Drug Evaluation
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Plerixafor for mobilization of blood stem cells in autologous transplantation: an update 1.
Introduction
2.
Plerixafor in proven or predicted poor mobilizers
3.
Preemptive use of plerixafor
4.
Cost-efficacy of plerixafor use
5.
Effects of plerixafor in graft cellular composition
6.
Outcome of patients receiving plerixafor mobilized grafts
7.
Future perspectives
8.
Expert opinion
Esa Jantunen† & Ville Varmavuo †
Kuopio University Hospital, Department of Medicine, Kuopio, Finland
Introduction: About 99% of all autologous transplants are now performed with blood stem cells. G-CSF alone or combined with chemotherapy have been used to mobilize CD34+ cells. Plerixafor is a novel drug used for mobilization purposes. Areas covered: We have evaluated recent data in regard to plerixafor use in predicted or proven poor mobilizers. In addition, we have looked for preemptive strategies to optimize the use of this expensive drug. Also cost-efficacy issues and effects of plerixafor on graft composition and post-transplant outcomes will be discussed. Expert opinion: Plerixafor added to G-CSF is superior than G-CSF alone for mobilization of CD34+ cells. This combination is also efficient in patients who have failed a previous mobilization attempt with other methods or in patients with risk factors for poor mobilization. Addition of plerixafor to G-CSF or chemotherapy plus G-CSF mobilization in patients who appear to mobilize poorly is under active investigation and algorithms for a preemptive use of this expensive agent have been proposed. Grafts collected after plerixafor appear to contain more lymphoid cells than the grafts collected without it. Whether this affects post-transplant outcomes such as immune reconstitution and risk of relapse needs to be evaluated. Keywords: autologous stem cell transplantation, graft cellular composition, outcome after autologous stem cell transplantation, plerixafor, poor mobilization, preemptive use of plerixafor, review Expert Opin. Biol. Ther. (2014) 14(6):851-861
1.
Introduction
High-dose therapy supported by autologous stem cell transplantation (ASCT) is an established therapy for some hematological disease. According to the registry of the European Group for Blood and Marrow Transplantation, > 18,600 first autotransplants were registered in 2011 [1]. The most common indications were multiple myeloma (MM) (8341 patients, 45%) and non-Hodgkin’s lymphomas (NHL) (5646 patients, 30%) followed by Hodgkin’s lymphoma (HL) (2066 patients, 11%). Blood stem cell grafts were used for supporting high-dose therapy in about 99% of all autotransplants. Historically, chemotherapy (cyclophosphamide or combination chemotherapy) plus G-CSF (chemomobilization) have been used for mobilizing blood stem cells for ASCT. More recently, the use of G-CSF alone has get more popularity due to its lower toxicity and easier prediction of peak mobilization [2,3], although combination of chemotherapy plus G-CSF is usually more efficient. The potential benefits of mobilization with chemotherapy plus G-CSF over G-CSF mobilization include the need for fewer apheresis sessions and potential antitumor activity, although the importance of the latter is dependent on disease and disease status of a given patient. Despite the method of mobilization used, 5 -- 30% of patients 10.1517/14712598.2014.902927 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name Phase
Plerixafor Approved by EMA in 2009 and by FDA in 2008 Indication To mobilize CD34+ cells for autologous stem cell transplantation in myeloma and NHL patients with G-CSF Pharmacology description A selective inhibitor of CXCR4 Route of administration Subcutaneous Chemical structure 1, 1¢-[1,4-phenylenebis (methylene)]-bis-1,4,8,11tetraazacyclotetradecane Pivotal trial(s) Two Phase III trials in MM [21] and NHL [20] Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com). MM: Multiple myeloma; NHL: Non-Hodgkin’s lymphomas.
intended for high-dose therapy are difficult to mobilize [4-8]. There appears to be no major differences in the incidence of mobilization and collection failure, whether G-CSF is used alone or in combination with a preceding chemotherapy [4,8]. According to some studies, lymphoma patients are more often hard-to-mobilize than MM patients [4,7]. Plerixafor (formerly AMD3100) is a small bicyclam molecule with a molecular weight of 502 Da. It was initially developed for the potential treatment of HIV infections [9,10] but was subsequently found to cause leukocytosis and an increase in the amount of blood CD34+ cells [11-13], including true stem cells based on functional studies [14]. The mechanism of action is a reversible antagonism against the chemokine receptor CXCR4, which blocks the interaction between CXCR4 and CXCL12 (formerly stromal derived factor-1 [SDF-1]), leading to liberation of CD34+ cells from their marrow niches to circulation [15,16]. SDF-1 released from bone marrow stromal cells appears to be an important mechanism of plerixafor for mobilization of hematopoietic progenitor cells in steady state [17]. CXCR4 is expressed in many hematopoietic and non-hematopoietic cell types [18], which explains the increase in the amount of neutrophils, eosinophils, basophils, monocytes and lymphocytes observed after plerixafor administration [13,14,19]. Plerixafor was studied mainly in combination with G-CSF (filgrastim) in several Phase II studies and after two Phase III randomized placebo-controlled studies [20,21] was accepted by the US FDA in December 2008 and by the European Medicines Agency (EMA) in July 2009 to be used in myeloma or lymphoma patients to mobilize stem cell for autologous transplantation. The approval for plerixafor was for patients mobilized with G-CSF, and the EMA approval also included an additional requirement of poor mobilization. Only one formal Phase II study of plerixafor added to chemotherapy 852
plus G-CSF mobilization has been published [22]. The recommended dose of 240 µg/kg plerixafor is given as a subcutaneous injection in G-CSF-treated patients, 6 -- 11 h before the start of apheresis. In patients with renal failure (estimated creatinine clearance < 50 ml/min), a reduced dose (160 µg/kg) is used. In this review, we try to update the data in using plerixafor (Box 1) for mobilization of CD34+ cells for ASCT, since our previous review of this subject in this forum [23]. We aim to concentrate on preemptive use of plerixafor, effects of plerixafor on graft cellular content and post-transplant outcomes. Also, cost-effectiveness issues and new data in regard to practical use of plerixafor will be discussed.
Plerixafor in proven or predicted poor mobilizers
2.
Plerixafor combined with G-CSF was shown to be an efficient stem cell mobilizing therapy in patients who had failed a previous mobilization attempt [4,24-28]. Based on these studies, 60 -- 90% of the patients failing at least one prior mobilization attempt can be successfully mobilized with plerixafor-based regimens [29]. Plerixafor has also been used in patients with risk factors for poor mobilization. Several risk factors have been identified [2,30,31]. Detailed discussion on this topic is beyond the scope of this review, but some points are briefly mentioned here. For example, higher age of the patients has been a risk factor for poor mobilization in some studies [5,32], although age as such may be less important when chemotherapy combined with G-CSF is used [33,34]. In myeloma patients, the use of lenalidomide before mobilization is known to be associated with inferior mobilization of CD34+ cells [35,36]. In lymphoma patients, the use of fludarabine has been associated with risk of poor mobilization [37]. An Italian group has recently proposed definitions for ‘poor mobilizers’ [38]. Their criteria for predicted poor mobilizers include at least one major criterion (previously failed mobilization attempt, extensive radiotherapy to bone marrow-bearing sites or full course of melphalan, fludarabine or other stem cell toxic agents) or at least two minor criteria (age > 65 years, bone marrow cellularity < 30%, extensive bone marrow infiltration, refractory disease or at least two previous treatment lines). By using these criteria, the addition of plerixafor to a mobilization with chemotherapy plus G-CSF resulted in successful collections in 73% of predicted poor mobilizers [39]. In a larger patients series, including 215 patients (143 proven, 64 predicted poor mobilizers), the success rate was 68% and this was not dependent whether the patients received plerixafor after steady state (G-CSF) or after a mobilization with chemotherapy plus G-CSF [40]. Previous fludarabine treatment and low platelet counts were the only negative predictors of mobilization success. The Phase III studies comparing G-CSF + plerixafor with G-CSF and placebo showed a similar efficacy and
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Plerixafor
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Table 1. Algorithms for preemptive plerixafor use. Study
Number of patients included
Disease(s)
Used mobilization method
Costa et al. [99]
50
Lymphomas, MM
G-CSF alone
Sinha et al. [100]
1556
Lymphomas, PCD
G-CSF alone
Chen et al. [101] Abhyankar et al. [102]
49 159
Lymphomas, MM Lymphomas, PCD, solid tumors
G-CSF alone G-CSF alone
Sancho et al. [8]
397
Lymphomas, MM, AML and others
Micallef et al. [58]
592
Lymphomas, PCD
G-CSF alone (mainly) or chemotherapy + G-CSF G-CSF alone
Jantunen et al. [49]
390
Milone et al. [48]
233
Lymphomas, PCD, and others Lymphomas, MM
Ozsan et al. [103]
396
MM
Hay et al. [104]
354
Farina et al. [105]
107
Lymphomas, MM, AML and others Lymphomas, MM
Chemotherapy + G-CSF Cyclophosphamide 4 g/m2 + G-CSF Cyclophosphamide 3 g/m2 + G-CSF Chemotherapy + G-CSF Disease-specific cyclophosphamide 3 -- 7 g/m2 + G-CSF
Suggested trigger/cut-off level for plerixafor
Calculated individually on day 4 based on B-CD34+ count and collection target B-CD34+ < 6 106/l on day 4 or B-CD34+ < 10 106/l on day 5 or first collection yield < 1.0 106 CD34 cells/kg B-CD34+ 5 -- 15 106/l on day 4 Target ‡ 2.5 106 CD34 cells/ kg: B-CD34+ < 10 106/l on day 5; Target ‡ 5.0 106 CD34 cells/ kg: B-CD34+ > 10 106/l but < 20 106/l on day 5 or first collection yield is < 50% of the desired target A peak value of B-CD34+ < 13.8 106/l
Algorithm I: B-CD34+ < 10 106/l on day 4 or day 5 or any collection yield < 0.5 106 CD34 cells/kg. Algorithm II: B-CD34+ < 10 106/l for single transplantation and < 20 106/l for multiple transplantations on day 4 or first collection yield < 1.5 106 CD34 cells/kg or any subsequent collection yield < 0.5 106 CD34 cells/kg B-CD34+ £ 10 106/l when WBC count > 5 109/l or > 10 109/l B-CD34+ < 6 106/l on day 12 or B-CD34+ < 10 106/l on day 13 B-CD34+ < 10 106/l on day 13 or 1 day after WBC count > 1 109/l A peak value of B-CD34+ < 16.5 106/l B-CD34+ £ 10 106/l and WBC count > 1 109/l or WBC count < 1 109/l after day 12/day 14 (myeloma/lymphoma)
AML: Acute myeloid leukemia; B: Blood; MM: Multiple myeloma; PCD: Plasma cell disorders; WBC: White blood cell.
