Summary
Acute myeloid leukemia (AML) is the most frequently encountered acute leukemia in adults, with a projection of more than 21,000 new diagnoses for this year in the US. As its name implies, AML is a particularly aggressive malignancy occurring in hematopoietic stem cells of the myeloid lineage. This hematologic malignancy is typically found in adults and frequently exhibits poor clinical outcomes and treatment resistance with currently available therapies. Consequently, the discovery of novel therapeutic approaches for treating this disease is an unmet clinical need.
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Original Article
A New Strategy for Selinexor in Newly Diagnosed, Elderly Patients With AML
Oncology Times
By Richard Simoneaux
Acute myeloid leukemia (AML) is the most frequently encountered acute leukemia in adults, with a projection of more than 21,000 new diagnoses for this year in the US. As its name implies, AML is a particularly aggressive malignancy occurring in hematopoietic stem cells of the myeloid lineage. This hematologic malignancy is typically found in adults and frequently exhibits poor clinical outcomes and treatment resistance with currently available therapies. Consequently, the discovery of novel therapeutic approaches for treating this disease is an unmet clinical need.
A recent therapeutic strategy in the treatment of malignancies is the use of selective inhibitors of nuclear export. One such compound is selinexor, a small molecule, orally bioavailable inhibitor of the nuclear export protein XPO1.
In preclinical studies, AML cells, when treated with selinexor, exhibited sensitivity to chemotherapy, in part, by blocking the nuclear export of topoisomerase II (Clin Cancer Res 2016;22(24):6142-6152). This, when coupled with the presence of an anthracycline antibiotic, resulted in an increased number of DNA strand breaks. In May 2019, the FDA approved the use of selinexor in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who received at least four prior therapies with disease refractory to at least two immunomodulatory agents, at least two proteasome inhibitors, and a CD38-targeting monoclonal antibody.
In 2018, a phase II clinical study (NCT02835222) was initiated to evaluate the efficacy of combining selinexor with induction, consolidation, and maintenance therapy in newly diagnosed, elderly (60 years or older) patients with AML. The principal investigator in this study is Timothy Pardee, MD, PhD, at the Comprehensive Cancer Center of Wake Forest Baptist Health. Regarding this study, he stated, “We have noted positive results in our initial findings from this study.” This research was presented by Pardee at the 2019 ASH Annual Meeting (Abstract 1388).
Among the secondary objectives for this study were the following: safety assessment for selinexor administration under the specified conditions, assessment of response and survival endpoints for the specified treatment regimen, and assessment of allogeneic stem cell transplantation rate.
Treatment Regimen
For induction therapy, patients received the standard “7+3” or “7+3” with selinexor. The standard “7+3” regimen consisted of the following: 100 mg/m2 cytarabine intravenously via continuous infusion on days 1-7; 60 mg/m2 daunorubicin hydrochloride IV on days 1-3; and 60 mg selinexor orally (PO) twice weekly (i.e., on days 1, 3, 8, 10, 15, and 17). Treatment was assessed on day 14 with a bone marrow biopsy to determine if there was residual disease present unless disease progression or unacceptable toxicity was noted.
Those patients with significant residual disease following induction therapy received an additional re-induction regimen that consisted of the following: cytarabine IV on days 1-5; daunorubicin hydrochloride IV on days 1-2, and selinexor PO twice weekly (if in the selinexor arm). Following this treatment, patients were allowed to recover their blood counts.
Those patients responding to induction therapy were then permitted to receive consolidation therapy, which consisted of 1.5 mg/m2 cytarabine IV every 12 hours on days 1, 3, and 5, and selinexor PO twice weekly (i.e., days 1, 3, 8, 10, 15, and 17 ). This regimen was repeated every 42 days for up to 3 courses, unless disease progression or unacceptable toxicity was noted.
Those patients who were in the selinexor arm who successfully completed consolidation therapy were permitted to receive maintenance therapy, consisting of single-agent selinexor (60 mg PO on days 1 and 8 every 21 days). Treatment was continued for 4 weeks in the absence of disease progression or unacceptable toxicity. Upon treatment completion, patients were monitored for 14 days, and then every 3 months for up to 1 year.
Study Results
A total of 13 patients were enrolled, however, only 12 of these were evaluable at the time of the abstract submission. These 12 patients were randomized in a 1:1 manner to either the selinexor or standard arm.
“Generally speaking, the combination was well-tolerated, with no patients having to discontinue selinexor secondary to treatment-related adverse events,” Pardee noted. “In the standard arm, three patients attained a complete remission (CR). Of these, one subsequently experienced a relapse, one received a stem cell transplant, and one completed consolidation chemotherapy.”
In the selinexor arm, five of the six patients achieved a CR, while one patient found to have attained a morphologic leukemia-free state.
“All patients receiving selinexor showed a clinical response,” Pardee noted, adding, “of the five responders, three have gone on to transplant, one completed 14 treatment cycles and is on maintenance therapy, and one is completing consolidation therapy.”
None of the patients in the standard arm died during induction therapy; however, three of the six did subsequently die from progressive disease. Although one patient in the selinexor arm did die during induction therapy, none of the remaining patients have undergone disease progression at the time of the abstract submission.
“It was encouraging to note that there was no difference in the AE profiles of the study arms; also, no unexpected side effects were observed,” Pardee said. “The one patient receiving long-term maintenance selinexor is, thus far, tolerating it without any difficulty.”
When questioned about the reasons for performing this study, he replied, “In older patients, AML is characterized by lower response rates and increased relapse rates; consequently, there is a clear clinical need for these patients.”
Concerning their findings, Pardee stated, “Selinexor in combination with standard induction and consolidation therapy appears highly active in older patients who are newly diagnosed with AML.”
Richard Simoneaux is a contributing writer.