Editorial
Plerixafor: what we still have to learn Francesco Lanza, Angelo Gardellini, Daniele Laszlo & Massimo Martino† †
1.
Introduction
2.
First question: patients’ selection and timing of PLX administration
3.
Second question: mobilization
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Exeter on 05/01/15 For personal use only.
in Hodgkin lymphoma patients 4.
Third question: mobilization in solid tumors
5.
Fourth question: overweight and obesity and stem-cell mobilization with PLX
6.
Fifth question: pharmacodynamic effect and the timing of PLX Sixth question: different graft composition
8.
Seventh question: disruption of the interaction of malignant cells with their protective environment by PLX and their sensitization to cytotoxic therapy Eighth question: PLX and healthy donors
Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with nonHodgkin’s lymphoma and multiple myeloma. Current evidence suggests that the addition of plerixafor with chemotherapy plus G-CSF is safe and effective in the large majority of the patients with low blood CD34+ cell count after mobilization and/or poor yield after the first collection. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug. Keywords: autologous transplantation, mobilization, peripheral blood stem cells, plerixafor Expert Opin. Biol. Ther. (2015) 15(2):143-147
7.
9.
Azienda Ospedaliera BMM, Department of Oncology and Hematology, Hematology and Bone Marrow Transplant Unit, Reggio Calabria, Italy
1.
Introduction
Plerixafor (PLX) is a new mobilization agent that is approved for use in combination with G-CSF to mobilize hematopoietic stem cells (HSCs) in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) and scheduled for high-dose chemotherapy and autologous transplant [1]. PLX significantly improves the mobilization capacity of G-CSF, and published data have shown that the association of PLX plus chemotherapy is feasible, safe and able to improve HSCs mobilization by several fold [2]. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug.
First question: patients’ selection and timing of PLX administration
2.
PLX is very expensive and one of the main issues remaining is patients’ selection and timing of PLX administration. Several factors may influence mobilization outcomes, including older age, a more advanced disease stage, the type of prior chemotherapy (e.g., fludarabine or melphalan), pre-mobilization low platelet count, prior irradiation or a higher number of prior treatment lines [2,3]. The optimal peripheral blood (PB) CD34+ cell threshold to be used for successful PLX use is still uncertain, although the pre-apheresis CD34+ cell count in PB should be the best predictor of CD34+ cells in the apheresis products [4]. Determination of the CD34+ cell count in PB before apheresis helps to identify patients at risk of poor HSCs collection and allows pre-emptive intervention to rescue mobilization in these patients; a peak of CD34+ cells > 20 µl can be considered a reliable indicator of a satisfactory mobilization ability [3]. Patients requiring PLX treatment can be selected based on the fact that they have failed a mobilization, the so-called proven poor mobilizers [3]. In this case, a second mobilization can be made with PLX + G-CSF with or without chemotherapy, which in itself is relatively expensive. Pharmacoeconomic analysis has been carried out in recent years to establish the cost--effectiveness of PLX. The majority of
10.1517/14712598.2015.971750 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
143
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Exeter on 05/01/15 For personal use only.
