The authors have declared that no competing interests exist.
In autologous hematopoietic stem cell transplantation patients for whom granulocyte-colony stimulating factor fails to mobilize a sufficient number of peripheral blood stem cells, plerixafor proposes an option for successful rescue mobilization. This paper evaluates the efficacy of plerixafor to mobilize peripheral blood stem cells (PBSCs) in patients who failed previous mobilization with G-CSF alone, by retrospectively analysing the PBSC results from lymphoma and myeloma (MM) patients between 2006 and 2011. Patients were classified according to the CD34+ cells/kg yield collected by apheresis: < 2 x 106 CD34+ cells/kg was considered collection failure, whereas ≥ 5 x 106 CD34+ cells/kg was considered good mobilization. 797 patients underwent one or more apheresis. The first mobilization success rate was 82%; 140 patients proved to be poor mobilizers. Suboptimal first mobilization was significantly associated with age >50 years (
Autologous stem cell transplantation (ASCT) remains an important part of front-line therapy in multiple myeloma (MM) and is mandatory in lymphoma relapse procedures. Mobilized peripheral blood stem cells (PBSCs) are currently used as the sole source of stem cells in these indications. PBSC collection is performed after granulocyte-colony stimulating factor (G-CSF) stimulation alone (steady-state) or following a chemotherapy cycle during the neutrophil recovery phase (chemo-primed). The CD34+ cell count in the autologous graft is one of the strongest contributing factors to successful fast engraftment; nevertheless, 10–15% of patients with haematological malignancies fail to mobilize an adequate quantity of PBSCs
In clinical studies of MM and lymphoma patients, plerixafor combined with G-CSF was well tolerated and significantly increased the number of PBSCs in patients who previously failed to mobilize PBSCs.
We retrospectively analysed the results of consecutive PBSC collections performed in lymphoma and MM patients from 2006 to 2011 at two university hospitals working with the Bourgogne Franche-Comte EFS (French Blood Establishment). Specifically speaking, patients received medical care and ASCT respectively in the Besançon and Dijon university hospital haematology departments. In accordance with local policies, all patients provided informed written consent for the collection and analysis of data in their medical files. When patients were included in a clinical trial, specific written informed consent was obtained. The study was designed and conducted in accordance with the declaration of Helsinki and was approved by the institutional ethics committees.
For the first collection of cells, PBSC mobilization was performed either using G-CSF alone at a daily dosage of 510 µg/kg (steady state protocol) or after a chemotherapy course of high dose cyclophosphamide in MM patients or after one of two different regimens in lymphoma patients, namely R-CHOP or R-ACVBP (chemo-primed protocol). When ≥ 2 x 106 CD34+ cells/kg were available after the first collection process, the collection was considered a success and ASCT or even 2 ASCTs in some MM patients, could be planned without further PBSC harvest. When < 2 x 106 CD34+ cells/kg were available, the collection was considered a failure. If the first mobilization failed, a new mobilization procedure was performed, most often using the chemo-primed protocol. The decision to add plerixafor was made by the local investigator after the first collection failure in patients considered at high risk of secondary PBSC mobilization failure.
In the steady-state protocol, the daily dose of plerixafor was 0.24 mg/kg administered 8-11 hours before the first apheresis session on the evening of the fourth day of G-CSF injection. Alternatively using the chemo-primed protocol, if the CD34+ cell count was < 15/mm3 and the leucocyte count > 1 G/l, plerixafor was administered on the evening 8-11 hours before the first apheresis session. If < 2 x 106 CD34+ cells/kg were collected after the first collection procedure, an additional dose of plerixafor could be delivered on day 2 or 3 following the collection.
PBSC harvesting started when the peripheral circulating CD34+ cell count increased to >15/mm3, which was generally on the 5th day of G-CSF administration in the steady-state protocol or when leucocytes increased to > 1 G/l in the chemo-primed protocol. The CD34+ cell count was then checked daily to determine this time point. Blood stem cells were collected with one of two blood cell separators: the Cobe Spectra (Terumo BCT®, Lakewood, CO, USA) or the COM.TEC (Fresenius Kabi®, Bad Homburg, Germany). At least two total blood volumes were processed at each apheresis session. Anticoagulant citrate dextrose solution was used. The quality of the harvested product was evaluated by counting the total nucleated and CD34+ cells, which was expressed as the number of cells/kg body weight of the patient. An apheresis session could be repeated on the following day until at least 2 x 106 CD34+ cells/kg were acquired. Alternatively, sessions were halted if the CD34+ count in the peripheral blood was < 15/mm3. The colony-forming unit-granulocyte macrophage (CFU-GM) content of the PBSCs was quantified systematically only when plerixafor mobilization was used.