safety profile in older patients (‡ 60 years) [41]. In patients failing a previous mobilization attempt, the success rate of achieving the minimum required collected CD34+ cell number (> 2 106/kg) was 69% in patients who had received lenalidomide (median 5 cycles) and was 58% in patients with a history of fludarabine exposure, respectively [42]. Another study [43] evaluated risk factors of poor mobilization with G-CSF plus plerixafor in patients with a previous mobilization failure. The minimum collection target (‡ 2 106/kg CD34+ cells) was achieved in 67.5% of 197 patients. Prior therapy with lenalidomide or melphalan, previous
radiotherapy, or a prior ASCT were not risk factors, but there was a trend for higher risk of failure in patients previously treated with purine analogs [43]. The current evidence suggests that the use of plerixafor abolishes the effects of some predicted criteria for poor mobilization, but especially patients treated with fludarabine may be more difficult to mobilize even with plerixafor. The choice between G-CSF plus plerixafor versus chemotherapy + G-CSF plus plerixafor appears to be dependent on the disease and disease status of a given patient. If there is no obvious need for further standard-dose chemotherapy, G-CSF plus plerixafor could be preferred.
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Table 2. Authors’ guidelines for preemptive plerixafor use. G-CSF mobilization B-CD34+ < 10 106/l on day 5 (after 4 days of G-CSF) Collection of < 1 106/l with the first apheresis* Chemotherapy + G-CSF mobilization WBC count rising > 5 -- 10 109/l and B-CD34+ < 10 106/l Collection of < 1 106/l with the first apheresis* Decreasing B-CD34+ cell counts during collections before the target has been reached
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*Depends on the collection target. B: Blood; d: Day; WBC: White blood cell.
3.
Preemptive use of plerixafor
Although a lot has been learned in regard to risk factors for poor mobilization, for unknown reasons, many patients with risk factors can still be successfully mobilized and collected. On the other hand, many patients without any major risk factors mobilize poorly. The idea of a preemptive or ‘just in time’ use of plerixafor is to prevent a collection failure or to reduce the number of collections needed in patients who appear to mobilize poorly with standard regimens, including G-CSF alone or combined with chemotherapy [44]. Mobilization of CD34+ cells is a dynamic process and the relatively quick action of plerixafor make this agent useful for this purpose. D’Addio et al. [45] used plerixafor in 13 patients mobilizing poorly with chemotherapy plus G-CSF, and minimal grafts > 2 106/kg CD34+ cells were collected from all the patients. According to our own initial experience in 16 patients, the addition of plerixafor to chemotherapy plus G-CSF mobilization resulted in a median fivefold increase in B-CD34+ counts, and in 13 patients (80%) the minimum collection target was achieved [46]. An increase of B-CD34+ cell counts from 7 to 17 106/l with a single plerixafor injection and successful collections in 87% of the patients was reported from a rescue use of plerixafor among 39 lymphoma or myeloma patients [47]. As plerixafor is an expensive drug, various algorithms have been proposed to guide preemptive use of plerixafor (Table 1). These algorithms are mainly based on retrospective data and need prospective validation. The situation is easier for G-CSF-mobilized patients, where the trigger point for plerixafor use after 4 days of G-CSF depends critically on collection target. In many instances, B-CD34+ count < 10 106/l on day +5, would indicate a need for plerixafor use. In regard to a mobilization with chemotherapy plus G-CSF, the situation is more complex as various chemotherapeutic regimens have variable time for hematopoietic recovery and optimal time of mobilization of CD34+ cells. In regard to intermediate-dose cyclophosphamide (4 g/m2), Milone et al. [48] have suggested that plerixafor should be used if B-CD34+ is < 10 106/l on day +13 or < 6 106/l on day +12. It is important that only a limited number of 854
mobilizing regimens are used in a single center so that typical mobilization kinetics is well known to optimize preemptive use of plerixafor, if needed. We have developed an algorithm based on blood leukocyte (WBC) and CD34+ cell counts in patients mobilized with chemotherapy plus G-CSF [49]. According to our retrospective analysis, plerixafor should be considered in these patients if WBC count is rising and is > 5 -- 10 109/l and B-CD34+ counts remain < 10 106/l. It might be useful to wait 1 or 2 days, if the platelet counts are not yet rising, if feasible. We have used this algorithm in our center since 2011. It is not clear whether plerixafor is useful in patients with practically absent B-CD34+ cells (< 2 106/l). Increase of G-CSF dose and waiting 1 or 2 days, if feasible, might be an option in these situations but prospective data is lacking. In our experience, if B-CD34+ is 5 -- 9 106/l prior to the first plerixafor dose, successful collections can be achieved in all patients. Another issue is stable low or even decreasing B-CD34+ counts prior to the start of apheresis or decreasing B-CD34+ cell counts during collections. In these situations, the foldincrease of B-CD34+ counts after plerixafor injection is less than in the case of low but rising counts, as discussed earlier, but in most patients adequate collections can be obtained to proceed to high-dose therapy. Some guidelines for preemptive plerixafor use are presented in Table 2. From 2010 to 2013, altogether 192 patients have been mobilized and submitted for stem cell collection in the adult hematology ward of Kuopio University Hospital. Altogether 188 patients (98%) received chemotherapy plus G-CSF, whereas 4 patients were mobilized with G-CSF alone. Sixtytwo patients (32%) had received plerixafor for poor or, in some case, for late mobilization (to avoid weekend collections). The minimum collection target (‡ 2 106/kg CD34+ cells) was not achieved in 14 plerixafor-treated patients (22%) (11/50 NHL patients, 2/8 MM patients and in 1/5 HL patients); three patients proceeded to ASCT with grafts containing 1.6 -- 1.9 106/kg CD34+ cells. Additional two patients with poor grafts (0.8 and 1.1 106/kg CD34+ cells) were remobilized and minimum grafts were achieved in both patients. During the 4-year period altogether 14 patients (6.6% of all mobilized patients) failed the first mobilization (no collections at all or too low yields to proceed with ASCT); in three patients, plerixafor was not given due to very low B-CD34+ cell counts. Milone et al. [50] recently presented data from a prospective study where they observed that failure to collect the minimum target of ‡ 2 106/kg CD34+ cells decreased from a historical 20.9 to 4%. Both these observations suggest that the failure rates can be decreased substantially with this strategy, but there still remains a patient group who cannot be effectively mobilized even with the addition of plerixafor. 4.
