Introduction: Pediatric and young adult patients (pts) with relapsed/refractory (R/R) acute leukemia have a poor prognosis. Selinexor is a first-in-class antagonist of exportin (XPO1) with single agent activity in adults with acute myelogenous leukemia (AML). Dose-defining non-hematologic toxicities in adult studies included nausea, weight loss and anorexia.

Methods: DFCI Protocol 13-563 was a Phase I dose-escalation trial conducted at nine institutions to test the safety, tolerability and pharmacokinetic (PK) characteristics of selinexor administered to pediatric and young adult pts with R/R acute leukemias. Selinexor was orally administered twice weekly during 4-week cycles. Three dose levels (DLs) were tested (30 mg/m2, 40 mg/m2 and 56 mg/m2) with dose-escalation decisions based on standard 3+3 Phase I design rules. Required supportive care medications included antiemetics and bacterial prophylaxis. All grade ≥2 non-hematologic adverse events (AEs) were recorded with the exception of non-clinically significant grade 2 laboratory abnormalities. Grades 1-4 hematologic AEs were expected in a relapsed leukemia patient population and were not considered AEs.

Results: Sixteen pts enrolled on study, including 5 with primary refractory disease and 7 with second or greater relapse; 6 pts had received prior hematopoietic stem cell transplant. Median age was 9.5 years (range 2.3-21.8). Twelve pts had AML and 4 had acute lymphoblastic leukemia (ALL). Median number of completed cycles was 1 (range 0-3). Thirteen pts (81%) were evaluable for dose limiting toxicity (DLT) assessment, having received at least 7 doses of selinexor during the first cycle. Of 9 pts enrolled at DL1 (30 mg/m2), 6 were DLT-evaluable; 1 pt experienced a DLT of grade 5 pancreatitis (possibly related to study treatment). Three pts enrolled at DL1 were not DLT-evaluable; 2 pts were removed from study due to disease progression and 1 pt died from complications of a pulmonary infection. Six pts enrolled at DL2 (40 mg/m2) and none experienced a DLT. One pt was treated at DL3 (56 mg/m2) and developed a DLT of cognitive impairment (grade 3). Further enrollment onto DL3 was suspended secondary to an amendment capping dose escalation at 40 mg/m2 (equivalent to recommended single-agent dose in adult AML). During Cycle 1, the most common selinexor treatment-related AE's were hyponatremia (31%), elevated alanine aminotransferase (25%), nausea (25%), hyperkalemia (25%), elevated aspartate aminotransferase (19%) and diarrhea (19%). The most common grade ≥ 3 selinexor treatment-related AE's were hyponatremia (31%), elevated alanine aminotransferase (19%), hyperglycemia (13%) and hyperkalemia (13%). In contrast to adults treated with selinexor, there were no cases of grade ≥ 3 weight loss or nausea and only one case of grade 3 anorexia. One AML pt, after 2 cycles, achieved a complete remission with incomplete recovery of platelet count and one ALL pt, after 1 cycle, achieved a partial response, resulting in a protocol-defined overall response rate of 12.5%. Two of 4 pts with ALL (one each in DLs 1 and 2) developed clinically significant (grade 4) TLS. These included the pt who achieved a PR and another pt with early T-cell precursor ALL. Overall, 9 pts (56%), including 6 AML and 3 ALL, experienced an objective response and/or an investigator-defined clinical benefit (e.g., reduction in transfusions, clearance of peripheral blasts, decreased pain) from therapy.

Conclusions: Selinexor, at a doses of 30 or 40 mg/m2 given twice weekly, was well tolerated in pediatric and young adult pts with R/R acute leukemia, demonstrating single agent clinical activity and less GI toxicity than had been seen in adults. The high frequency of TLS in ALL pts is particularly notable as treatment of ALL with selinexor has not been previously reported. Analysis of pharmacokinetic and correlative biology studies are underway. Based on the results of this Phase I study, the recommended Phase II dose of single-agent selinexor in children with R/R acute leukemia is 40 mg/m2 administered twice weekly. These results also support the continued investigation of selinexor in combination with multiagent chemotherapy.


Burke:AMGEN: Speakers Bureau; JAZZ: Speakers Bureau; Shire: Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.

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