The post-ASCT haematological engraftment was analysed to determine neutrophil recovery. Neutrophils were counted from the day of ASCT until a neutrophil count ≥ 0.5 G/l was achieved. The duration of the hospital stay was also recorded and was measured from the day of the ASCT infusion until discharge.
The study was divided into two time periods: 2006-2008 (period 1, without plerixafor use) and 2009-2011 (period 2, plerixafor mostly used for remobilization). Patients were classified according to the CD34+ cells/kg yield that was collected by apheresis (before freezing). Patients with a total collected cell count < 2 x 106 CD34+ cells/kg were considered poor mobilizers. Conversely, patients with cumulative yields ≥ 5 x 106 CD34+ cells/kg were considered good mobilizers. Descriptive analyses were used to summarize the patient characteristics, risk factors, CD34+ cell collection parameters and time to neutrophil engraftment. We analysed the features of the first mobilization to identify mobilization failure risk factors. Next the results of rescue protocols to evaluate the efficacy of plerixafor were evaluated. Data are presented as median (range). We performed univariate and multivariate analyses, and the differences between categorical variables were calculated with the
During the two periods studied, 797 patients underwent one or more apheresis procedure for PBSC collection. There were no statistically significant differences between the populations recruited in Besançon and Dijon. The detailed baseline and demographic characteristics are summarized in
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Besançon Hospital | 144 | 155 | 299 |
Dijon Hospital | 218 | 280 | 398 |
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55 (3–76) | 58 (3–77) | 57 (3–77) |
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1.74 | 1.65 | 1.70 |
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Multiple myeloma | 145 | 206 | 351 |
Lymphoma | 169 | 186 | 355 |
Other | 48 | 43 | 91 |
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1 (1–5) | 1 (1–5) | 1 (1–5) |
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Lenalidomide | 23 | 67 | 90 |
Bortezomib | 105 | 197 | 302 |
Anthracycline | 261 | 240 | 501 |
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All 797 patients were included in this analysis. Of these, 140 patients presented mobilization failures. The following parameters were tested in univariate analysis: median age, sex, inclusion period, diagnosis, number of previous cycles of chemotherapy, drugs (anthracyclines, vincristine, lenalidomide, and bortezomib) and type of mobilization procedure (
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P |
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P | ||
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797 | 140 (18) | |||||
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2006–2008 | 362 | 65 (18) | |||||
2009–2011 | 435 | 75 (17) |
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≤50 years old | 235 | 26 (11) | |||||
>50 years old | 562 | 114 (20) |
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1.93 | (1.22–3.06) |
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Yes | 351 | 75 (21) | |||||
No | 446 | 65 (15) |
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0.65 | - |
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Lenalidomide | 90 | 33 (37) |
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Bortezomib | 302 | 69 (23) |
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Chemotherapy + G-CSF | 618 | 97 (16) | |||||
G-CSF alone | 179 | 43 (24) |
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1.54 | (1.03–2.32) |
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MM: multiple myeloma; PBSCs: peripheral blood stem cells; G-CSF: Granulocyte –colony stimulating factor
A total of 149 rescue protocols were managed in 117 of the 140 patients who were poor mobilizers; 32 patients were remobilized a third and/or a fourth time. Of these 140 patients, 71 received plerixafor as part of the rescue mobilization protocol (22 after a steady-state protocol and 49 after a chemo-primed protocol). The use of plerixafor in the first rescue protocol was similar between the two sites. In Dijon, 39 (38%) of the 103 patients with a first mobilization failure received plerixafor, while 20 (54%) of the 37 patients with a first mobilization failure in Besançon received plerixafor; this difference was not significant (
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P | |||||
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149 | 70 | ||||||||
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2006–2008 | 67 | 44 (66) | ||||||||
2009–2011 | 82 | 26 (32) |
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- | - |
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≤50 years old | 29 | 13 (45) | ||||||||
>50 years old | 120 | 57 (47.5) |
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≤55 years old | 50 | 26 (52) | ||||||||
>55 years old | 99 | 44 (44) |
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≤60 years old | 82 | 28 (34) | ||||||||
>60 years old | 67 | 42 (63) |
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Myeloma | 79 | 26 (33) | ||||||||
Other malignancies | 70 | 44 (63) |
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0.35 | (1.75–6.66) |
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Yes | 71 | 25 (36) | ||||||||
No | 78 | 45 (58) |
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0.47 | (0.23–0.94) |
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PBSCs: peripheral blood stem cells