F. Lanza et al.
published studies are from the US, and as health care systems vary greatly from country to country, the results cannot be directly generalized for other countries. Different retrospective studies have compared chemotherapy mobilization, particularly cyclophosphamide-based regimen in association with G-CSF 5 mcg/kg versus PLX 0.24 mcg/kg + G-CSF 10 mcg/kg [5--7] in the upfront use. Although the total cost of mobilization was higher in the PLX + G-CSF group, chemomobilization was associated with increased risks for the patients (i.e., increased incidence of febrile neutropenia and more hospital admissions). Moreover, the benefit of higher cell yields with a chemomobilization may be offset by less predictability of timing (weekend apheresis procedures) [7]. An alternative, which could have the advantage of avoiding a second mobilization attempt, is to use PLX during first mobilization in patients selected by having factors predictive of poor mobilization and defined ‘predicted poor mobilizers’ [3]. This approach is limited by the poor reliability of the factors predicting mobilization in patients who have not been extensively pretreated. A third way of using PLX is to administer it during first mobilization, selecting patients based on early signs of mobilization failure (‘on demand’ use, also called ‘pre-emptive use’ or use ‘just in time’) [8]. The best time to use ‘on demand’ PLX treatment in a poor mobilizer is not known and requires a better comprehension of the variability of CD34+ mobilization kinetics and the establishment of an early time-point at which mobilization may be judged to have failed. The preemptive use of PLX may be the most cost--effective way to use this new drug by preventing mobilization failure and need for re-mobilization or marrow harvest and to avoid inappropriate use. The addition of PLX to G-CSF or chemotherapy mobilization in patients who mobilize poorly is under investigation and various algorithms for a preemptive or just-in-time use of this agent have been proposed. These algorithms need validations in prospective studies [9]. Vishnu et al. [10] in a prospective study employed a riskadaptive strategy to use PLX only in patients with NHL or MM who were at high risk of mobilization failure. This strategy allowed a significant reduction of mobilization failure with a cost-saving up to $19,000 per patient. Most of this cost-saving was related to fewer numbers of HSCs collection days and increased number of patients undergoing transplantation. Micallef et al. [11] showed the helpful use of a risk-adapted algorithm for the use of PLX in autologous HSCs mobilization. This earlier identification of ineffective mobilization increased the per-patient costs ($20,000), but if PLX had been used universally, the median cost would have been ~$34,000 per patient. Thus the risk-adapted algorithm by selecting only patients who truly need PLX was safe, efficacious, and cost saving compared to universal use. Moreover, a considerable amount of patients in many centers receive PLX triggered by an insufficient amount of collected HSCs in the first apheresis session (rescue 144
mobilization) and the published data demonstrate that this strategy is effective and with economic benefit [12]. Taken together, the currently available pharmacoeconomic data do not support the use of PLX as an upfront mobilization in all patients considered for autologous transplantation. The ‘just in time’ approach can decrease the time and the resources of HSCs, principally by reducing the number of apheresis per patient and remobilizations.
Second question: mobilization in Hodgkin lymphoma patients
3.
Limited information is available on its use in HL patients. A recent study showed that PLX can be used in HL patients with poor mobilization as a rescue agent and boosts mobilization sufficiently in most patients in the same collection attempt, thus not only permitting transplantation, but also avoiding remobilization and the associated costs and treatment delays [13].
Third question: mobilization in solid tumors
4.
High-dose chemotherapy and HSCs transplant work well in certain solid tumors in both the adult and pediatric settings [14]. The rapid kinetics of CD34+ stem cells induced by PLX could be of particular interest in children. In children, a mobilization regimen consisting of one injection of PLX alone in hematological steady state provides a faster and shorter mobilization than in adults [15]. This strategy may be an attractive option for completing an insufficient graft and more studies are warranted to optimize the use of PLX both in children and adults.
Fourth question: overweight and obesity and stem-cell mobilization with PLX
5.
Recently, it has been reported that higher body-mass index (BMI) may correlate with less efficient mobilization with standard regimens based on administration of G-CSF [16]. This result may be related with the altered pharmacokinetics of G-CSF in obese individuals [17]. Moreover, hypercholesterolemia, which frequently accompanies increased BMI, promotes HSCs mobilization [18]. Although a recent analysis revealed that an increased BMI does not impair the ability to collect HSCs after mobilization with PLX and G-CSF [17], relationship between overweight, obesity, hypercholesterolemia and PLX-driven HSCs mobilization are still the object of debate.
Fifth question: pharmacodynamic effect and the timing of PLX
6.
Pharmacodynamic studies show peak PB CD34+ cell counts at 10 -- 14 h after PLX administration [1] and the current
Expert Opin. Biol. Ther. (2015) 15(2)
Plerixafor
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Exeter on 05/01/15 For personal use only.
Table 1. Critical issues and considerations associated with an optimal use of plerixafor. The use in proven, poor and in predicted poor mobilizer patients (who have previously failed an HSCs mobilization) is highly recommended Plerixafor can overcome negative effects of most predictors of poor mobilization to achieve satisfactory harvest both in proven and predicted poor mobilizers Previous fludarabine treatment and pre-mobilization low platelet count can be regarded as predictors of unsuccessful mobilization even in plerixafor-treated patients Use on demand or ‘just in time’ or pre-emptive is highly recommended in patients having CD34+ levels
Plerixafor: what we still have to learn Francesco Lanza, Angelo Gardellini, Daniele Laszlo & Massimo Martino† †
1.