Cost-efficacy of plerixafor use
In the study by Shaughnessy et al. [51], the total costs in the patients mobilized with G-CSF plus plerixafor were
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Plerixafor
comparable to those mobilized with cyclophosphamide (3 -- 5 g/m2) plus G-CSF, but mobilization was more predictable in the plerixafor group. The preemptive use of plerixafor in selected high-risk patients or poor mobilizers has resulted in similar or even lower total costs when compared to traditional mobilization methods [52]. Both Markov simulated model comparing G-CSF + plerixafor with G-CSF alone [53] or a risk-adapted use of G-CSF plus plerixafor has met the accepted criteria for cost-effectiveness [54]. Results from the studies based on prospectively collected data corroborate with the results of retrospective studies [50,55]. In some other studies, combination of plerixafor and G-CSF was more effective [56] or was of comparable efficacy [57], but it was also more expensive compared to a mobilization with low-dose and intermediate-dose cyclophosphamide and G-CSF in myeloma patients. Total costs of mobilization and collection have been reported to be higher even if an algorithm has been used to guide plerixafor administration [58]. Most of the available studies are based on historical data (retrospectively collected). Studies are also subject to a number of limitations and this should be taken into consideration before making final conclusions [16]. Some potential costs including those associated with a delayed transplant, emotional costs and convenience costs have not been evaluated in these studies [29], but they may still be important. In addition, since the majority of published pharmacoeconomic studies are from the USA and as healthcare systems vary greatly from country to country, the results cannot be directly generalized for other countries. In conclusion, even though plerixafor is an expensive drug and some patients may require multiple doses, it may be possible to reduce the total costs of mobilization and collection process if remobilizations and/or prolonged apheresis sessions can be avoided.
Effects of plerixafor in graft cellular composition
5.
As all mobilizing agents have a different and unique potential to mobilize stem cells, the mobilization method used has an impact on the cellular composition of the collected stem cell grafts [59]. In addition, the mobilization method may alter the characteristics and functions of mobilized cells [60]. The collected and transplanted cells may have importance in terms of engraftment and long-term outcome after ASCT [61,62]. A small percentage of all CD34+ stem cells are considered be more primitive than the ‘normal’ stem cells. These primitive stem cells have been shown to have high self-renewal potential and to be progenitors of many different cell types [63,64]. In clinical practice, these primitive stem cells have been linked with engraftment [65,66]. Plerixafor plus G-CSF has been shown to mobilize more primitive stem cells when compared to the G-CSF alone [61,67] or a mobilization with chemotherapy plus G-CSF [68,69]. In our own study of NHL patients mobilized with chemotherapy plus G-CSF, the median amount of the most primitive stem cells (defined
as CD34+CD133+CD38-) from all CD34+ stem cells in the graft was about threefold higher among patients mobilized with chemotherapy plus G-CSF and treated with plerixafor when compared to the group of patients mobilized without plerixafor. There was no significant difference in the total amount of CD34+ cells between these groups. All patients engrafted successfully after ASCT, and early and late engraftment (up to 12 months) were similar between the groups [68]. In addition to CD34+ cells, plerixafor has been shown to enhance the mobilization of lymphocytes, when compared to G-CSF mobilization [70]. This may be important as higher infused lymphocyte dose has been reported to be a prognostic factor for overall survival (OS) and progression-free survival (PFS) after ASCT [71-73]. Higher infused lymphocyte numbers have been associated with earlier lymphocyte recovery [74] and may also be associated with better patient outcome [75]. The blood stem cell grafts collected from NHL patients mobilized with chemotherapy plus G-CSF and treated with plerixafor may contain about four times more CD3+ T lymphocytes (including CD4+ helper T lymphocytes and CD8+ suppressor T lymphocytes) when compared to the patients mobilized with chemotherapy plus G-CSF but without plerixafor [68]. Further, T lymphocytes mobilized with plerixafor may differ from the cells mobilized with G-CSF alone [76]. This may be meaningful at least if plerixafor is used in mobilizing allografts (off-label use). Plerixafor also mobilizes more natural killer (NK) cells (CD3-CD16/56+) [68]. It is of interest that plerixafor alone or combined with G-CSF seems to increase the mobilization of functional NK cells in mice [77]. CD19+ B lymphocytes are only rarely found in grafts collected from B-cell lymphoma patients, as the majority of the patients have been treated with monoclonal B-cell antibodies (CD20 antibodies, for example, rituximab). In this patient group, plerixafor does not seem to enhance the mobilization of potentially malignant B cells [68]. However, it should be noted that interindividual variations in the amounts of all different lymphoid cells are quite large whether plerixafor is used or not [68,78]. This also suggests that factors (e.g., disease, previously given therapies) other than the use of plerixafor may alter the mobilization of lymphoid cell subsets. Although it is fascinating to speculate the importance of graft cellular composition with post-transplant outcomes, further studies evaluating potential correlates between the doses of various cell types in the graft and hematopoietic and immune recovery are needed in the era of plerixafor. These will shed more light to the discussion of optimal graft characteristics, as some of these issues may be possible to manipulate at least to some extent with the selection of mobilization regimen.
Outcome of patients receiving plerixafor mobilized grafts
6.
An important issue in case of plerixafor use for mobilization of CD34+ cells for ASCT is the potential effects of plerixafor
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in terms of mobilizing various cell types to the graft (see Section 5) as well as the potential concern of tumor cell mobilization [79]. Therefore, analysis of engraftment as well as long-term outcomes such as PFS is of major interest. In the Phase III studies in patients with MM or NHL, no significant differences were observed in the time to engraftment after high-dose therapy in patients mobilized with or without plerixafor [20,21]. Also, survival at 12 months was comparable. The follow up presented in the original papers is clearly too short to make any conclusions except for engraftment, and long-term follow up of these studies are awaited with interest. Moreb et al. [80] evaluated 17 patients (9 lymphoma, 8 MM) mobilized with G-CSF plus plerixafor in the compassionate use program. They observed no difference in the time to engraftment or hospital stay, when compared to the control group. In another retrospective study, including 32 NHL or MM patients mobilized with G-CSF plus plerixafor, Alexander et al. [81] observed that if the CD34+ cell doses were matched, the early neutrophil and platelet engraftment was slower in plerixafor-mobilized patients. However, no difference in engraftment was encountered at 100 days after the graft infusion. We have analyzed both early and late hematopoietic engraftments among 89 NHL patients of which 33 received plerixafor added to chemotherapy plus G-CSF [82]. Despite the fact that the CD34+ cell dose (measured after collection before freezing) was higher in the control patients (4.2 vs 3.5 106/kg), the early and late engraftment were comparable between the groups except for lower hemoglobin level at 3 months in the plerixafor group. The PFS was 79% in the plerixafor group and 86% in the control group at 1 year (p = NS), also 2 years PFS was comparable (70 vs 83%). The OS was 82 versus 89% at 1 year and 71 versus 85% at 2 years, respectively [82]. The patient groups were not balanced as there were more relapsed patients (51 vs 32%, p = 0.023) in the plerixafor group. A single center analysis, including 17 NHL patients mobilized with the addition of plerixafor, observed an event-free survival of 77% and an OS of 93% with a median observation time of 2 years, respectively [83]. A single center retrospective analysis of 148 MM patients mobilized either with cyclophosphamide + G-CSF or G-CSF plus plerixafor suggested a significantly shorter time to progression in plerixafor-mobilized patients (13 vs 25 months) [84]. The groups were unbalanced in regard to, for example, longer time from the diagnosis to transplantation and the patients in the plerixafor group had received more commonly melphalan dose < 200 mg/m2, but the Cox regression analysis showed that the use of plerixafor was associated with poorer PFS. There was, however, no difference in OS between these groups. Clearly, more information is needed in this respect. It is unlikely that the use of cyclophosphamide 3 g/m2 for mobilization purposes would significantly change the disease course after modern induction therapy as such. Although previous studies have not observed an excessive 856
mobilization of myeloma cells in patients mobilized with G-CSF plus plerixafor compared to the patients mobilized with G-CSF alone [85], potential mobilization of tumor cells may in part explain the shortened PFS observed in this retrospective analysis. Longer follow up of the Phase III studies by DiPersio et al. [20,21] could shed more light at this point. A recent analysis of 49 plerixafor-mobilized lymphoma or myeloma patients revealed a high incidence of myelodysplastic syndrome (MDS)/acute leukemia with a cumulative incidence of 17% at 42 months [86]. Another retrospective study, including 283 patients (86%) with MM, observed clinical MDS/acute leukemia in 10 patients (3.5%) and additionally cytogenetic features of MDS was observed in 10 patients [87]. The authors concluded that the risk of MDS in the plerixafor-mobilized patients was comparable to their experience observed using intensive total therapy protocols in MM patients mobilized without plerixafor. It is likely that the risk of developing MDS is independent of the plerixafor use and may be due to more advanced disease status and more treatment lines in patient who need plerixafor to augment mobilization of CD34+ cells. Younger myeloma patients not uncommonly receive two or even three cycles of high-dose melphalan with stem cell support and may also receive cyclophosphamide and lenalidomide during their disease course which all may be associated with the risk of developing MDS in patients surviving long enough. Again, the long-term follow up of the Phase III studies [20,21] would be helpful in elucidating this issue at least to some point. Taken together, plerixafor-mobilized patients appear to have roughly comparable engraftment after high-dose therapy compared with the patients mobilized with other methods. Clearly more data are needed in regard to long-term outcomes. The CALM study of the European Blood and Marrow Transplantation group will evaluate long-term outcomes of a large number of myeloma or lymphoma patients mobilized with or without plerixafor [88]. We have started a nationwide Graft and Outcome in Autologous Transplantation study to evaluate the effects of various mobilization methods on graft cellular composition as well as posttransplant outcomes, including hematopoietic and immune reconstitution and risk of relapse [89]. 7.
