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, Edward Allan Racela Sison, Sharyn D. Baker, Lie Li, Amina Ahmed, Tanya Trippett, Lia Gore, Margaret E. Macy, Aru Narendran, Keith August, Michael J. Absalon, Jessica Boklan, Jessica Pollard, Daniel Magoon, Patrick A Brown

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalPediatric Blood and Cancer
DOIs
StateAccepted/In press - 2017

Fingerprint

Myelodysplastic Syndromes
Cytarabine
Etoposide
Leukemia
Research Personnel
Pediatrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Therapeutics
Young Adult
Febrile Neutropenia
Hypokalemia
JM 3100
Bone Marrow
Drug Therapy

Keywords

  • CXCR4
  • Leukemia
  • Pediatric
  • Plerixafor
  • Tumor microenvironment

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

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). / Cooper, Todd M.; Sison, Edward Allan Racela; Baker, Sharyn D.; Li, Lie; Ahmed, Amina; Trippett, Tanya; Gore, Lia; Macy, Margaret E.; Narendran, Aru; August, Keith; Absalon, Michael J.; Boklan, Jessica; Pollard, Jessica; Magoon, Daniel; Brown, Patrick A.

In: Pediatric Blood and Cancer, 2017.

Research output: Contribution to journalArticle

Cooper, Todd M. ; Sison, Edward Allan Racela ; Baker, Sharyn D. ; Li, Lie ; Ahmed, Amina ; Trippett, Tanya ; Gore, Lia ; Macy, Margaret E. ; Narendran, Aru ; August, Keith ; Absalon, Michael J. ; Boklan, Jessica ; Pollard, Jessica ; Magoon, Daniel ; Brown, Patrick A. / 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). In: Pediatric Blood and Cancer. 2017.
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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.",
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T1 - 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

T2 - A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03)

AU - Cooper, Todd M.

AU - Sison, Edward Allan Racela

AU - Baker, Sharyn D.

AU - Li, Lie

AU - Ahmed, Amina

AU - Trippett, Tanya

AU - Gore, Lia

AU - Macy, Margaret E.

AU - Narendran, Aru

AU - August, Keith

AU - Absalon, Michael J.

AU - Boklan, Jessica

AU - Pollard, Jessica

AU - Magoon, Daniel

AU - Brown, Patrick A

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - CXCR4

KW - Leukemia

KW - Pediatric

KW - Plerixafor

KW - Tumor microenvironment

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U2 - 10.1002/pbc.26414

DO - 10.1002/pbc.26414

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