Plerixafor was recently approved by the US Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to enhance stem cell mobilization for autologous transplant in patients with lymphoma and multiple myeloma. In this study, we present the first European compassionate use experience in mobilization failures, patients who are hardest to remobilize but were not included in registration trials. A total of 56 consecutive patients from 15 centers in Spain and the United Kingdom were included: age 60 (33–69) years; 29 men (32 with myeloma and 24 with lymphoma); 2 lines of previous chemotherapy (1–10); 73 previously failed mobilization attempts with G-CSF (28), chemotherapy plus G-CSF (43) or G-CSF plus SCF(2). Overall, 71% of patients reached ⩾10 CD34+ cells per μL with plerixafor on day 5 after a 7.6-fold expansion from day 4. A total of 42 patients (75%) collected ⩾2 × 106, average 3.0±1.7 (0.4–10.6) CD34+ cells per kg with plerixafor plus G-CSF. There were no severe drug-related adverse events. In all, 35 patients (63%) underwent transplant, receiving an average of 3.1±1.2 (1.9–7.7) × 106 CD34+ cells per kg. All patients engrafted neutrophils (day 12; 13.4±0.8; 8–30) and platelets (day 15; 18.5±2.4; 8–33). In our experience, plerixafor offers an effective alternative to collect sufficient CD34+ cells for autologous SCT from patients who fail conventional mobilization methods, with good tolerance and a high success rate.
High-dose chemotherapy and autologous SCT (auto-SCT) have become a standard of care for many patients with hematological malignancies, in particular chronic lymphoproliferative disorders.1, 2, 3 Several studies have shown that mobilized PBSCs are advantageous for autologous rescue compared with BM.4, 5 In Europe, 99% of nearly 13 000 auto-SCTs performed for lymphoproliferative disorders in 2007 used PBSCs.6 It is well established that the dose of PBSCs infused is critical to the success and the rate of hematopoietic recovery after auto-SCT.7 A dose of ⩾5 million PBSCs per kg, as determined by the expression of CD34, results in a more reliable and predictable hematopoietic recovery, in particular for platelets.8, 9 On the contrary, a dose of <2 million CD34+ cells per kg is insufficient to ensure rapid and sustained hematopoietic engraftment.10, 11, 12 With conventional mobilization methods, a significant proportion of auto-SCT candidates fail to collect the minimum ⩾2 × 106 per kg normally required to proceed to high-dose therapy.8, 13, 14, 15 Such mobilization failures leave 5–30% of eligible patients facing further mobilization attempts, BM collections or even suboptimal alternative treatment strategies in the absence of sufficient autologous PBSCs.
Plerixafor (AMD3100, Mozobil, Genzyme Corporation, Cambridge, MA, USA) has been recently approved by the US Food and Drug Administration (FDA; December 2008) and the European Medicines Evaluation Agency (EMEA; July 2009) to enhance mobilization of hematopoietic stem cells in combination with G-CSF in patients with lymphoma and multiple myeloma (MM). Plerixafor is a small-molecule bicyclam derivative, which selectively and reversibly antagonizes the CXCR4 chemokine receptor and blocks binding to its cognate ligand, SDF-1α (stromal cell-derived factor-1α) (also known as CXCL12). The interruption of the CXCR4/SDF-1α interaction results in mobilization of CD34+ cells to the peripheral blood.16 The efficacy of plerixafor has been demonstrated in two blinded randomized phase III placebo-controlled studies in patients with MM and non-Hodgkin's lymphoma (NHL).17, 18 In both studies, the percentage of patients who reached the primary end point of ⩾5 × 106 CD34+ cells per kg in NHL and ⩾6 × 106 CD34+ cells per kg in MM, and who successfully engrafted, was significantly higher in the plerixafor group than in the placebo group: (1) 57 vs 19% of patients with NHL and (2) 70 vs 34% of patients with MM. Plerixafor registration trials excluded patients who had failed conventional mobilization attempts before consideration for trial entry. These are, however, the transplant candidates at a greater need of novel mobilizing strategies that can rescue them and make this life-saving procedure possible for them.
A plerixafor named-patient compassionate use program (CUP) opened in Europe in July 2008 to provide access to the drug for patients with MM and lymphoma, who had previously failed to mobilize adequate numbers of PBSCs with traditional mobilization regimens and who were not eligible for plerixafor registration trials. This study presents efficacy and safety data of plerixafor in the first cohort of patients enrolled in this CUP for previous mobilization failures to be reported in Europe. Approximately 75% of these patients were successfully rescued with plerixafor plus G-CSF after one or more previous failures, achieving a PBSC collection of ⩾2 million CD34+ cells per kg. The drug was well tolerated with a safety profile similar to that observed in previous studies.