Future perspectives
Although plerixafor has been in clinical use for about 5 years, several open questions still remain. Initially plerixafor was evaluated for a subcutaneous use. More recently, intravenous administration has also been investigated [90]. In this Phase II study, 39 lenalidomide-treated MM patients were included. In 97% of the patients, the collection target (> 3 106/kg) was achieved with 1 -- 2 apheresis. The plerixafor was given intravenously with a standard dose (240 µg/kg) in the morning followed by the start of apheresis 4 -- 5 h later. This appears to be a safe and efficient strategy and if confirmed in further studies may change clinical practice, where
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Plerixafor
plerixafor is typically given subcutaneously 6 -- 11 h prior to start of apheresis, late in the evening. Another important issue is the timing of plerixafor in case of subcutaneous use. In a study including 48 patients mobilized with G-CSF, plerixafor was given at 17.00 h, that is, 15 h before the planned apheresis. Successful collections were achieved in all but one patient [91]. Another study evaluated plerixafor dosing 17 h before the start of apheresis [92]; the target CD34+ cell numbers were collected with a single apheresis in 73% of the patients and in all patients with three aphereses. A recent study suggested that mobilization of CD34+ may continue up to 18 h after the plerixafor injection in standard mobilizers and longer time from the plerixafor injection may increase the proportion of more primitive CD34+CD38- cells [93]. On the other hand, in very poor mobilizers, the kinetics of CD34+ cell mobilization may be different as suggested by the study of Lefre`re et al. [94]. In this study, a very early mobilization, as early as 3 h, was observed after plerixafor administration and was followed by an early decrease at 8 -- 12 h in 7 out of 11 patients. Analysis of CD34+ cell counts outside daytime is not possible in the majority of transplant and collection centers. Clearly, more data is needed in regard to optimal timing of plerixafor especially in proven poor mobilizers. As not all patients can be mobilized even with plerixafor, novel agents are still needed. A novel CXCR4 antagonist evaluated in clinical trials was BKT140, which was shown to be safe and effective in myeloma patients [95]. Another interesting molecule is ALT-1188, which was more effective than plerixafor in mice [96]. Also POL5551 appears to be more potent in terms of mobilizing hematopoietic stem and progenitor cells than plerixafor in preclinical studies [97]. A combination of FLT3 and plerixafor was shown to be associated with increased mobilization of T regulatory cells, NK cells and plasmacytoid dendritic cells in mice [98]. Taken together, it might be possible in a near future, in addition, Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Passweg JR, Baldomero H, Bregni M, et al. Hematopoietic SCT in Europe: data and trends in 2011. Bone Marrow Transplant 2013;48:1161-7 Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant 2009;43:181-95 Gertz MA. Current status of stem cell mobilization. Br J Haematol 2010;150:647-62
to mobilize CD34+ cell more efficiently in patients mobilizing poorly but also to some extent effect cellular composition of the grafts collected by selection of mobilizing regimens. 8.
Expert opinion
Plerixafor added to G-CSF is superior to G-CSF alone for mobilization of CD34+ cells for ASCT. This combination is also efficient in patients who have failed a previous mobilization attempt with other methods or in patients with known risk factors for poor mobilization. Currently, the addition of plerixafor to G-CSF or chemotherapy plus G-CSF mobilization in patients who appear to mobilize poorly is under active investigation and various algorithms for a preemptive or just-in-time use of this expensive agent have been proposed. These algorithms need prospective validation. This type of use may be more cost-effective than routine use of plerixafor. Clearly, plerixafor has facilitated collection of minimum grafts in larger percentage of patients intended for ASCT than a cytokine alone or combined with chemotherapy, but not all patients can be successfully collected even with plerixafor. The grafts collected after plerixafor injection appears to contain more lymphoid cells than the grafts collected without it. Whether this affects post-transplant outcomes such as immune reconstitution and risk of infections or relapse needs to be evaluated in prospective studies.
Declaration of interest E Jantunen has received honoraria from Genzyme and Sanofi. V Varmavuo declares no conflict. 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.
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Hu¨bel K, Liles WC, Broxmeyer H, et al. Leukocytosis and mobilization of CD34+ hematopoietic progenitor cells by AMD3100, a CXCR antagonist. Support Cancer Ther 2004;1:165-72
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Nagasawa T, Tachibana K, Kishimoto T. A novel CXC chemokine PBSF/SDF1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Semin Immunol 1998;10:179-85
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and monocyte counts in addition to CD34+ counts in patients with non-Hodgkin lymphoma mobilizing poorly with chemotherapy plus G-CSF: implications for apheresis and graft composition. Transfus Apher Sci 2012;46:257-62
de Clercq E, Yamamoto N, Pauwels R, et al. Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc Natl Acad Sci USA 1992;89:5286-90
Varmavuo V, Ma¨ntymaa P, Kuittinen T, et al. Pre-emptive plerixafor injection increases blood neutrophil, lymphocyte
DiPersio JF, Micallef IN, Stiff PJ, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol 2009;27:4767-73 A Phase III study of plerixafor in non-Hodgkin’s lymphoma patients. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113:5720-6 A Phase III study in multiple myeloma patients. Dugan MJ, Maziarz RT, Bensinger WI, et al. Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin’s lymphoma undergoing stem cell mobilization. Bone Marrow Transplant 2010;45:39-47
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Jantunen E. Novel strategies for blood stem cell mobilization: special focus on plerixafor. Expert Opin Biol Ther 2011;11:1241-8
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Calandra G, McCarty J, McGuirk J, et al. AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data. Bone Marrow Transplant 2008;41:331-8 The first study of compassionate use of plerixafor in patients who had failed a previous mobilization attempt.
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Micallef IN, Stiff PJ, DiPersio JF, et al. Successful stem cell remobilization using plerixafor (mozobil) plus granulocyte colony-stimulating factor in patients with
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Basak GW, Knopinska-Posluszny W, Matuszak M, et al. Hematopoietic stem cell mobilization with the reversible CXCR4 receptor inhibitor plerixafor (AMD3100)-Polish compassionate use experience. Ann Hematol 2011;90:557-68
27.
Duarte RF, Shaw BE, Marı´n P, et al. Plerixafor plus granulocyte CSF can mobilize hematopoietic stem cells from multiple myeloma and lymphoma patients failing previous mobilization attempts: EU compassionate use data. Bone Marrow Transplant 2011;46:52-8
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Hu¨bel K, Fresen MM, Apperley JF, et al. European data on stem cell mobilization with plerixafor in non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and multiple myeloma patients. A subgroup analysis of the European Consortium of stem cell mobilization. Bone Marrow Transplant 2012;47:1046-50
29.
Tanhehco YC, Vogl DT, Stadtmauer EA, et al. The evolving role of plerixafor in hematopoietic progenitor cell mobilization. Transfusion 2013;53:2314-26 Review of current and future use of plerixafor.
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Jantunen E, Kvalheim G. Mobilization strategies in hard-to-mobilize patients with lymphoid malignancies. Eur J Haematol 2010;85:463-71
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To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood 2011;118:4530-40
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Morris CL, Siegel E, Barlogie B, et al. Mobilization of CD34+ cells in elderly patients (>/= 70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen. Br J Haematol 2003;120:413-23
33.
