General AML

Selinexor combined with cladribine, cytarabine, and G-CSF for the treatment of relapsed or refractory acute myeloid leukemia

The dysregulation of tumor suppressor proteins (TSPs) and other proteins regulating growth are crucial for the tumorigenesis of acute myeloid leukemia (AML). TSPs require nuclear localization to function, and excess nuclear export of critical TSPs can lead to their functional inactivation in tumor cells. Selinexor, a first-in-class, selective inhibitor of nuclear export is a novel agent that can block Exportin 1 (XPO1), allowing for accumulation of TSPs in the nucleus, eventually leading to cell cycle arrest and apoptosis. Therefore, Abboud and Chendamarai, Washington University School of Medicine in St. Louis, St. Louis, US,  and colleagues initiated a preclinical and phase I/II study (NCT02416908) to examine the efficacy and safety of selinexor in combination with chemotherapy for the treatment of relapsed or refractory (R/R) AML. The results of the study were published in Haematologica in November 2019.1

Preclinical data

  • Mice were treated with either: vehicle, oral selinexor only (15 mg/kg), subcutaneous injection of cytarabine (AraC) (200 mg/kg), or the combination of selinexor plus AraC. Treatment was administered three days a week for two weeks
  • In a mouse tumor model, male C57BL/6J mice were injected with primary murine AML tumor cells (1×106 cells/mouse) and treated 3 days after tumor engraftment
    • The overall survival (OS) of tumor-bearing mice was prolonged when selinexor and AraC were combined, with a median of 58 days, compared to chemotherapy treatment or vehicle alone (p < 0.0001)
  • Male C57BL/6J mice were used to test the effect of selinexor on normal hematopoiesis
  • The presence of common lymphoid progenitor cells was significantly decreased in both the selinexor only arm (p = 0.007) and the selinexor plus AraC arm (p < 0.0001) compared with the AraC only arm
  • Whole bone marrow transplantation from mice treated with selinexor plus AraC into congenic recipients showed engraftment efficiency of CD45.2+ donor cells to be significantly reduced in the selinexor plus AraC arm compared to the selinexor only arm (p = 0.0005) and AraC only arm (p < 0.0001)
  • Overall, data showed that there was an increased antitumor effect with the combination of selinexor and AraC, however there was potential for hematopoietic toxicity

Phase I/II study

Based on the preclinical data, an open-label, phase I/II study commenced of selinexor combined with cladribine, cytarabine, and granulocyte-colony stimulating factor (G-CSF; CLAG) regimen for the treatment of patients with R/R AML. The study enrolled 40 patients (Table 1) between June 6, 2015 and January 28, 2018

Dosing
  • Patients received selinexor 60 mg orally once per day on Days 1, 5, 10, and 12
  • Cladribine administered intravenously (IV) (5 mg/m2 /day) on Days 4–8
  • G-CSF 300 mcg was subcutaneously injected once per day on Days 3–8
  • Cytarabine 2,000 mg/m2 /day IV on Days 4– 8
Inclusion criteria:
  • Patients with R/R AML, aged 18–70 years, and had one of the following:
  • Primary refractory disease after ≤ 2 cycles of induction chemotherapy
  • No previous unsuccessful salvage chemotherapy
  • R/R to therapy with a DNA hypomethylating agent
Phase I
  • Six patients were allocated to a phase I portion of the study in order to ensure that safety was acceptable and Grade 3–4 non-hematologic toxicity did not exceed 20%. Based on the phase I study, the dose of 60 mg selinexor twice weekly was continued in the phase II study
Phase II
  • The primary endpoint of the phase II study was complete remission (CR) or CR with incomplete blood count recovery (CRi)
Table 1. Patient characteristics (N = 40)1
Age, years (median, range) 55.5 (21–70)
Female gender (%) 37.5
Status at study entry (%)  
Primary refractory disease following 2 or less cycles of induction chemotherapy 30
First relapse with no prior unsuccessful salvage chemotherapy 67.5
R/R to hypomethylating agent 2.5
Cytogenetic risk (%)  
Favorable 5.0
Intermediate 67.5
Poor 22.5
Not available 5.0

R/R, relapsed/refractory

Results

Safety 
  • The most common hematopoietic toxicity was thrombocytopenia with delayed neutrophil recovery. Nevertheless, the risk of bleeding was relatively low and resulted mostly in Grade ≥3 hematuria occurring in 10% of patients
  • Gastrointestinal toxicity was deemed low and manageable with Grade 3 nausea and Grade 3 diarrhea, observed in 7.5% of patients.
  • Common Grade 1/2 events were nausea and vomiting that were observed in 57.5% of patients, respectively, and diarrhea was observed in 40% of patients
  • Treatment-related adverse events were observed in 7.5% of patients
  • The mortality rate for Day 30 and 60 were 2.5% and 7.5%, respectively
Efficacy
  • CR/Cri, achieved in 45% of patients, did not differ significantly from the prespecified institution’s historical rate of 33% (p = 0.16), thus the phase II portion was considered to have failed to meet its primary endpoint
  • Neutrophil and platelet engraftment occurred at median time of 28 days and 38 days, respectively
  • The median event-free survival was 6.1 months (95% CI, 4.5–7.8)
  • Median relapse-free survival was 5.8 months (95% CI, 3.0–11.1)
  • Median OS was 7.8 months (95% CI, 5.7–14.1)
  • The median duration of remission was 9.1 months
  • 60% of patients on the study received allogeneic hematopoietic cell transplantation after treatment
  • 15 patients were alive at the time of the last follow-up

Conclusion

The investigators concluded that the results from this study show that selinexor in combination with CLAG is an anthracycline-free regimen which has a manageable safety and acceptable efficacy profile in patients with R/R AML. It may, therefore, be potentially used as a bridge to allogeneic hematopoietic cell transplantation in some patients.

Adverse events, such as gastrointestinal toxicity and prolonged thrombocytopenia, were seen with selinexor treatment, which is consistent with results from other studies using selinexor. According to the investigators, the rate of gastrointestinal and hematopoietic side effects can be considered low, probably due to the fact that selinexor was given at a relatively low, flat dose of 60 mg twice weekly and supportive premedication with 5-HT3 antagonists and dexamethasone was provided to all patients.

References
  1. Abboud R. & Chendamarai E. et al., Selinexor combined with cladribine, cytarabine, and filgrastim in relapsed or refractory acute myeloid leukemia. Haematologica. 2019 Nov 21. DOI: 10.3324/haematol.2019.236810
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