Design and methods
Patient inclusion and exclusion in EU plerixafor CUP
The EU CUP granted access to plerixafor treatment to patients with the following inclusion criteria: (1) aged 18–78 years; (2) candidates to auto-SCT for MM, NHL or Hodgkin's disease; (3) who had failed to collect a minimum of ⩾2 × 106 per kg or did not even proceed to apheresis based on a low peripheral blood CD34+ count (usually <10 cells per μL) with conventional mobilization attempts; (4) adequate organ function to undergo apheresis and transplantation; (5) ECOG (Eastern Cooperative Oncology Group) performance status <2; (6) preserved blood test results, including WBC count >2.5 × 109 per L, ANC >1.5 × 109 per L, platelet count >85 × 109 per L, serum creatinine ⩽1.5 mg per 100 ml, serum aspartate aminotransferase, serum alanine aminotransferase and total bilirubin <2 × upper limit of normal; (7) no active hepatitis B or C; (8) approved form of contraception for women of child-bearing potential or female partners of male patients; and (9) signed informed consent. Exclusion criteria included: (1) diagnosis of any form of acute or chronic leukemia (including plasma cell leukemia) or myelodysplastic syndrome; (2) comorbid conditions which render the patient at high risk from treatment complications; (3) vasculitis or autoimmune disorders; (4) brain metastases, carcinomatous meningitis or any other malignancy unless the patient had been disease free for at least 5 years after curative intent therapy; (5) clinically significant heart disease; (6) acute infection and/or fever (temperature >38 °C); (7) hypercalcemia (>1 mg per 100 ml above the upper limit of normal); (8) pregnant or breastfeeding women and male or female patients of child-bearing potential unwilling to implement adequate birth control; (9) HIV positive; (10) obese patients exceeding 175% of ideal body weight; and (11) other experimental treatments.
Patients received G-CSF as per site standard protocol, typically as a 10 μg/kg daily s.c. injection each morning for four consecutive days. In the evening of the fourth day (approximately at 2200 hours), patients received a single s.c. dose of 0.24 mg/kg of plerixafor. On the morning of the fifth day, G-CSF was administered and apheresis began at approximately 10–12 h after plerixafor and at 1 h after G-CSF administration. Aphereses and administration of plerixafor and G-CSF were repeated daily until the patient collected sufficient cells for auto-SCT (minimum ⩾2 × 106 per kg) or the investigator decided that the patient had failed to mobilize enough PBSCs to warrant continuation. Apheresis blood volumes were processed following site standard protocols. The numbers of CD34+ cells collected during each apheresis session were recorded. Conditioning regimen for auto-SCT, support care and posttransplant follow-up were carried out as per site preference. Both ANC and platelet count engraftment and durability were assessed and determined for 6 months after transplant. All laboratory tests were conducted at local site laboratories.
Outcome criteria and adverse event reporting
The primary end point was a collection of ⩾2 × 106 CD34+ cells per kg with the combination of plerixafor and G-CSF at any time point or number of aphereses. Secondary end points were: (1) PBSC mobilization efficacy as determined by CD34+ count after plerixafor treatment in cells per μL; (2) posttransplant neutrophil and platelet engraftment; and (3) treatment toxicity and adverse events. Engraftment was assessed using conventional EBMT criteria considering the transplant day as day 0. Neutrophil engraftment was defined as the first of three consecutive days on which the neutrophil count reached ⩾0.5 × 109 per L. Platelet engraftment was defined as the first of three consecutive days on which the platelet count reached ⩾20 × 109 per L without platelet transfusion for at least 48 h. All serious adverse events that were considered to be related to the use of plerixafor and that occurred from the time of the first dose of plerixafor were reported to the sponsor within 24 h of the physician's first knowledge of the event. Investigators were asked to assess the severity of adverse events as mild, moderate and severe, as well as the relationship between the adverse event and the study drug and/or procedure. For this report, we included related adverse events judged to be possibly, probably or definitely associated with the study drug.