Jantunen E, Kuittinen T, Penttila¨ K, et al. High-dose melphalan (200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (>or=65 years) myeloma patients: comparison with younger patients treated on the same protocol. Bone Marrow Transplant 2006;37:917-22
Plerixafor
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Tempescul A, Ianotto JC, Hardy E, et al. Peripheral blood stem cell collection in elderly patients. Ann Hematol 2010;89:317-21 Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment postperipheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 2007;21:2035-42
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Jantunen E, Lemoli R. Preemptive use of plerixafor in difficult-to-mobilize patients: an emerging concept. Transfusion 2012;52:906-14
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D’Addio A, Curti A, Worel N, et al. The addition of plerixafor is safe and allows adequate PBSC collection in multiple myeloma and lymphoma patients poor mobilizers after chemotherapy and G-CSF. Bone Marrow Transplant 2011;46:356-63
Popat U, Saliba R, Thandi R, et al. Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma. Biol Blood Marrow Transplant 2009;15:718-23 Laszlo D, Galieni P, Raspadori D, et al. Fludarabine containing-regimens may adversely affect peripheral blood stem cell collection in low-grade non Hodgkin lymphoma patients. Leuk Lymphoma 2000;37:157-61 Olivieri A, Marchetti M, Lemoli R, et al. Proposed definition of ’poor mobilizer’ in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group Gruppo Italiano Trapianto di Midollo Osseo. Bone Marrow Transplant 2012;47:342-51
cyclophosphamide. Biol Blood Marrow Transplant 2011;17:729-36 52.
Li J, Hamilton E, Vaughn L, et al. Effectiveness and cost analysis of “just-intime” salvage plerixafor administration in autologous transplant patients with poor stem cell mobilization kinetics. Transfusion 2011;51:2175-82
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Kymes SM, Pusic I, Lambert DL, et al. Economic evaluation of plerixafor for stem cell mobilization. Am J Manag Care 2012;18:33-41
54.
Vishnu P, Roy V, Paulsen A, et al. Efficacy and cost-benefit analysis of risk-adaptive use of plerixafor for autologous hematopoietic progenitor cell mobilization. Transfusion 2012;52:55-62
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Jantunen E, Kuittinen T, Mahlama¨ki E, et al. Efficacy of pre-emptively used plerixafor in patients mobilizing poorly after chemomobilization: a single centre experience. Eur J Haematol 2011;86:299-304
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Alesˇ T, Veronika V, Zdeneˇk K, et al. Cost-effectiveness of hematopoietic stem cell mobilization strategies including plerixafor in multiple myeloma and lymphoma patients. J Clin Apher 2013;28:395-403
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Gopal AK, Karami M, Mayor J, et al. The effective use of plerixafor as a realtime rescue strategy for patients poorly mobilizing autologous CD34(+) cells. J Clin Apher 2012;27:81-7
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Milone G, Tripepi G, Martino M, et al. Early measurement of CD34+ cells in peripheral blood after cyclophosphamide and granulocyte colony-stimulating factor treatment predicts later CD34+ mobilisation failure and is a possible criterion for guiding “on demand” use of plerixafor. Blood Transfus 2013;11:94-101
Chaudhary L, Awan F, Cumpston A, et al. Peripheral blood stem cell mobilization in multiple myeloma patients treat in the novel therapy-era with plerixafor and G-CSF has superior efficacy but significantly higher costs compared to mobilization with low-dose cyclophosphamide and G-CSF. J Clin Apher 2013;28:359-67
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Awan F, Kochuparambil ST, Falconer DE, et al. Comparable efficacy and lower cost of PBSC mobilization with intermediate-dose cyclophosphamide and G-CSF compared with plerixafor and G-CSF in patients with multiple myeloma treated with novel therapies. Bone Marrow Transplant 2013;48:1279-84
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Micallef IN, Sinha S, Gastineau DA, et al. Cost-effectiveness analysis of a risk-adapted algorithm of plerixafor use for autologous peripheral blood stem cell mobilization. Biol Blood Marrow Transplant 2013;19:87-93
59.
Mene´ndez P, Caballero MD, Prosper F, et al. The composition of leukapheresis products impacts on the hematopoietic recovery after autologous transplantation independently of the mobilization regimen. Transfusion 2002;42:1159-72
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Cesana C, Regazzi E, Garau D, et al. Clonogenic potential and phenotypic analysis of CD34+ cells mobilized by different chemotherapy regimens. Haematologica 1999;84:771-8
Attolico I, Pavone V, Ostuni A, et al. Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collection in predicted poor mobilizer patients with multiple myeloma or lymphoma. Biol Blood Marrow Transplant 2012;18:241-9 Lanza F, Lemoli RM, Olivieri A, et al. Factors affecting successful mobilization with plerixafor: an Italian prospective survey in 215 patients with multiple myeloma and lymphoma. Transfusion 2014;54:331-9
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Micallef IN, Stiff P, Stadtmauer EA, et al. Safety and efficacy of upfront plerixafor + G-CSF versus placebo + G-CSF for mobilization of CD34(+) hematopoietic progenitor cells in patients ‡60 and
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Plerixafor for mobilization of blood stem cells in autologous transplantation: an update 1.
Introduction
2.
Plerixafor in proven or predicted poor mobilizers
3.
Preemptive use of plerixafor
4.
Cost-efficacy of plerixafor use
5.
Effects of plerixafor in graft cellular composition
6.
Outcome of patients receiving plerixafor mobilized grafts
7.
Future perspectives
8.
Expert opinion
Esa Jantunen† & Ville Varmavuo †
Kuopio University Hospital, Department of Medicine, Kuopio, Finland
Introduction: About 99% of all autologous transplants are now performed with blood stem cells. G-CSF alone or combined with chemotherapy have been used to mobilize CD34+ cells. Plerixafor is a novel drug used for mobilization purposes. Areas covered: We have evaluated recent data in regard to plerixafor use in predicted or proven poor mobilizers. In addition, we have looked for preemptive strategies to optimize the use of this expensive drug. Also cost-efficacy issues and effects of plerixafor on graft composition and post-transplant outcomes will be discussed. Expert opinion: Plerixafor added to G-CSF is superior than G-CSF alone for mobilization of CD34+ cells. This combination is also efficient in patients who have failed a previous mobilization attempt with other methods or in patients with risk factors for poor mobilization. Addition of plerixafor to G-CSF or chemotherapy plus G-CSF mobilization in patients who appear to mobilize poorly is under active investigation and algorithms for a preemptive use of this expensive agent have been proposed. Grafts collected after plerixafor appear to contain more lymphoid cells than the grafts collected without it. Whether this affects post-transplant outcomes such as immune reconstitution and risk of relapse needs to be evaluated. Keywords: autologous stem cell transplantation, graft cellular composition, outcome after autologous stem cell transplantation, plerixafor, poor mobilization, preemptive use of plerixafor, review Expert Opin. Biol. Ther. (2014) 14(6):851-861
1.
Introduction
High-dose therapy supported by autologous stem cell transplantation (ASCT) is an established therapy for some hematological disease. According to the registry of the European Group for Blood and Marrow Transplantation, > 18,600 first autotransplants were registered in 2011 [1]. The most common indications were multiple myeloma (MM) (8341 patients, 45%) and non-Hodgkin’s lymphomas (NHL) (5646 patients, 30%) followed by Hodgkin’s lymphoma (HL) (2066 patients, 11%). Blood stem cell grafts were used for supporting high-dose therapy in about 99% of all autotransplants. Historically, chemotherapy (cyclophosphamide or combination chemotherapy) plus G-CSF (chemomobilization) have been used for mobilizing blood stem cells for ASCT. More recently, the use of G-CSF alone has get more popularity due to its lower toxicity and easier prediction of peak mobilization [2,3], although combination of chemotherapy plus G-CSF is usually more efficient. The potential benefits of mobilization with chemotherapy plus G-CSF over G-CSF mobilization include the need for fewer apheresis sessions and potential antitumor activity, although the importance of the latter is dependent on disease and disease status of a given patient. Despite the method of mobilization used, 5 -- 30% of patients 10.1517/14712598.2014.902927 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name Phase
Plerixafor Approved by EMA in 2009 and by FDA in 2008 Indication To mobilize CD34+ cells for autologous stem cell transplantation in myeloma and NHL patients with G-CSF Pharmacology description A selective inhibitor of CXCR4 Route of administration Subcutaneous Chemical structure 1, 1¢-[1,4-phenylenebis (methylene)]-bis-1,4,8,11tetraazacyclotetradecane Pivotal trial(s) Two Phase III trials in MM [21] and NHL [20] Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com). MM: Multiple myeloma; NHL: Non-Hodgkin’s lymphomas.
