Novel Combination Strategy Active in Poor-Risk AML

Pam Harrison

October 17, 2019

An induction cycle of decitabine (Dacogen, Janssen Cilag) followed by twice-weekly selinexor (Xpovio, Karyopharm Therapeutics) has significant clinical activity in relapsed/refractory (R/R) acute myeloid leukemia (AML) as well as in older patients with newly diagnosed AML, a small phase 1 study suggests.

"Long-term survival for patients with relapsed/refractory disease and older (> 60 years) AML patients remains poor, thereby underscoring the need for more innovative therapies that are both effective and well-tolerated," Bhavana Bhatnagar, MD, Ohio State University Comprehensive Cancer Center, Columbus, and colleagues write.

"The combination of 10-day decitabine followed by twice-weekly doses of selinexor appears to be an active regimen for patients with poor risk," the researchers state.

The study was published online September 23 in Leukemia & Lymphoma.

Dose-Escalation Study

The phase 1, dose-escalation study included 25 patients with R/R AML as well as previously untreated patients over the age of 60 years with newly diagnosed AML.

Twenty patients had R/R AML and five patients had newly diagnosed AML.

Patients received a standard 10-day course of decitabine induction at a dose of 20 mg/m2 given intravenously on days 1 to 10 for up to four, 28-day cycles.

This was followed by oral selinexor, initially given on days 11, 13, 28, 20, 25, and 27. As investigators explain, decitabine is a hypomethylating agent while selinexor selectively inhibitors the nuclear transport protein exportin-1 (XPO1).

XPO1 is overexpressed in various types of cancer, including AML, and XPO1-mediated nuclear transport is one mechanism used to inactivate tumor suppressor proteins.

Compounds such as selinexor prevent XPO1-mediated transport of these proteins and, eventually, causes leukemia cell death.

Four doses of selinexor were evaluated from 23 mg/m2 up to 55 mg/m2, as researchers note.

However, the dose of selinexor was later modified to a flat dose of 60 mg or approximately 35 mg/m2 twice a week given for only 2 weeks following decitabine induction to improve the tolerability of the regimen.

"Safety and tolerability were evaluated by assessments of drug-related dose-limiting toxicity," Bhatnagar and colleagues observe.

Grade 3 and higher treatment-related toxicities were common. Asymptomatic hyponatremia was reported in 68% of patients, and febrile neutropenia and sepsis were each reported in 44% of patients.

As investigators note, sodium levels normalized in all patients with grade 3 and higher hyponatremia when selinexor was temporarily discontinued and supportive intravenous fluids and salt tablets, if needed, were given.

Some 40% of patients also developed hyperglycemia, another 40% developed hypertension, 36% experienced hypophosphatemia, and 28% developed pneumonia.

"With the addition of protocol-mandated supportive medications...these symptoms improved and resulted in fewer elective study withdrawals," the authors note.

However, despite modifications of the dose and schedule of selinexor, "the majority of patients were still only able to receive one cycle of therapy due to grade 1 or 2 nausea or anorexia," investigators observe.

There were also a total of 59 serious adverse events, seven of which were felt to be probably or possibly related to decitabine or selinexor, although none were dose-limiting toxicities.

Four serious adverse events were fatal, as investigators add. 

Treatment Response

"Among all 25 patients, 10 responded to therapy," for an overall response rate of 40%, researchers report.

Separating the R/R AML and newly diagnosed older AML patients, investigators found that six out of the 20 patients with R/R AML responded to therapy — three achieved complete remission (CR); one achieved CR with incomplete count recovery (CRi), and two achieved a morphologic leukemia-free state. 

Among the five patients with newly diagnosed AML, four responded to treatment, with two achieving a CR and the other two achieving a CRi.

"The median overall survival (OS) for the entire cohort was 5.9 (95% CI, 3.9 - 10.4) months, and progression-free survival (PFS) for the entire cohort was also 5.9 (95% CI, 2.4 - 8.7) months," researchers report.

However, for those who responded to the novel regimen, the PFS rate was essentially double that for the overall cohort, at 11.8 months, as was OS at 12.9 months, they note.

Among those who did not respond to the regimen, PFS was only 4.4 months and OS was only 5.9 months.

Investigators also assessed whether recurrent AML mutations were associated with treatment response.

Results from a targeted resequencing analysis in 22 patients did not identify any specific mutation that predicted response to treatment, the study authors observe. 

"The combination of these two agents demonstrates preliminary evidence of improved disease activity, although a larger confirmatory study is needed to support this finding," Bhatnagar and colleagues note.

Importantly, treatment allowed four of five R/R AML responders to proceed to allogeneic stem cell transplantation and none of these patients had any evidence of disease at time of transplant, they add.

However, researchers caution that low-grade treatment-related side effects including anorexia and fatigue make the combination of decitabine followed by selinexor "challenging" to use in an elderly population with AML, and they recommend strategies be pursued to improve the tolerability of the regimen.

Bhatnagar has reported receiving research support from Karyopharm Therapeutics, the manufacture of selinexor.

Leuk Lymphoma. Published online September 23, 2019. Abstract

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