A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is characterized by a poor prognosis with a 5-year survival rate of approximately 30% [1]. Even patients who achieve remission to initial therapy often relapse, and certain subgroups such as those with therapy-related AML, older patients, and those with relapsed or refractory disease have a particularly poor outcome [2, 3]. Novel agents that are active and able to be widely applied are imperative. Selinexor (KPT-330), an exportin 1 (XPO1) inhibitor, may be such an agent.

XPO1 is the exclusive, nuclear exporter of most major tumor suppressor proteins (TSP) and growth regulatory proteins (GRP), including p53, p21, p73, FOXO1, and NPM1 [4‐6]. In leukemia and solid tumors, XPO1 is overexpressed leading to enhanced transport of these proteins to the cytoplasm, thereby neutralizing their anti-neoplastic functions and functionally inactivating TSP/GRP. Elevated levels of XPO1 have been independently associated with a worse prognosis in adults with AML [7, 8]. These findings presented an attractive target for the development of a novel class of XPO1 inhibitors. However, the earliest compounds of XPO1 inhibitors had faced significant toxicities in phase I clinical trials requiring discontinuation, while others were never studied in a clinical setting [9].

Selinexor (KPT-330) is an oral, first-in-class, slowly reversible, and potent agent that was among the next group of selective inhibitor of nuclear export (SINE) compounds to be developed, which also included KPT-335, KPT-185, KPT-276, and KPT-251, many of which have since been studied in clinical trials. The SINE compounds bind to residue Cys528 of XPO1 and blocks the transport of cargo proteins [5]. In both AML primary samples and murine xenograft models, SINE compounds have been shown to reduce XPO1 levels and enhance the nuclear accumulation of p53 [10, 11]. A phase I clinical trial of selinexor in patients with advanced AML demonstrated it to have a manageable safety profile at 35 mg/m² (60 mg) and to be efficacious in a single-agent setting [12].

In vivo and in vitro evidence suggest synergistic activity against leukemic cells by combining selinexor with anthracyclines or DNA-damaging agents [13]. The combination of high-dose cytarabine (HiDAC) with the anthracycline mitoxantrone (Mito) is an effective induction regimen for patients with AML [14‐17] and is frequently utilized at the University of Chicago as frontline therapy for patients with high-risk AML, either de novo or relapsed/refractory. The HiDAC/Mito regimen demonstrated an overall response rate (ORR) of 55% in the high-risk AML population at this institution [16] and an ORR of 82% in another study of previously untreated patients with therapy-related myeloid neoplasms [17].

Based on phase I safety and efficacy data of selinexor in patients with AML, the promising results with HiDAC/Mito induction, and the in vivo and in vitro data suggesting synergistic killing of AML cell lines by combining selinexor and anthracyclines, we hypothesized that selinexor would sensitize AML cells to the cytotoxic effects of HiDAC/Mito. We monitored the impact on minimal residual disease (MRD) by tracking the level of Wilms tumor 1 (WT1) expression. WT1 levels in the peripheral blood predict relapse after remission, and their levels after consolidation therapy are closely correlated with survival and early relapse [18, 19]. In this phase I study, we describe the safety, tolerability, correlative molecular studies, and activity of selinexor in combination with HiDAC/Mito for remission induction in patients with previously untreated or relapsed/refractory (R/R) AML.

The combination of selinexor with HiDAC/Mito for induction chemotherapy in AML is a feasible, tolerable, and effective regimen. This study resulted in an ORR of 70% and a low induction death rate of 5%. This phase I study demonstrates that this first-in-class SINE compound has an acceptable toxicity profile at the tested doses of 60 and 80 mg. The MTD was not determined, and no DLT was observed in the dose escalation phase. However, a frequent hematologic toxicity was prolonged thrombocytopenia and delayed neutrophil recovery. Four patients received filgrastim to promote count recovery, but this did not shorten count recovery time. Moreover, studies on filgrastim have not demonstrated a consistent benefit with respect to lower rates of infections and improved survival [25, 26]. While patients eventually recovered blood counts, one patient with secondary AML had a hypocellular bone marrow prior to induction therapy and hence failed to recover blood counts by day 56. Prior studies of selinexor alone have not reported any adverse effects on hematopoietic function [7, 12, 27]. Nevertheless, based on this experience, patients with a hypocellular marrow prior to induction should receive this regimen with particular caution, and dose-reduction of selinexor should be considered based on marrow cellularity and age.

Commonly reported non-infectious toxicities included diarrhea, anorexia, electrolyte abnormalities, nausea, vomiting, and fatigue, consistent with prior selinexor studies [12, 27‐29]. The Larson et al. study [16] of HiDAC/Mito alone in high-risk AML patients offered some insight into the independent contribution of selinexor to the toxicity profile. The study reported 64% of patients with neutropenic fever (vs 70% in our study), 12% with diarrhea (vs 40%), 14% with bacteremia (vs 25%), and 10% with cardiac toxicity (vs 25%), an expected toxicity in the setting of Mito exposure [30]. Additionally, more febrile neutropenia and bacteremia were observed likely due to the longer period of myelosuppression. Despite the higher number of toxicities, the majority were low grade and manageable with supportive therapies. The single case of cerebellar toxicity could be attributed to HiDAC [31, 32], as the patient was 61 years old at the time and had reduced glomerular filtration rate, yet it is worth noting that this was also observed in other phase I studies involving selinexor [7, 28]. One patient’s protracted nausea and vomiting which required TPN was assessed as selinexor-related [12, 27]. While GI toxicities were a common reason for patient withdrawal or dose modifications in other selinexor studies [12], no patients withdrew or needed modification to the dosing during induction due to toxicities. Those who proceeded to consolidation therapy continued to tolerate the regimen, although dose reductions were needed in a couple of cases, suggesting that the 80-mg dose was less tolerable for extended longer-term use. Based on these findings, the recommended phase 2 dose of selinexor is 80 mg (~ 50 mg/m²) twice a week for four doses in combination with HiDAC/Mito for induction therapy.

The major limitations of this study were the small sample size, heterogeneous population, and short duration of follow-up that precluded drawing any definitive conclusions. Moreover, new data on a second-generation XPO1 inhibitor reported better tolerability due to decreased CNS penetration of the drug as compared to selinexor in the pre-clinical setting [33]. The development of a second-generation agent offers additional avenues for further study as a single agent or in combination therapy.

The novel class of XPO1 inhibitors have demonstrated effectiveness in disrupting cellular mechanisms that promote tumorigenesis. Selinexor is one such agent within this class that has been well studied as a single agent in AML. We demonstrated that selinexor can be feasibly combined with an existing AML regimen HiDAC/Mito, and this combination is safe with a tolerable toxicity profile. This study reported an ORR of 70% with a low induction death rate of 5%. Given the potential promise of the preliminary data, further study is needed in a large phase II trial to see if these trends would continue. The RP2D of selinexor is 80 mg (~ 50 mg/m²) twice a week for four doses in combination with HiDAC/Mito.