EMA Recommendation for the Pediatric Indications of Plerixafor (Mozobil) to Enhance Mobilization of Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Children with Lymphoma or Malignant Solid Tumors

Abstract

On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony‐stimulating factor (G‐CSF) to pediatric patients (aged 1 year to <18 years) to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. This treatment is indicated either preemptively, when circulating stem cell count on the predicted day of collection after adequate mobilization with G‐CSF (with or without chemotherapy) is expected to be insufficient with regard to desired hematopoietic stem cells yield, or in children who previously failed to collect sufficient hematopoietic stem cells. The efficacy and safety of plerixafor were evaluated in an open label, multicenter, phase I/II, dose‐ranging, and randomized controlled study (DFI12860) in pediatric patients with solid tumors, including neuroblastoma, sarcoma, Ewing sarcoma, or lymphoma, who were eligible for autologous hematopoietic stem cell transplantation. Forty‐five patients (aged 1 year to <18 years) were randomized, 2:1, using 0.24 mg/kg of plerixafor plus standard mobilization (G‐CSF with or without chemotherapy) versus control (standard mobilization alone). The primary analysis showed that 80% of patients in the plerixafor arm experienced at least a doubling of the peripheral blood (PB) CD34+ count, observed from the morning of the day preceding the first planned apheresis to the morning prior to apheresis, versus 28.6% of patients in the control arm (p = .0019). The median increase in PB CD34+ cell counts from baseline to the day of apheresis was 3.2‐fold in the plerixafor arm versus by 1.4‐fold in the control arm. The observed safety profile in the pediatric population was consistent with that in adults, with adverse events mainly related to injection site reactions, hypokalemia, and increased blood bicarbonate. Importantly, plerixafor exposure did not seem to negatively affect transplant efficiency. This article summarizes the scientific review of the application leading to regulatory approval in the European Union. Implications for Practice This review of the marketing authorization of plerixafor will raise awareness of pediatric indication granted for this medicinal product.

A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders

“…In the phase I part of their study (n = 27), Morland et al determined the dose of plerixafor in children to be 240 μg/kg which was the dose received by majority of patients in our cohort. Previous studies have reported a median 3.2 to 13-fold 3,7,21,22 increase in PB CD34+ count following plerixafor administration, we observed a median 4-fold increase in PB CD34+ counts using this agent. In phase II study from Europe, 80% of children who received plerixafor upfront with SM achieved doubling of PB CD34+ vs 28.6% of those who received SM alone.…”

Plerixafor‐based mobilization in pediatric healthy donors with unfavorable donor/recipient body weight ratio resulted in a better CD34+ collection yield: A retrospective analysis

“…Even though G‐CSF remains the standard for PBSC mobilization, alternative mobilization policy, such as twice daily G‐CSF schedule (split dose) or the use of molecules like AMD3100, might be considered for donors who turn out to be poor mobilizers. Plerixafor (AMD3100) was approved in adult patients in 2009 by the European Medicines Agency for use in combination with G‐CSF, to enhance the mobilization of hematopoietic stem cells to peripheral blood, and recently has received a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency for its use in combination with G‐CSF in pediatric patients to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors 37,38 …”

“…Considering the pharmacokinetic and pharmacodynamic differences between the pediatric and adult population, direct extrapolation of adult data is not possible. To address these issues, a two‐phase study (DFI12860) was designed, containing a dose‐ranging part (phase I) followed by a small randomized comparative study (phase II) to support the extension of the indication of plerixafor to pediatric patients 38 . It is worth mentioning the association that was found between exposure to the drug, with age and weight.…”

“…Plerixafor (AMD3100) was approved in adult patients in 2009 by the European Medicines Agency for use in combination with G-CSF, to enhance the mobilization of hematopoietic stem cells to peripheral blood, and recently has received a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency for its use in combination with G-CSF in pediatric patients to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. 37,38 Considering the pharmacokinetic and pharmacodynamic differences between the pediatric and adult population, direct extrapolation of adult data is not possible. To address these issues, a two-phase study (DFI12860) was designed, containing a dose-ranging part (phase I) followed by a small randomized comparative study (phase II) to support the extension of the indication of plerixafor to pediatric patients.…”

“…To address these issues, a two-phase study (DFI12860) was designed, containing a dose-ranging part (phase I) followed by a small randomized comparative study (phase II) to support the extension of the indication of plerixafor to pediatric patients. 38 It is worth mentioning the association that was found between exposure to the drug, with age and weight. Interestingly, they observed that the exposure to medication (area under the curve and maximum serum concentration) depended on both age and weight, leading to a twofold lower exposure in the group aged <6 years compared with the group aged 12 to 18 years and a more than twofold lower exposure in the <15 kg weight cohort compared with the >40 kg cohort, which could explain the lower rate of adverse effects in relation to mobilization in this group of donors.…”