A Phase II study of selinexor plus cytarabine and idarubicin in patients with relapsed/refractory acute myeloid leukaemia

Fiedler, Walter; Chromik, Jöerg; Amberg, Stefanie; Kebenko, Maxim; Thol, Felicitas; Schlipfenbacher, Vera; Wilke, Anne C.; Modemann, Franziska; Janning, Melanie; Ganser, Arnold; Bokemeyer, Carsten; Theile, Susann; Deppermann, Ute; Kranich, Anne L.; Heuser, Michael

doi:10.1111/bjh.16804

Cited by 18 publications

(14 citation statements)

References 11 publications

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“…A definite causal relationship between mutational status and response could not be ascertained. A phase II study [ N = 42] of selinexor with 7 + 3 backbone for R/R AML patients found 3 out of 4 NPM1 mutated patients in their trial with CR [ 50 , 51 ]. XPO1 inhibition in NPM1 mutated AML provides multiple targetable strategies either as monotherapy or in combination with, e.g., menin/KMT2A inhibitors [ 52 ], as it was shown to decrease expression of HOX/Meis1 as well.…”

Section: Introductionmentioning

confidence: 99%

“…with R/R AML, 5 pts. ≥60 years with R/R AML [ 50 ] Selinexor + idarubicin and cytarabine (7 + 3) Two cohorts: 40 mg/m 2 twice weekly for 4 weeks and 60 mg flat dose twice weekly 3 out 4 weeks 20 CR/CRi and ORR 47·6%. 35·7% (15/42) were transplanted Febrile neutropenia 67% (28/42), thrombocytopenia 62% (26/42), anemia 57% (24/42), diarrhea 50% (21/42) NCT02485535 Phase 1 12 pts.…”

Section: Introductionmentioning

confidence: 99%

“…Selinexor was better tolerated at 60 mg (flat dose) given twice a week for 2 weeks after decitabine treatment. Selinexor was also combined with other DNA-damaging conventional chemotherapies in several small early phase studies that included N/D poor-risk AML or R/R disease [ 50 , 71 – 74 ]. A single-arm phase 1 study of selinexor with the traditional 7 + 3 regimen [cytarabine and daunorubicin] for N/D poor-risk AML patients [ 74 ] showed a CR/CRi of 53% (10/19: 8CR, 2CRi).…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of nuclear export: a promising approach in the shifting treatment paradigms for hematological neoplasms

2022

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Novel targeted therapeutics alone or in rational combinations are likely to dominate the future management of various hematological neoplasms. However, the challenges currently faced are the molecular heterogeneity in driver lesions and genetic plasticity leading to multiple resistance pathways. Thus, progress has overall been gradual. For example, despite the advent of targeted agents against actionable drivers like FLT3 in acute myeloid leukemia (AML), the prognosis remains suboptimal in newly diagnosed and dismal in the relapsed/refractory (R/R) setting, due to other molecular abnormalities contributing to inherent and acquired treatment resistance. Nuclear export inhibitors are of keen interest because they can inhibit several active tumorigenic processes simultaneously and also synergize with other targeted drugs and chemotherapy. XPO1 (or CRM1, chromosome maintenance region 1) is one of the most studied exportins involved in transporting critical cargoes, including tumor suppressor proteins like p27, p53, and RB1. Apart from the TSP cargo transport and its role in drug resistance, XPO1 inhibition results in retention of master transcription factors essential for cell differentiation, cell survival, and autophagy, rendering cells more susceptible to the effects of other antineoplastic agents, including targeted therapies. This review will dissect the role of XPO1 inhibition in hematological neoplasms, focusing on mechanistic insights gleaned mainly from work with SINE compounds. Future potential combinatorial strategies will be discussed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective inhibition of nuclear export: a promising approach in the shifting treatment paradigms for hematological neoplasms

