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Clinical Trial
. 2017 Aug;64(8):10.1002/pbc.26414.
doi: 10.1002/pbc.26414. Epub 2017 Apr 14.

A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03)

Todd M Cooper  1 , Edward Allan Racela Sison  2 , Sharyn D Baker  3 , Lie Li  3 , Amina Ahmed  4 , Tanya Trippett  4 , Lia Gore  5 , Margaret E Macy  5 , Aru Narendran  6 , Keith August  7 , Michael J Absalon  8 , Jessica Boklan  9 , Jessica Pollard  10 , Daniel Magoon  11 , Patrick A Brown  11
Affiliations
Clinical Trial

A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03)

Todd M Cooper et al. Pediatr Blood Cancer. 2017 Aug.

Abstract

Background: Plerixafor, a reversible CXCR4 antagonist, inhibits interactions between leukemic blasts and the bone marrow stromal microenvironment and may enhance chemosensitivity. A phase 1 trial of plerixafor in combination with intensive chemotherapy in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) was performed to determine a tolerable and biologically active dose.

Procedure: Plerixafor was administered daily for 5 days at four dose levels (6, 9, 12, and 15 mg/m2 /dose) followed 4 hr later by high-dose cytarabine (every 12 hr) and etoposide (daily).

Results: Nineteen patients (13 with AML, 5 with ALL, 1 with MDS) were treated. The most common grade 3 or greater nonhematologic toxicities attributable to plerixafor were febrile neutropenia and hypokalemia. There were no dose-limiting toxicities (DLTs). Plerixafor exposure increased with increasing dose levels and clearance was similar on days 1 and 5. Eighteen patients were evaluable for response. Two patients achieved complete remission (CR) and one patient achieved CR with incomplete hematologic recovery (CRi): all three had AML. No responses were seen in patients with ALL or MDS. Plerixafor mobilized leukemic blasts into the peripheral blood in 14 of 16 evaluable patients (median 3.4-fold increase), and the degree of mobilization correlated with surface CXCR4 expression.

Conclusions: Plerixafor, in combination with high-dose cytarabine and etoposide, was well tolerated in children and young adults with relapsed/refractory acute leukemias and MDS. While biologic responses were observed, clinical responses in this heavily pretreated cohort were modest.

Keywords: CXCR4; leukemia; pediatric; plerixafor; tumor microenvironment.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors have no relevant financial interests to disclose.

Figures

Figure 1
Figure 1
Summary of correlative biology studies. Data points represent individual patients and are color-coded by disease type (ALL in blue, AML in red, AML/MDS in black). (A) Surface expression of CXCR4 in leukemic blasts is higher in ALL than AML/MDS. Surface expression of CXCR4 was measured in bone marrow leukemic blasts at study entry (baseline). CXCR4 MFI in leukemic blast populations were normalized to isotype control. Average CXCR4 MFI was significantly higher in patients with ALL compared to patients with AML or AML/MDS (ALL 167.5 vs. AML 51.94, p=0.025). (B) Plerixafor mobilizes leukemic blasts into the peripheral blood. Blood was collected prior to dose 1 of plerixafor (hour 0) and at hour 4. Mobilization of leukemic blasts by plerixafor was observed in 14 of 16 patients, with a median 3.4-fold increase in circulating leukemic blasts (p=0.006). (C) Mobilization of leukemic blasts by plerixafor is dependent on CXCR4 expression. Baseline surface CXCR4 expression and fold change in leukemic blast count after dose 1 of plerixafor were compared. The degree of leukemic blast mobilization correlated positively with baseline surface CXCR4 expression (r=0.56, p=0.023). (D) Treatment with plerixafor resulted in increased surface CXCR4 expression in circulating leukemic blasts. CXCR4 MFI of circulating leukemic blasts was measured prior to dose 1 of plerixafor (hour 0) and at hour 4. Plerixafor treatment induced a significant increase in surface CXCR4 expression (p=0.004). (E) Surface CXCR4 expression in bone marrow blasts did not differ significantly between baseline and the end of cycle 1. Surface expression of CXCR4 was measured in bone marrow leukemic blasts at study entry (baseline) and at the end of cycle 1.
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