intended for high-dose therapy are difficult to mobilize [4-8]. There appears to be no major differences in the incidence of mobilization and collection failure, whether G-CSF is used alone or in combination with a preceding chemotherapy [4,8]. According to some studies, lymphoma patients are more often hard-to-mobilize than MM patients [4,7]. Plerixafor (formerly AMD3100) is a small bicyclam molecule with a molecular weight of 502 Da. It was initially developed for the potential treatment of HIV infections [9,10] but was subsequently found to cause leukocytosis and an increase in the amount of blood CD34+ cells [11-13], including true stem cells based on functional studies [14]. The mechanism of action is a reversible antagonism against the chemokine receptor CXCR4, which blocks the interaction between CXCR4 and CXCL12 (formerly stromal derived factor-1 [SDF-1]), leading to liberation of CD34+ cells from their marrow niches to circulation [15,16]. SDF-1 released from bone marrow stromal cells appears to be an important mechanism of plerixafor for mobilization of hematopoietic progenitor cells in steady state [17]. CXCR4 is expressed in many hematopoietic and non-hematopoietic cell types [18], which explains the increase in the amount of neutrophils, eosinophils, basophils, monocytes and lymphocytes observed after plerixafor administration [13,14,19]. Plerixafor was studied mainly in combination with G-CSF (filgrastim) in several Phase II studies and after two Phase III randomized placebo-controlled studies [20,21] was accepted by the US FDA in December 2008 and by the European Medicines Agency (EMA) in July 2009 to be used in myeloma or lymphoma patients to mobilize stem cell for autologous transplantation. The approval for plerixafor was for patients mobilized with G-CSF, and the EMA approval also included an additional requirement of poor mobilization. Only one formal Phase II study of plerixafor added to chemotherapy 852
plus G-CSF mobilization has been published [22]. The recommended dose of 240 µg/kg plerixafor is given as a subcutaneous injection in G-CSF-treated patients, 6 -- 11 h before the start of apheresis. In patients with renal failure (estimated creatinine clearance < 50 ml/min), a reduced dose (160 µg/kg) is used. In this review, we try to update the data in using plerixafor (Box 1) for mobilization of CD34+ cells for ASCT, since our previous review of this subject in this forum [23]. We aim to concentrate on preemptive use of plerixafor, effects of plerixafor on graft cellular content and post-transplant outcomes. Also, cost-effectiveness issues and new data in regard to practical use of plerixafor will be discussed.
Plerixafor in proven or predicted poor mobilizers
2.
Plerixafor combined with G-CSF was shown to be an efficient stem cell mobilizing therapy in patients who had failed a previous mobilization attempt [4,24-28]. Based on these studies, 60 -- 90% of the patients failing at least one prior mobilization attempt can be successfully mobilized with plerixafor-based regimens [29]. Plerixafor has also been used in patients with risk factors for poor mobilization. Several risk factors have been identified [2,30,31]. Detailed discussion on this topic is beyond the scope of this review, but some points are briefly mentioned here. For example, higher age of the patients has been a risk factor for poor mobilization in some studies [5,32], although age as such may be less important when chemotherapy combined with G-CSF is used [33,34]. In myeloma patients, the use of lenalidomide before mobilization is known to be associated with inferior mobilization of CD34+ cells [35,36]. In lymphoma patients, the use of fludarabine has been associated with risk of poor mobilization [37]. An Italian group has recently proposed definitions for ‘poor mobilizers’ [38]. Their criteria for predicted poor mobilizers include at least one major criterion (previously failed mobilization attempt, extensive radiotherapy to bone marrow-bearing sites or full course of melphalan, fludarabine or other stem cell toxic agents) or at least two minor criteria (age > 65 years, bone marrow cellularity < 30%, extensive bone marrow infiltration, refractory disease or at least two previous treatment lines). By using these criteria, the addition of plerixafor to a mobilization with chemotherapy plus G-CSF resulted in successful collections in 73% of predicted poor mobilizers [39]. In a larger patients series, including 215 patients (143 proven, 64 predicted poor mobilizers), the success rate was 68% and this was not dependent whether the patients received plerixafor after steady state (G-CSF) or after a mobilization with chemotherapy plus G-CSF [40]. Previous fludarabine treatment and low platelet counts were the only negative predictors of mobilization success. The Phase III studies comparing G-CSF + plerixafor with G-CSF and placebo showed a similar efficacy and
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Plerixafor
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Table 1. Algorithms for preemptive plerixafor use. Study
Number of patients included
Disease(s)
Used mobilization method
Costa et al. [99]
50
Lymphomas, MM
G-CSF alone
Sinha et al. [100]
1556
Lymphomas, PCD
G-CSF alone
Chen et al. [101] Abhyankar et al. [102]
49 159
Lymphomas, MM Lymphomas, PCD, solid tumors
G-CSF alone G-CSF alone
Sancho et al. [8]
397
Lymphomas, MM, AML and others
Micallef et al. [58]
592
Lymphomas, PCD
G-CSF alone (mainly) or chemotherapy + G-CSF G-CSF alone
Jantunen et al. [49]
390
Milone et al. [48]
233
Lymphomas, PCD, and others Lymphomas, MM
Ozsan et al. [103]
396
MM
Hay et al. [104]
354
Farina et al. [105]
107
Lymphomas, MM, AML and others Lymphomas, MM
Chemotherapy + G-CSF Cyclophosphamide 4 g/m2 + G-CSF Cyclophosphamide 3 g/m2 + G-CSF Chemotherapy + G-CSF Disease-specific cyclophosphamide 3 -- 7 g/m2 + G-CSF
Suggested trigger/cut-off level for plerixafor
Calculated individually on day 4 based on B-CD34+ count and collection target B-CD34+ < 6 106/l on day 4 or B-CD34+ < 10 106/l on day 5 or first collection yield < 1.0 106 CD34 cells/kg B-CD34+ 5 -- 15 106/l on day 4 Target ‡ 2.5 106 CD34 cells/ kg: B-CD34+ < 10 106/l on day 5; Target ‡ 5.0 106 CD34 cells/ kg: B-CD34+ > 10 106/l but < 20 106/l on day 5 or first collection yield is < 50% of the desired target A peak value of B-CD34+ < 13.8 106/l
Algorithm I: B-CD34+ < 10 106/l on day 4 or day 5 or any collection yield < 0.5 106 CD34 cells/kg. Algorithm II: B-CD34+ < 10 106/l for single transplantation and < 20 106/l for multiple transplantations on day 4 or first collection yield < 1.5 106 CD34 cells/kg or any subsequent collection yield < 0.5 106 CD34 cells/kg B-CD34+ £ 10 106/l when WBC count > 5 109/l or > 10 109/l B-CD34+ < 6 106/l on day 12 or B-CD34+ < 10 106/l on day 13 B-CD34+ < 10 106/l on day 13 or 1 day after WBC count > 1 109/l A peak value of B-CD34+ < 16.5 106/l B-CD34+ £ 10 106/l and WBC count > 1 109/l or WBC count < 1 109/l after day 12/day 14 (myeloma/lymphoma)
AML: Acute myeloid leukemia; B: Blood; MM: Multiple myeloma; PCD: Plasma cell disorders; WBC: White blood cell.
safety profile in older patients (‡ 60 years) [41]. In patients failing a previous mobilization attempt, the success rate of achieving the minimum required collected CD34+ cell number (> 2 106/kg) was 69% in patients who had received lenalidomide (median 5 cycles) and was 58% in patients with a history of fludarabine exposure, respectively [42]. Another study [43] evaluated risk factors of poor mobilization with G-CSF plus plerixafor in patients with a previous mobilization failure. The minimum collection target (‡ 2 106/kg CD34+ cells) was achieved in 67.5% of 197 patients. Prior therapy with lenalidomide or melphalan, previous
radiotherapy, or a prior ASCT were not risk factors, but there was a trend for higher risk of failure in patients previously treated with purine analogs [43]. The current evidence suggests that the use of plerixafor abolishes the effects of some predicted criteria for poor mobilization, but especially patients treated with fludarabine may be more difficult to mobilize even with plerixafor. The choice between G-CSF plus plerixafor versus chemotherapy + G-CSF plus plerixafor appears to be dependent on the disease and disease status of a given patient. If there is no obvious need for further standard-dose chemotherapy, G-CSF plus plerixafor could be preferred.
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Table 2. Authors’ guidelines for preemptive plerixafor use. G-CSF mobilization B-CD34+ < 10 106/l on day 5 (after 4 days of G-CSF) Collection of < 1 106/l with the first apheresis* Chemotherapy + G-CSF mobilization WBC count rising > 5 -- 10 109/l and B-CD34+ < 10 106/l Collection of < 1 106/l with the first apheresis* Decreasing B-CD34+ cell counts during collections before the target has been reached
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*Depends on the collection target. B: Blood; d: Day; WBC: White blood cell.
3.
