Phase I Study of the Safety and Pharmacokinetics of Plerixafor in Children Undergoing a Second Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Leukemia

Abstract

The safety, pharmacokinetics and biological effect of plerixafor in children as part of a conditioning regimen for chemo-sensitization in allogeneic hematopoietic stem cell transplantation (HSCT) have not been studied. This is a phase I study of plerixafor designed to evaluate its tolerability at dose of 0.24 mg/kg given intravenously on day -4 (level 1), day -4, and day -3 (level 2), or day -4, -3, and day -2 (level 3) in combination with fludarabine, thiotepa, melphalan, and rabbit anti-thymocytic globulin for a second allogeneic HSCT in children with refractory or relapsed leukemia. Immunophenotype analysis was performed on blood and bone marrow prior to and after plerixafor administration. Twelve patients were enrolled. Plerixafor at all 3 levels was well tolerated without dose-limiting toxicity. Transient gastrointestinal side effects of National Cancer Institute grade 1 or 2 in severity were the most common adverse events. The area under the concentration-time curve increased proportionally to the dose level. Plerixafor clearance was higher in males, and increased linearly with body weight, and glomerular filtration rate. The clearance decreased and the elimination half-life increased significantly from dose level 1 to 3 (P < 0.001). Biologically, the proportion of CXCR4-positive blasts and lymphocytes both in the bone marrow and peripheral blood, increased after plerixafor administration.

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)

“…As reported in other trials of plerixafor in children and adults with acute leukemias, 27,28,32 we observed that plerixafor mobilized leukemic blasts into the peripheral blood. Despite heterogeneous expression of surface CXCR4, mobilization occurred in the vast majority of patients in this trial.…”

Plerixafor is safe and efficacious for mobilization of peripheral blood stem cells in pediatric patients

“…Also, in a study examining plerixafor administration for allogeneic stem cell transplantation seven of 12 patients had at least one adverse event possibly related to plerixafor. Nausea and vomiting were the most common adverse effect that occurred in patients in this study (occurring in three patients each), as well as in the study reported by Maschan and colleagues …”

“…When plerixafor binds to CXCR4, it blocks the binding of its cognate ligand CXCL12, allowing for the mobilization of HSCs out of the marrow . While efficacy of plerixafor has been proven in adult patients, data are limited for efficacy in pediatric patients . Therefore, we conducted a retrospective chart review evaluating the safety and efficacy of plerixafor in pediatric patients.…”

Targeting CXCR4 in AML and ALL

“…Of the 12 patients enrolled, only two experienced disease relapse post-transplantation and six were alive at a median follow-up of 67 months ( 120 ). In the third trial, plerixafor was included as part of a myeloablative conditioning regimen for 12 pediatric patients with rrAML undergoing a second allogeneic HSCT (NCT01068301) ( 121 ). With a median duration of follow-up of 332 days, four of the 12 patients (33%) were alive with two being disease free.…”