentioning

confidence: 99%

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

Long

Hou

et al. 2023

IJMS

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Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of XPO1 and eIF4E was elevated in AML patient cohorts, respectively. XPO1 and elF4E overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.

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A phase I trial of selinexor plus FLAG-Ida for the treatment of refractory/relapsed adult acute myeloid leukemia patients

Cited by 10 publications

References 26 publications

Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma

Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma

Non-Immunotherapy Approaches for Relapsed or Refractory AML: An Update for 2024

Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

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