Plerixafor: what we still have to learn

Abstract

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 non-Hodgkin’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

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.

2. First question: patients’ selection and timing of PLX administration

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 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, 6, 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 risk-adaptive 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 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.

3. Second question: mobilization in Hodgkin lymphoma patients

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].

4. Third question: mobilization in solid tumors

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.

5. Fourth question: overweight and obesity and stem-cell mobilization with PLX

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.

6. Fifth question: pharmacodynamic effect and the timing of PLX

Pharmacodynamic studies show peak PB CD34⁺ cell counts at 10 – 14 h after PLX administration [1] and the current guidelines on HSCs collection recommend the initiation of apheresis 10 – 11 h later [19]. There are few data on CD34⁺ cell counts in the first hours after drug administration. Some recently published data suggest that endogenous progenitor rhythms may be altered by the pharmacodynamic effect and the timing of PLX 20, 21 and, in very poor mobilizers, the CD34⁺ cell count can peak more rapidly than previously reported [22]. We believe that it is mandatory to examine whether HSCs mobilization has a specific kinetic profile with PLX. A simple change of collection time to coincide with the peak of circadian egress might theoretically optimize the number of HSCs collected and the time of drug administration.

7. Sixth question: different graft composition

Another issue that the scientific community needs to learn is related to the knowledge that mobilization with G-CSF plus PLX results in different graft composition when compared to G-CSF alone mobilization [23], including more CD34+CD38- cells as well as more Natural Killer-cells and T cells 24, 25. There are lack of data on the graft content other than CD34+ cell dose in patients mobilized with a combination of chemotherapy, G-CSF and PLX [26]. Further studies are needed to evaluate as graft composition might significantly alter post-transplant immune events.

8. Seventh question: disruption of the interaction of malignant cells with their protective environment by PLX and their sensitization to cytotoxic therapy

A very intriguing topic of study is represented by the concept of ‘chemo-sensitization’ approach using PLX. Recently, a resistant, quiescent population of leukemia cells that have limitless self-renewal potential has been described [27]. The identification of these ‘leukemia stem cells’ (LSCs) could provide, in the future, an additional strategy in treating and preventing relapsed/refractory acute leukemia. Part of the chemotherapy resistance of LSCs is because they are anchored in the stem cell niche and not circulating and protection is afforded to LSCs via the interaction between stem cell derived growth factor (CXCL-12/SDF-1α) and its receptor, CXCR4. These interactions are implicated in chemotaxis, homing and survival/apoptosis of LSCs and progenitor cells. PLX blocks CXCL-12 binding to and signaling through CXCR4, thus disrupting tumor–stroma interactions and mobilizing leukemia cells from their protective stromal environment. The interruption of the SDF-1/CXCR4 axis using the selective CXCR4 antagonist PLX may be useful as an LSCs mobilizing agent for patients who are refractory to standard dose chemotherapy and in relapse after an allogeneic transplant.

The safety and effect of chemosensitization with PLX have been recently studied in vivo in relapsed or refractory leukemia in adult patients [28], and, as part of a conditioning regimen in allogeneic transplantation in children [29]. Biologically, the proportion of CXCR4(+) blasts and lymphocytes both in the bone marrow and PB increased after PLX administration.

Similar experiences have been applied in other hematologic malignancies. Azab et al. [30] showed that PLX disrupts the interaction of MM cells to the BM in vitro and in vivo, leading to enhanced sensitivity to bortezomib. This concept may lead to novel approaches in MM therapy, by modulating the capacity of malignant cells to reside in their microenvironment. These experiments provide a proof of concept for the use of agents that disrupt the interaction with the microenvironment for enhancement of efficacy of cytotoxic agents in cancer therapy.

9. Eighth question: PLX and healthy donors

PBHSCs are the most popular source of stem cells for allogeneic transplantation because of technical ease of collection and faster engraftment. Considering the shortcomings of G-CSF and the demonstrated potential of PLX in trials with autologous stem cell transplantation patients, it would be logical to investigate the efficacy of PLX in healthy donors for allogeneic transplant. However, the biological impact of PLX in this context on T cells and other cellular populations contained within the allograft are unknown. If combining PLX with G-CSF has no negative impact on the immune populations involved in Graft-Versus-Host-Disease and Graft-Versus-Leukemia effects, a ‘one-day’ mobilization regimen, consisting of one injection of 240 μg/kg PLX alone, should be examined in allogeneic donors. Trials comparing PLX versus PLX plus G-CSF in normal healthy donors are ongoing and the investigators suspect that the stem cell graft mobilized by PLX and G-CSF will provide a superior graft to that mobilized by PLX alone [31], without forgetting that it is mandatory to obtain data on the short- and long-term adverse events.

The critical issues associated with PLX use for PBSCs are summarized in Table 1. In the same table, we have highlighted our considerations and expert opinions for an optimal use of PLX both in NHL/MM and other conditions.

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 <20 ul in PB

The optimal PB CD34^+ cell threshold to be used for a successful plerixafor use is still uncertain

A specific algorithm for the plerixafor use in combination with each chemotherapy regimen has to be developed in order to define the timing for its use in patients with non-Hodgkin lymphoma and multiple myeloma

Cost–effectiveness of plerixafor use needs to be assessed in prospective studies

It is well known that plerixafor is typically given subcutaneously 10 – 14 h prior to the start of apheresis, late in the evening. Prospective data are needed in order to define the timing of its use in the various patient categories

Relationship between overweight, obesity, hypercholesterolemia and plerixafor-driven HSCs mobilization is still an object of debate

The clinical implication related to the high content of lymphoid cells in HSCs preparations collected after plerixafor is still under evaluation

The engraftment capacity of HSCs preparations containing a high content of neutrophil granulocytes has to be evaluated in prospective studies

Data on long-term engraftment, safety and clinical outcome of plerixafor-mobilized patients are lacking. Current data support the notion that plerixafor-mobilized patients appear to have roughly comparable engraftment after high-dose therapy compared with the patients mobilized with other methods [32]

Accumulating evidence support the use of plerixafor in several solid tumors prior to HSCs transplantation. However, at present time, its use in this setting is not indicated by the Food and Drug Administration

Plerixafor use in acute leukemia is still an object of debate. Experimental studies and a few clinical data have shown that plerixafor may sensitize blast cells to cytostatic drugs, thus improving clinical response to induction treatment

Preliminary data have shown that plerixafor is capable of mobilizing HSCs in normal donors. Authors believe that long-term data on safety and ethical issues need to be solved before its use in the clinical practice

HSCs: Hematopoietic stem cells; PB: Peripheral blood.

Declaration of interest

F Lanza acted as a consultant for Sanofi in the years 2011 – 2014. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.