Preemptive use of plerixafor
Although a lot has been learned in regard to risk factors for poor mobilization, for unknown reasons, many patients with risk factors can still be successfully mobilized and collected. On the other hand, many patients without any major risk factors mobilize poorly. The idea of a preemptive or ‘just in time’ use of plerixafor is to prevent a collection failure or to reduce the number of collections needed in patients who appear to mobilize poorly with standard regimens, including G-CSF alone or combined with chemotherapy [44]. Mobilization of CD34+ cells is a dynamic process and the relatively quick action of plerixafor make this agent useful for this purpose. D’Addio et al. [45] used plerixafor in 13 patients mobilizing poorly with chemotherapy plus G-CSF, and minimal grafts > 2 106/kg CD34+ cells were collected from all the patients. According to our own initial experience in 16 patients, the addition of plerixafor to chemotherapy plus G-CSF mobilization resulted in a median fivefold increase in B-CD34+ counts, and in 13 patients (80%) the minimum collection target was achieved [46]. An increase of B-CD34+ cell counts from 7 to 17 106/l with a single plerixafor injection and successful collections in 87% of the patients was reported from a rescue use of plerixafor among 39 lymphoma or myeloma patients [47]. As plerixafor is an expensive drug, various algorithms have been proposed to guide preemptive use of plerixafor (Table 1). These algorithms are mainly based on retrospective data and need prospective validation. The situation is easier for G-CSF-mobilized patients, where the trigger point for plerixafor use after 4 days of G-CSF depends critically on collection target. In many instances, B-CD34+ count < 10 106/l on day +5, would indicate a need for plerixafor use. In regard to a mobilization with chemotherapy plus G-CSF, the situation is more complex as various chemotherapeutic regimens have variable time for hematopoietic recovery and optimal time of mobilization of CD34+ cells. In regard to intermediate-dose cyclophosphamide (4 g/m2), Milone et al. [48] have suggested that plerixafor should be used if B-CD34+ is < 10 106/l on day +13 or < 6 106/l on day +12. It is important that only a limited number of 854
mobilizing regimens are used in a single center so that typical mobilization kinetics is well known to optimize preemptive use of plerixafor, if needed. We have developed an algorithm based on blood leukocyte (WBC) and CD34+ cell counts in patients mobilized with chemotherapy plus G-CSF [49]. According to our retrospective analysis, plerixafor should be considered in these patients if WBC count is rising and is > 5 -- 10 109/l and B-CD34+ counts remain < 10 106/l. It might be useful to wait 1 or 2 days, if the platelet counts are not yet rising, if feasible. We have used this algorithm in our center since 2011. It is not clear whether plerixafor is useful in patients with practically absent B-CD34+ cells (< 2 106/l). Increase of G-CSF dose and waiting 1 or 2 days, if feasible, might be an option in these situations but prospective data is lacking. In our experience, if B-CD34+ is 5 -- 9 106/l prior to the first plerixafor dose, successful collections can be achieved in all patients. Another issue is stable low or even decreasing B-CD34+ counts prior to the start of apheresis or decreasing B-CD34+ cell counts during collections. In these situations, the foldincrease of B-CD34+ counts after plerixafor injection is less than in the case of low but rising counts, as discussed earlier, but in most patients adequate collections can be obtained to proceed to high-dose therapy. Some guidelines for preemptive plerixafor use are presented in Table 2. From 2010 to 2013, altogether 192 patients have been mobilized and submitted for stem cell collection in the adult hematology ward of Kuopio University Hospital. Altogether 188 patients (98%) received chemotherapy plus G-CSF, whereas 4 patients were mobilized with G-CSF alone. Sixtytwo patients (32%) had received plerixafor for poor or, in some case, for late mobilization (to avoid weekend collections). The minimum collection target (‡ 2 106/kg CD34+ cells) was not achieved in 14 plerixafor-treated patients (22%) (11/50 NHL patients, 2/8 MM patients and in 1/5 HL patients); three patients proceeded to ASCT with grafts containing 1.6 -- 1.9 106/kg CD34+ cells. Additional two patients with poor grafts (0.8 and 1.1 106/kg CD34+ cells) were remobilized and minimum grafts were achieved in both patients. During the 4-year period altogether 14 patients (6.6% of all mobilized patients) failed the first mobilization (no collections at all or too low yields to proceed with ASCT); in three patients, plerixafor was not given due to very low B-CD34+ cell counts. Milone et al. [50] recently presented data from a prospective study where they observed that failure to collect the minimum target of ‡ 2 106/kg CD34+ cells decreased from a historical 20.9 to 4%. Both these observations suggest that the failure rates can be decreased substantially with this strategy, but there still remains a patient group who cannot be effectively mobilized even with the addition of plerixafor. 4.
Cost-efficacy of plerixafor use
In the study by Shaughnessy et al. [51], the total costs in the patients mobilized with G-CSF plus plerixafor were
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comparable to those mobilized with cyclophosphamide (3 -- 5 g/m2) plus G-CSF, but mobilization was more predictable in the plerixafor group. The preemptive use of plerixafor in selected high-risk patients or poor mobilizers has resulted in similar or even lower total costs when compared to traditional mobilization methods [52]. Both Markov simulated model comparing G-CSF + plerixafor with G-CSF alone [53] or a risk-adapted use of G-CSF plus plerixafor has met the accepted criteria for cost-effectiveness [54]. Results from the studies based on prospectively collected data corroborate with the results of retrospective studies [50,55]. In some other studies, combination of plerixafor and G-CSF was more effective [56] or was of comparable efficacy [57], but it was also more expensive compared to a mobilization with low-dose and intermediate-dose cyclophosphamide and G-CSF in myeloma patients. Total costs of mobilization and collection have been reported to be higher even if an algorithm has been used to guide plerixafor administration [58]. Most of the available studies are based on historical data (retrospectively collected). Studies are also subject to a number of limitations and this should be taken into consideration before making final conclusions [16]. Some potential costs including those associated with a delayed transplant, emotional costs and convenience costs have not been evaluated in these studies [29], but they may still be important. In addition, since the majority of published pharmacoeconomic studies are from the USA and as healthcare systems vary greatly from country to country, the results cannot be directly generalized for other countries. In conclusion, even though plerixafor is an expensive drug and some patients may require multiple doses, it may be possible to reduce the total costs of mobilization and collection process if remobilizations and/or prolonged apheresis sessions can be avoided.
Effects of plerixafor in graft cellular composition
5.
As all mobilizing agents have a different and unique potential to mobilize stem cells, the mobilization method used has an impact on the cellular composition of the collected stem cell grafts [59]. In addition, the mobilization method may alter the characteristics and functions of mobilized cells [60]. The collected and transplanted cells may have importance in terms of engraftment and long-term outcome after ASCT [61,62]. A small percentage of all CD34+ stem cells are considered be more primitive than the ‘normal’ stem cells. These primitive stem cells have been shown to have high self-renewal potential and to be progenitors of many different cell types [63,64]. In clinical practice, these primitive stem cells have been linked with engraftment [65,66]. Plerixafor plus G-CSF has been shown to mobilize more primitive stem cells when compared to the G-CSF alone [61,67] or a mobilization with chemotherapy plus G-CSF [68,69]. In our own study of NHL patients mobilized with chemotherapy plus G-CSF, the median amount of the most primitive stem cells (defined
as CD34+CD133+CD38-) from all CD34+ stem cells in the graft was about threefold higher among patients mobilized with chemotherapy plus G-CSF and treated with plerixafor when compared to the group of patients mobilized without plerixafor. There was no significant difference in the total amount of CD34+ cells between these groups. All patients engrafted successfully after ASCT, and early and late engraftment (up to 12 months) were similar between the groups [68]. In addition to CD34+ cells, plerixafor has been shown to enhance the mobilization of lymphocytes, when compared to G-CSF mobilization [70]. This may be important as higher infused lymphocyte dose has been reported to be a prognostic factor for overall survival (OS) and progression-free survival (PFS) after ASCT [71-73]. Higher infused lymphocyte numbers have been associated with earlier lymphocyte recovery [74] and may also be associated with better patient outcome [75]. The blood stem cell grafts collected from NHL patients mobilized with chemotherapy plus G-CSF and treated with plerixafor may contain about four times more CD3+ T lymphocytes (including CD4+ helper T lymphocytes and CD8+ suppressor T lymphocytes) when compared to the patients mobilized with chemotherapy plus G-CSF but without plerixafor [68]. Further, T lymphocytes mobilized with plerixafor may differ from the cells mobilized with G-CSF alone [76]. This may be meaningful at least if plerixafor is used in mobilizing allografts (off-label use). Plerixafor also mobilizes more natural killer (NK) cells (CD3-CD16/56+) [68]. It is of interest that plerixafor alone or combined with G-CSF seems to increase the mobilization of functional NK cells in mice [77]. CD19+ B lymphocytes are only rarely found in grafts collected from B-cell lymphoma patients, as the majority of the patients have been treated with monoclonal B-cell antibodies (CD20 antibodies, for example, rituximab). In this patient group, plerixafor does not seem to enhance the mobilization of potentially malignant B cells [68]. However, it should be noted that interindividual variations in the amounts of all different lymphoid cells are quite large whether plerixafor is used or not [68,78]. This also suggests that factors (e.g., disease, previously given therapies) other than the use of plerixafor may alter the mobilization of lymphoid cell subsets. Although it is fascinating to speculate the importance of graft cellular composition with post-transplant outcomes, further studies evaluating potential correlates between the doses of various cell types in the graft and hematopoietic and immune recovery are needed in the era of plerixafor. These will shed more light to the discussion of optimal graft characteristics, as some of these issues may be possible to manipulate at least to some extent with the selection of mobilization regimen.