Introduction
2.
First question: patients’ selection and timing of PLX administration
3.
Second question: mobilization
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Exeter on 05/01/15 For personal use only.
in Hodgkin lymphoma patients 4.
Third question: mobilization in solid tumors
5.
Fourth question: overweight and obesity and stem-cell mobilization with PLX
6.
Fifth question: pharmacodynamic effect and the timing of PLX Sixth question: different graft composition
8.
Seventh question: disruption of the interaction of malignant cells with their protective environment by PLX and their sensitization to cytotoxic therapy Eighth question: PLX and healthy donors
Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with nonHodgkin’s lymphoma and multiple myeloma. Current evidence suggests that the addition of plerixafor with chemotherapy plus G-CSF is safe and effective in the large majority of the patients with low blood CD34+ cell count after mobilization and/or poor yield after the first collection. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug. Keywords: autologous transplantation, mobilization, peripheral blood stem cells, plerixafor Expert Opin. Biol. Ther. (2015) 15(2):143-147
7.
9.
Azienda Ospedaliera BMM, Department of Oncology and Hematology, Hematology and Bone Marrow Transplant Unit, Reggio Calabria, Italy
1.
Introduction
Plerixafor (PLX) is a new mobilization agent that is approved for use in combination with G-CSF to mobilize hematopoietic stem cells (HSCs) in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) and scheduled for high-dose chemotherapy and autologous transplant [1]. PLX significantly improves the mobilization capacity of G-CSF, and published data have shown that the association of PLX plus chemotherapy is feasible, safe and able to improve HSCs mobilization by several fold [2]. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug.
First question: patients’ selection and timing of PLX administration
2.
PLX is very expensive and one of the main issues remaining is patients’ selection and timing of PLX administration. Several factors may influence mobilization outcomes, including older age, a more advanced disease stage, the type of prior chemotherapy (e.g., fludarabine or melphalan), pre-mobilization low platelet count, prior irradiation or a higher number of prior treatment lines [2,3]. The optimal peripheral blood (PB) CD34+ cell threshold to be used for successful PLX use is still uncertain, although the pre-apheresis CD34+ cell count in PB should be the best predictor of CD34+ cells in the apheresis products [4]. Determination of the CD34+ cell count in PB before apheresis helps to identify patients at risk of poor HSCs collection and allows pre-emptive intervention to rescue mobilization in these patients; a peak of CD34+ cells > 20 µl can be considered a reliable indicator of a satisfactory mobilization ability [3]. Patients requiring PLX treatment can be selected based on the fact that they have failed a mobilization, the so-called proven poor mobilizers [3]. In this case, a second mobilization can be made with PLX + G-CSF with or without chemotherapy, which in itself is relatively expensive. Pharmacoeconomic analysis has been carried out in recent years to establish the cost--effectiveness of PLX. The majority of
10.1517/14712598.2015.971750 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
143
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Exeter on 05/01/15 For personal use only.