Data collection and statistical analysis
This study is an independent investigator-led audit of all consecutive patients entering the EU plerixafor CUP in the participating centers. A purpose-built spreadsheet was developed, data were collected and analysis was performed by the investigators. All patients signed informed consents for CUP inclusion and for clinical data collection. Descriptive statistics were used to define characteristics of patients and patient subsets. Comparisons of means were performed with paired or independent Student's t-test, as appropriate. Chi-squared test or Fisher's exact test when appropriate were used to compare mobilization outcome between patient groups. The time to hematopoietic recovery was estimated using inverse Kaplan–Meier curves and compared using the log-rank test. A two-tailed P-value of <0.05 was considered statistically significant. All analyses were carried out using statistical software SPSS (version 13.0, SPSS Inc., Chicago, IL, USA).
This report comprises outcomes and safety data obtained from a group of 56 patients consecutively enrolled in the EU plerixafor CUP at 15 centers in Spain and the United Kingdom. A total of 32 patients (57%) had MM and 24 (43%) had lymphoma, including diffuse large B-cell (37%), follicular (29%), mantle cell (25%) and Hodgkin's lymphoma (8%). There were no statistically significant differences between patients in the MM and lymphoma groups in terms of their demographic characteristics (Table 1). Patients had received a median of two lines of chemotherapy (1–10) before CUP entry. Within the MM group, these lines included lenalidomide in four patients (13%) and a previous auto-SCT in seven (22%). Among the lymphoma patients, seven had been treated with combination chemotherapy containing fludarabine (29%). Overall, there were 73 failed previous mobilization attempts in this series (1.3±0.6 per patient). In all, 43 of these attempts combined chemotherapy and G-CSF (59%), and the other 30 (41%) used G-CSF alone, or in combination with SCF in 2 cases. A total of 36 patients (64%) had 1, 16 (29%) had 2 and 2 cases had 3 (4%) failed mobilization attempts before CUP entry. As a result of these previous attempts, 19 patients (9 MM and 10 lymphomas) had collected variable numbers of PBSCs before study entry, for a median of 0.77 × 106 per kg CD34+ cells (0.16–1.48). Waivers for specific inclusion criteria were granted to a number of patients who were believed to benefit from the treatment without posing an increased risk, on request from the investigators. Two patients entered the CUP without a previous mobilization attempt. The first case was a 57-year-old man with MM and a history of six lines of therapy, including a previous auto-SCT following relapse with bortezomib and lenalidomide who was cytopenic at study entry. The second case was a 42-year-old woman with follicular lymphoma and a history of two lines of therapy, including fludarabine and cytopenia at study entry. In addition, nine patients who did not meet the blood cell count inclusion criteria (five for low platelet count and four for low ANC and/or WBC) entered the study.
Mobilization with plerixafor plus G-CSF in CUP patients had a good safety profile. Adverse events, summarized in Table 2, occurred in 34% of the cases (19/56), were all mild, did not prevent completion of treatment in any of the patients and were comparable between patients with MM and lymphoma.
Treatment with plerixafor increased the levels of circulating CD34+ cells before PBSC collection, reaching an average 24.9 cells per μL (median 17.9). Overall, 71% (73% in MM and 68% in lymphoma) met the secondary end point target of ⩾10 CD34+ cells per μL. In a subgroup of 30 patients wherein PB CD34+ cell levels were available both before (day +4) and after (morning of day +5) the dose of plerixafor, an average 7.6-fold increase could be shown after plerixafor treatment (Table 3). Overall, patients underwent a median of two apheresis procedures. In all, 75% of the patients in this series (42/56) successfully reached the primary end point of collecting ⩾2 × 106 CD34+ cells per kg after plerixafor plus G-CSF treatment (Table 3). Success rate appeared to be higher in patients with MM (27/32; 84%) than in those with lymphoma (15/24; 63%), although with a borderline statistical significance (P=0.06). In particular, plerixafor rescued six of seven recipients of a previous auto-SCT, three of four treated with lenalidomide, as well as four of seven treated with combination chemotherapy containing fludarabine as part of the lines of therapy before CUP entry. The baseline platelet count had a moderate correlation with the total number of CD34 cells per kg collected with plerixafor (Pearson's r=0.387; P=0.011), so that patients with baseline platelets >100 × 109 per L were more successful to meet the primary collection end point (2 × 106 per kg) than were those with platelets <100 × 109 per L (P=0.017). Plerixafor plus G-CSF treatment was equally effective in rescuing patients who had previously failed mobilization attempts with chemotherapy plus G-CSF or with G-CSF only (P=0.734), and also equally successful in rescuing patients who had suffered two or three previous unsuccessful mobilization attempts compared with those after one single previous failure (P=1.0).