Outcome of patients receiving plerixafor mobilized grafts
6.
An important issue in case of plerixafor use for mobilization of CD34+ cells for ASCT is the potential effects of plerixafor
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in terms of mobilizing various cell types to the graft (see Section 5) as well as the potential concern of tumor cell mobilization [79]. Therefore, analysis of engraftment as well as long-term outcomes such as PFS is of major interest. In the Phase III studies in patients with MM or NHL, no significant differences were observed in the time to engraftment after high-dose therapy in patients mobilized with or without plerixafor [20,21]. Also, survival at 12 months was comparable. The follow up presented in the original papers is clearly too short to make any conclusions except for engraftment, and long-term follow up of these studies are awaited with interest. Moreb et al. [80] evaluated 17 patients (9 lymphoma, 8 MM) mobilized with G-CSF plus plerixafor in the compassionate use program. They observed no difference in the time to engraftment or hospital stay, when compared to the control group. In another retrospective study, including 32 NHL or MM patients mobilized with G-CSF plus plerixafor, Alexander et al. [81] observed that if the CD34+ cell doses were matched, the early neutrophil and platelet engraftment was slower in plerixafor-mobilized patients. However, no difference in engraftment was encountered at 100 days after the graft infusion. We have analyzed both early and late hematopoietic engraftments among 89 NHL patients of which 33 received plerixafor added to chemotherapy plus G-CSF [82]. Despite the fact that the CD34+ cell dose (measured after collection before freezing) was higher in the control patients (4.2 vs 3.5 106/kg), the early and late engraftment were comparable between the groups except for lower hemoglobin level at 3 months in the plerixafor group. The PFS was 79% in the plerixafor group and 86% in the control group at 1 year (p = NS), also 2 years PFS was comparable (70 vs 83%). The OS was 82 versus 89% at 1 year and 71 versus 85% at 2 years, respectively [82]. The patient groups were not balanced as there were more relapsed patients (51 vs 32%, p = 0.023) in the plerixafor group. A single center analysis, including 17 NHL patients mobilized with the addition of plerixafor, observed an event-free survival of 77% and an OS of 93% with a median observation time of 2 years, respectively [83]. A single center retrospective analysis of 148 MM patients mobilized either with cyclophosphamide + G-CSF or G-CSF plus plerixafor suggested a significantly shorter time to progression in plerixafor-mobilized patients (13 vs 25 months) [84]. The groups were unbalanced in regard to, for example, longer time from the diagnosis to transplantation and the patients in the plerixafor group had received more commonly melphalan dose < 200 mg/m2, but the Cox regression analysis showed that the use of plerixafor was associated with poorer PFS. There was, however, no difference in OS between these groups. Clearly, more information is needed in this respect. It is unlikely that the use of cyclophosphamide 3 g/m2 for mobilization purposes would significantly change the disease course after modern induction therapy as such. Although previous studies have not observed an excessive 856
mobilization of myeloma cells in patients mobilized with G-CSF plus plerixafor compared to the patients mobilized with G-CSF alone [85], potential mobilization of tumor cells may in part explain the shortened PFS observed in this retrospective analysis. Longer follow up of the Phase III studies by DiPersio et al. [20,21] could shed more light at this point. A recent analysis of 49 plerixafor-mobilized lymphoma or myeloma patients revealed a high incidence of myelodysplastic syndrome (MDS)/acute leukemia with a cumulative incidence of 17% at 42 months [86]. Another retrospective study, including 283 patients (86%) with MM, observed clinical MDS/acute leukemia in 10 patients (3.5%) and additionally cytogenetic features of MDS was observed in 10 patients [87]. The authors concluded that the risk of MDS in the plerixafor-mobilized patients was comparable to their experience observed using intensive total therapy protocols in MM patients mobilized without plerixafor. It is likely that the risk of developing MDS is independent of the plerixafor use and may be due to more advanced disease status and more treatment lines in patient who need plerixafor to augment mobilization of CD34+ cells. Younger myeloma patients not uncommonly receive two or even three cycles of high-dose melphalan with stem cell support and may also receive cyclophosphamide and lenalidomide during their disease course which all may be associated with the risk of developing MDS in patients surviving long enough. Again, the long-term follow up of the Phase III studies [20,21] would be helpful in elucidating this issue at least to some point. Taken together, plerixafor-mobilized patients appear to have roughly comparable engraftment after high-dose therapy compared with the patients mobilized with other methods. Clearly more data are needed in regard to long-term outcomes. The CALM study of the European Blood and Marrow Transplantation group will evaluate long-term outcomes of a large number of myeloma or lymphoma patients mobilized with or without plerixafor [88]. We have started a nationwide Graft and Outcome in Autologous Transplantation study to evaluate the effects of various mobilization methods on graft cellular composition as well as posttransplant outcomes, including hematopoietic and immune reconstitution and risk of relapse [89]. 7.
Future perspectives
Although plerixafor has been in clinical use for about 5 years, several open questions still remain. Initially plerixafor was evaluated for a subcutaneous use. More recently, intravenous administration has also been investigated [90]. In this Phase II study, 39 lenalidomide-treated MM patients were included. In 97% of the patients, the collection target (> 3 106/kg) was achieved with 1 -- 2 apheresis. The plerixafor was given intravenously with a standard dose (240 µg/kg) in the morning followed by the start of apheresis 4 -- 5 h later. This appears to be a safe and efficient strategy and if confirmed in further studies may change clinical practice, where
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plerixafor is typically given subcutaneously 6 -- 11 h prior to start of apheresis, late in the evening. Another important issue is the timing of plerixafor in case of subcutaneous use. In a study including 48 patients mobilized with G-CSF, plerixafor was given at 17.00 h, that is, 15 h before the planned apheresis. Successful collections were achieved in all but one patient [91]. Another study evaluated plerixafor dosing 17 h before the start of apheresis [92]; the target CD34+ cell numbers were collected with a single apheresis in 73% of the patients and in all patients with three aphereses. A recent study suggested that mobilization of CD34+ may continue up to 18 h after the plerixafor injection in standard mobilizers and longer time from the plerixafor injection may increase the proportion of more primitive CD34+CD38- cells [93]. On the other hand, in very poor mobilizers, the kinetics of CD34+ cell mobilization may be different as suggested by the study of Lefre`re et al. [94]. In this study, a very early mobilization, as early as 3 h, was observed after plerixafor administration and was followed by an early decrease at 8 -- 12 h in 7 out of 11 patients. Analysis of CD34+ cell counts outside daytime is not possible in the majority of transplant and collection centers. Clearly, more data is needed in regard to optimal timing of plerixafor especially in proven poor mobilizers. As not all patients can be mobilized even with plerixafor, novel agents are still needed. A novel CXCR4 antagonist evaluated in clinical trials was BKT140, which was shown to be safe and effective in myeloma patients [95]. Another interesting molecule is ALT-1188, which was more effective than plerixafor in mice [96]. Also POL5551 appears to be more potent in terms of mobilizing hematopoietic stem and progenitor cells than plerixafor in preclinical studies [97]. A combination of FLT3 and plerixafor was shown to be associated with increased mobilization of T regulatory cells, NK cells and plasmacytoid dendritic cells in mice [98]. Taken together, it might be possible in a near future, in addition, Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Expert opinion
Plerixafor added to G-CSF is superior to G-CSF alone for mobilization of CD34+ cells for ASCT. This combination is also efficient in patients who have failed a previous mobilization attempt with other methods or in patients with known risk factors for poor mobilization. Currently, the addition of plerixafor to G-CSF or chemotherapy plus G-CSF mobilization in patients who appear to mobilize poorly is under active investigation and various algorithms for a preemptive or just-in-time use of this expensive agent have been proposed. These algorithms need prospective validation. This type of use may be more cost-effective than routine use of plerixafor. Clearly, plerixafor has facilitated collection of minimum grafts in larger percentage of patients intended for ASCT than a cytokine alone or combined with chemotherapy, but not all patients can be successfully collected even with plerixafor. The grafts collected after plerixafor injection appears to contain more lymphoid cells than the grafts collected without it. Whether this affects post-transplant outcomes such as immune reconstitution and risk of infections or relapse needs to be evaluated in prospective studies.
Declaration of interest E Jantunen has received honoraria from Genzyme and Sanofi. V Varmavuo declares no conflict. 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.
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