F. Lanza et al.
published studies are from the US, and as health care systems vary greatly from country to country, the results cannot be directly generalized for other countries. Different retrospective studies have compared chemotherapy mobilization, particularly cyclophosphamide-based regimen in association with G-CSF 5 mcg/kg versus PLX 0.24 mcg/kg + G-CSF 10 mcg/kg [5--7] in the upfront use. Although the total cost of mobilization was higher in the PLX + G-CSF group, chemomobilization was associated with increased risks for the patients (i.e., increased incidence of febrile neutropenia and more hospital admissions). Moreover, the benefit of higher cell yields with a chemomobilization may be offset by less predictability of timing (weekend apheresis procedures) [7]. An alternative, which could have the advantage of avoiding a second mobilization attempt, is to use PLX during first mobilization in patients selected by having factors predictive of poor mobilization and defined ‘predicted poor mobilizers’ [3]. This approach is limited by the poor reliability of the factors predicting mobilization in patients who have not been extensively pretreated. A third way of using PLX is to administer it during first mobilization, selecting patients based on early signs of mobilization failure (‘on demand’ use, also called ‘pre-emptive use’ or use ‘just in time’) [8]. The best time to use ‘on demand’ PLX treatment in a poor mobilizer is not known and requires a better comprehension of the variability of CD34+ mobilization kinetics and the establishment of an early time-point at which mobilization may be judged to have failed. The preemptive use of PLX may be the most cost--effective way to use this new drug by preventing mobilization failure and need for re-mobilization or marrow harvest and to avoid inappropriate use. The addition of PLX to G-CSF or chemotherapy mobilization in patients who mobilize poorly is under investigation and various algorithms for a preemptive or just-in-time use of this agent have been proposed. These algorithms need validations in prospective studies [9]. Vishnu et al. [10] in a prospective study employed a riskadaptive strategy to use PLX only in patients with NHL or MM who were at high risk of mobilization failure. This strategy allowed a significant reduction of mobilization failure with a cost-saving up to $19,000 per patient. Most of this cost-saving was related to fewer numbers of HSCs collection days and increased number of patients undergoing transplantation. Micallef et al. [11] showed the helpful use of a risk-adapted algorithm for the use of PLX in autologous HSCs mobilization. This earlier identification of ineffective mobilization increased the per-patient costs ($20,000), but if PLX had been used universally, the median cost would have been ~$34,000 per patient. Thus the risk-adapted algorithm by selecting only patients who truly need PLX was safe, efficacious, and cost saving compared to universal use. Moreover, a considerable amount of patients in many centers receive PLX triggered by an insufficient amount of collected HSCs in the first apheresis session (rescue 144
mobilization) and the published data demonstrate that this strategy is effective and with economic benefit [12]. Taken together, the currently available pharmacoeconomic data do not support the use of PLX as an upfront mobilization in all patients considered for autologous transplantation. The ‘just in time’ approach can decrease the time and the resources of HSCs, principally by reducing the number of apheresis per patient and remobilizations.
Second question: mobilization in Hodgkin lymphoma patients
3.
Limited information is available on its use in HL patients. A recent study showed that PLX can be used in HL patients with poor mobilization as a rescue agent and boosts mobilization sufficiently in most patients in the same collection attempt, thus not only permitting transplantation, but also avoiding remobilization and the associated costs and treatment delays [13].
Third question: mobilization in solid tumors
4.
High-dose chemotherapy and HSCs transplant work well in certain solid tumors in both the adult and pediatric settings [14]. The rapid kinetics of CD34+ stem cells induced by PLX could be of particular interest in children. In children, a mobilization regimen consisting of one injection of PLX alone in hematological steady state provides a faster and shorter mobilization than in adults [15]. This strategy may be an attractive option for completing an insufficient graft and more studies are warranted to optimize the use of PLX both in children and adults.
Fourth question: overweight and obesity and stem-cell mobilization with PLX
5.
Recently, it has been reported that higher body-mass index (BMI) may correlate with less efficient mobilization with standard regimens based on administration of G-CSF [16]. This result may be related with the altered pharmacokinetics of G-CSF in obese individuals [17]. Moreover, hypercholesterolemia, which frequently accompanies increased BMI, promotes HSCs mobilization [18]. Although a recent analysis revealed that an increased BMI does not impair the ability to collect HSCs after mobilization with PLX and G-CSF [17], relationship between overweight, obesity, hypercholesterolemia and PLX-driven HSCs mobilization are still the object of debate.
Fifth question: pharmacodynamic effect and the timing of PLX
6.
Pharmacodynamic studies show peak PB CD34+ cell counts at 10 -- 14 h after PLX administration [1] and the current
Expert Opin. Biol. Ther. (2015) 15(2)
Plerixafor
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Exeter on 05/01/15 For personal use only.
Table 1. Critical issues and considerations associated with an optimal use of plerixafor. The use in proven, poor and in predicted poor mobilizer patients (who have previously failed an HSCs mobilization) is highly recommended Plerixafor can overcome negative effects of most predictors of poor mobilization to achieve satisfactory harvest both in proven and predicted poor mobilizers Previous fludarabine treatment and pre-mobilization low platelet count can be regarded as predictors of unsuccessful mobilization even in plerixafor-treated patients Use on demand or ‘just in time’ or pre-emptive is highly recommended in patients having CD34+ levels