A total of 35 (63%) of the patients had proceeded to transplant at the time of analysis, 19 patients with MM (59%) and 16 patients with lymphoma (67%). The median dose of PBSCs infused was 2.8 × 106 CD34+ cells per kg (Table 4). Eight patients received pooled cells, plerixafor-mobilized PBSCs and products from previous collections, either to reach ⩾2 × 106 CD34+ cells per kg if the plerixafor product was lower (4/8), or to optimize total cell dose if the plerixafor product was 2–5 × 106 CD34+ cells per kg (4/8). All other patients received plerixafor-mobilized PBSCs only, including one lymphoma patient receiving a borderline dose of 1.9 × 106 CD34+ cells per kg who had not collected any PBSCs in previous attempts. All patients engrafted neutrophils and platelets after plerixafor-mobilized auto-SCT, with no differences between plerixafor-only cells and pooled cells, or between MM and lymphoma patients. Neutrophil engraftment was carried out at a median of 12 days, mean 13.4±0.8, between days 8 and 30 (Figure 1). Platelet engraftment was performed at a median of 15 days, mean 18.5±2.4, between days 8 and 33, with one single outlier engrafting platelets at day 79. Three patients died during the 6-month follow-up period: (1) a 58-year-old man with heavily treated DLBCL who died from a lower respiratory tract infection on day +23 of auto-SCT having engrafted neutrophils successfully on day +14; (2) a 62-year-old man with MM who died on day +71 from disease progression; and (3) a 46-year-old woman with MM who unfortunately developed a generalized varicella zoster viral infection on day +6, complicated with a viral pneumonia which required mechanical ventilation and intensive care unit admission; she had a somewhat delayed neutrophil and platelet engraftment (both on day +30), and although the graft remained stable thereafter, the patient died on day +105 from viral pneumonitis. All other transplanted patients were alive with stable grafts at 6 months after transplant. The most common causes not to proceed to auto-SCT by the time inclusion in the analysis closed are described in Table 4. Only five patients altogether could not proceed to auto-SCT for mobilization failure with plerixafor plus G-CSF.
Two recent phase III, blinded, randomized, placebo-controlled studies in patients with NHL and MM have shown that the addition of plerixafor to G-CSF as a first-line mobilization strategy increased the number of patients achieving both the minimum and target stem cell levels in fewer apheresis sessions, increased the predictability of stem cell yield and timing, was well tolerated, as well as allowing more patients to proceed to transplant. Graft durability rates were comparable in the plerixafor plus G-CSF and placebo plus G-CSF trial arms.17, 18 These outstanding results led to the approval of plerixafor to enhance PBSC mobilization in patients with lymphoma and MM (FDA), in particular for those who mobilize poorly (EMEA). Among all patients at risk to mobilize poorly, the subgroup most difficult to treat includes those patients who have already failed mobilization attempts. Unfortunately, such patients were not included in plerixafor registration clinical trials. In this study, we present the first report of the European experience with the use of plerixafor, on a named-patient compassionate use basis, specifically for auto-SCT candidates with MM or lymphoma who previously suffered mobilization failures with conventional methods.
Overall, 75% of our patients reached ⩾2 × 106 per kg CD34+ cells with a median of two apheresis procedures. In particular, 84% of our patients with MM met the primary end point target. This included patients who had already had a previous auto-SCT (6/7; 86%) or had been treated with lenalidomide (3/4; 75%), which is known to have a significant negative effect on PBSC collection efficacy.19 There was a trend toward better efficacy in MM than in lymphoma patients. Otherwise, the number of previous failed mobilization attempts or whether they were G-CSF only or with chemotherapy had no impact on plerixafor efficacy. Moreover, the success of mobilization could not be distinguished by differences in baseline full blood counts (data not shown). These findings extend and confirm the results from two recent studies with data from the US plerixafor CUP for mobilization failures, one coming from a Genzyme Corporation-led data audit of the US CUP,20 and the other one from a single-center experience,21 which showed success rates for this combination from 66 to 85%, respectively.