2022

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“…Preclinical studies with selinexor have demonstrated that XPO1 inhibition causes NPM1c nuclear relocation, loss of HOX expression, differentiation, and growth arrest of NPM1-mutated cells 6,8,9 . However, patients with NPM1-mutated AML showed suboptimal responses to this compound in early-phase clinical trials [10][11][12][13] . Selinexor has a half-life of 6 hours 10 and can be administered once or twice per week as more frequent dosing significantly increases the incidence of adverse effects, particularly nausea and anorexia 14 .…”

Section: Introductionmentioning

confidence: 99%

Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML

et al. 2022

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NPM1 is the most frequently mutated gene in adult acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and XPO1 causes the aberrant cytoplasmic dislocation of NPM1c and promotes high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in NPM1-mutated patients. Here, we show that this dosing strategy results in only temporary disruption of the XPO1-NPM1c interaction, limiting the efficacy of selinexor. Since the second-generation XPO1 inhibitor eltanexor can be administered more frequently, we tested the anti-leukemic activity of prolonged XPO1 inhibition in NPM1-mutated AML models. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation and prolonged survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML.

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“…Preclinical studies have demonstrated that XPO1 inhibition cause NPM1c nuclear relocation, loss of HOX expression, differentiation, and growth arrest of NPM1mutated cells 7,9,10 . However, patients with NPM1-mutated AML showed suboptimal responses to Selinexor in early-phase clinical trials [11][12][13][14] . As Selinexor has a half-life of 6 hours 11 and was administered once or twice/week, we hypothesized that intermittent dosing may not stably inhibit the NPM1c-XPO1 interaction, limiting its efficacy.…”

Section: Introductionmentioning

confidence: 99%

Prolonged XPO1 inhibition is essential for optimal anti-leukemic activity in NPM1-mutated AML

Pianigiani

Gagliardi

Mezzasoma

et al. 2021

Preprint

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NPM1 encodes for a nucleolar multifunctional protein and is the most frequently mutated gene in adult acute myeloid leukemia (AML). NPM1 mutations cause the aberrant accumulation of mutant NPM1 (NPM1c) in the cytoplasm of leukemic cells, that is mediated by the nuclear exporter Exportin-1 (XPO1). Recent work has demonstrated that the interaction between NPM1c and XPO1 promotes high homeobox (HOX) genes expression, which is critical for maintaining the leukemic state of NPM1-mutated cells. However, the XPO1 inhibitor Selinexor administered once or twice/week in early-phase clinical trials did not translate into clinical benefit for NPM1-mutated AML patients. Here, we demonstrate that this dosing strategy results in only temporary disruption of the XPO1-NPM1c interaction and transient HOX genes downregulation, limiting the efficacy of Selinexor in the context of NPM1-mutated AML. Since second-generation XPO1 inhibitors can be administered more frequently, we compared intermittent (twice/week) versus prolonged (5 days/week) XPO1 inhibition in NPM1-mutated AML models. Integrating in vitro and in vivo data, we show that only prolonged XPO1 inhibition results in stable HOX downregulation, cell differentiation and remarkable anti-leukemic activity. This study lays the groundwork for the accurate design of clinical trials with second-generation XPO1 inhibitors in NPM1-mutated AML.

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A Phase II study of selinexor plus cytarabine and idarubicin in patients with relapsed/refractory acute myeloid leukaemia

Abstract: Additional supporting information may be found online in the Supporting Information section at the end of the article.Fig S1 . The karyotype of 46,XY,add(7)(q22),dup(8) (q11.2q24).Supplementary Methods S1. Methods of whole exome sequencing, transcriptome sequencing, and pedigree analysis.

Cited by 18 publications

References 11 publications

Selective inhibition of nuclear export: a promising approach in the shifting treatment paradigms for hematological neoplasms

Selective inhibition of nuclear export: a promising approach in the shifting treatment paradigms for hematological neoplasms

Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML

Prolonged XPO1 inhibition is essential for optimal anti-leukemic activity in NPM1-mutated AML

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