The overall success rate with plerixafor plus G-CSF in mobilization failures appears superior to that described previously with other alternative remobilization protocols, including higher doses of G-CSF, combinations of G-CSF with SCF or GM-CSF, pegylated G-CSF, as well as a number of single- and multiple-agent chemotherapy regimens combined with growth factors.22, 23, 24, 25, 26, 27 The success rate of such alternative remobilization protocols varies among different studies, with collections of ⩾2 × 106 per kg CD34+ cells being reported for a range of 20–50% of patients.22, 23, 24, 25, 26 One study in a Letter to the Editor reported a success rate of 65% for remobilization using G-CSF at 10 μg/kg 7 days after a failure of mobilization with chemotherapy plus G-CSF (5 μg/kg).27 However, this contrasts with reported success rates of only 18–24% with the same strategy at even higher doses (G-CSF 10–32 μg/kg) in some of the other series.22, 26 Without a doubt, comparison of such studies is not straightforward, given their heterogeneity in terms of patient characteristics, previous lines of therapy, apheresis history, criteria for analysis of success and other factors. Nevertheless, the largest series of remobilizations after failure published to date (n=269) also showed an overall success of remobilization of only 23%.26 In particular, only 18% of 217 patients remobilizing with G-CSF±GM-CSF, and only 26% of 34 patients remobilizing with chemotherapy plus G-CSF achieved ⩾2 × 106 per kg CD34+ cells. Interestingly, this study included a small subgroup of 18 patients remobilized with plerixafor plus G-CSF, 13 of whom (72%) successfully collected ⩾2 × 106 of kg CD34+ cells, compared with other strategies (P=0.03). In addition to a lower success rate, some of these possible alternatives have additional caveats. For instance, the occurrence of neutropenic sepsis as a result of mobilization with chemotherapy plus G-CSF leads to substantially increased morbidity and costs.28
All patients engrafted neutrophils and platelets as expected, and there were no cases of secondary graft failure during the 6-month follow-up period. Engraftment kinetics were similar in MM and lymphoma patients in the series. One patient died from disease progression and two others from infective complications (varicella zoster pneumonia and lower respiratory tract infection). Neither these infective complications nor their unfortunate outcome were considered to be related to the treatment with plerixafor. All other auto-SCT recipients remained alive with stable grafts at 6-month follow-up. Previous plerixafor trials have shown the drug to be generally safe and well tolerated in healthy volunteers,29 HIV-positive individuals,30 as well as in patients with MM and lymphoma.17, 18 The most common adverse events related to plerixafor in these studies were diarrhea, nausea/vomiting and injection site reactions. In our series, there were no cases of severe adverse events, and the safety profile of plerixafor was very similar to that previously reported in the registration trials, despite the potentially more severe background conditions of a CUP population with mobilization failures.
Results obtained from phase III clinical trials and CUP reports, including our own data, show that plerixafor is a safe and well-tolerated novel mobilizing agent that increases PBSC collection predictability and yield in fewer apheresis sessions on first-line use, reproducibly rescues the majority of failed mobilizers on second-line remobilization use, as well as allowing more patients overall to proceed to auto-SCT as planned. These encouraging data in combination with future studies will allow institutions to develop clinical algorithms to appropriately mobilize PBSCs in patients with lymphoma and MM in their own clinical settings. Although such research including cost-effectiveness studies is available, we believe that the results from our study, in combination with the easy applicability of plerixafor treatment on day 4 of G-CSF mobilization, set the ground for a preemptive model of plerixafor use based on day 4 PB CD34+ cell counts. Prospective monitoring of CD34+ levels on day 4 would allow centers to identify patients for whom the benefit derived from the enhanced mobilization capacity of plerixafor can be maximized. Patients with day 4 CD34+ levels that predict for suboptimal CD34+ cell collections based on institutional experience may benefit from plerixafor addition to enhance mobilization on day +5. As a matter of fact, even among patients with very low CD34+ cells per μL such as those in our series, who are hardest to mobilize, >70% achieved adequate CD34+ cell collections after a seven-fold cell expansion after plerixafor treatment, which appeared comparably safer and more effective than other mobilization alternatives. On the basis of our data, such a preemptive approach may potentially reduce the percentage of failure in first-line mobilizations from the current 5–30% to <10%, and it may also increase the percentage of optimal collections, avoiding treatment delays and costs associated with second mobilization attempts while optimizing the use of plerixafor to guaranty an adequate or optimal PBSC target dose collection. The ultimate role and strategic positioning of such a promising drug will nevertheless require further research.
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HA and PJG are employees of Genzyme Corporation. RFD and NHR report consultancy and speaker fees from Genzyme Corporation. The remaining authors have nothing to disclose. This study has been presented in part at the annual meeting of the EBMT 2009 (Bone Marrow Transplant 43: S80 (Abstract O421).
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Duarte, R., Shaw, B., Marín, 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 46, 52–58 (2011). https://doi.org/10.1038/bmt.2010.54
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