The mean yield of CD34+ cells harvested after the first mobilization was 6 x 106 CD34+ cells/kg (range, 0–83.50), which was better than the yield after a remobilization procedure, 2.05 x 106 CD34+ cells/kg (range, 0–18.25)(
To determine predictive factors for plerixafor efficacy, we retrospectively studied the pre-apheresis blood counts of the 71 patients who received plerixafor. In the patients treated with plerixafor, blood tests performed on the morning of apheresis suggested that the presence of >200 myelocytes/mm3 in the peripheral blood could predict PBSCs collection success (
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46 | 25 |
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Nb cells/mm3 (range) | 25 (3.2–222.2) | 4 (0–50.7) |
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Patient with myelemia <200 myelocytes/mm3 | 6 (23) | 20 (77) |
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Patient with myelemia ≥200 myelocytes/mm3 | 39 (88) | 5 (11) | ||
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106/kg (range) | 4.84 (2.06–18.25) | 0.32 (0–1.73) |
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104/kg (range) | 84.69 (0–373.6) | 7.7 (0–58.3) |
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Of the 797 patients in the study, 732 (92%) secondarily underwent ASCT. We evaluated haematological recovery by studying the median time to neutrophil recovery (neutrophils >0.5 G/l). For the 657 patients grafted after the first mobilization, the median time to neutrophil recovery was 9 days (range, 4–11). For the 117 patients that required a rescue protocol, the median time to neutrophil recovery increased to 13 days (range, 6–42;
Mobilization of autologous PBSCs remains of primary interest for performing ASCTs, especially in patients with refractory lymphoma or in young patients with MM. This mobilization process remains one of the factors that limit the feasibility of ASCT. The objective of PBSC mobilization is to obtain as many CD34+ cells as possible, because PBSC counts are correlated with bone marrow aplasia duration.
This study retrospectively evaluates the efficacy of plerixafor for remobilizing patients who failed previous mobilizations. We recruited a cohort of consecutive patients that needed ASCT; the study included a large number of patients who were treated at two centres with similar patient management practices and working with the same collection centre for PBSC harvesting. There were no significant differences in plerixafor prescription between the two hospitals (p=0.18), so this cohort offers a reliable and homogeneous representation of the population that needs to undergo ASCT for the treatment of lymphoma or MM. In our study, the first mobilization success rate was 82%, which is similar to rates reported in the literature.
Various factors have been reported to impact stem cell mobilization and identification of risk factors of PBSC mobilization failure is important for making the decision about whether to prescribe plerixafor or not for the subsequent mobilization attempt. In our multivariate analysis of the first mobilization course, age >50 years old and absence of chemotherapy in prior PBSC stimulation were significantly associated with suboptimal mobilization. These factors have already been identified in previous studies and the nature of pre-mobilization chemotherapy schemes have also been identified as significant risk factors.
We also found that the use of chemo-primed protocols with plerixafor do not have a beneficial impact on PBSC' remobilization as compared to steady-state protocols. These results are in opposition to those of many studies, which concluded that chemo-primed protocols are superior to steady-state protocols in terms of PBSC collection. The addition of G-CSF can increase by 2.5 times the circulating CD34+ cell level because G-CSF boosts hematopoietic restoration after aplasia induced by chemotherapy.
The third part of the study described the differences in blood test results during the ASCT procedure. Notably, high PBSC content correlates not only with transplant feasibility but also with lower incidences of complications, infections, and transfusion requierements.
We decided to evaluate only the qualitative blood samples of the 71 patients who received plerixafor. To our knowledge, this outbreak of myelemia has not been studied yet in this setting. Only a limited bone marrow reserve, characterized by a low platelet count, a low peripheral blood CD34+ number and a low bone marrow cellularity is a risk factor for poor PBSC mobilization.
Times to haematological recovery were also studied across the entire cohort. Patients who underwent rescue protocols demonstrated no significant difference in outcome between patients who did or did not receive plerixafor (
Our study was limited to the investigation of plerixafor efficacy which means it did not take into account economic factors. That said, the cost of plerixafor could limit its use; this drug does not have a current and clear defined place in mobilization protocols for ASCT. Accordingly, it would be worthwhile to study PBSC failure risk factors and plerixafor efficacy in order to optimize the adequate prescription of this drug. Several models of risk adapted algorithms for optimal utilization of the drug have already been made. Some of them recommended a pre-emptive use of plerixafor. In March 2015, a retrospective study compared PBSC mobilization in MM patients using fractioned high-dose cyclophosphamide and G-CSF with G-CSF plus pre-emptive plerixafor. The total average cost of mobilization was slightly higher in the plerixafor group ($7886 vs $7536; p= 0.16), but a chemo–mobilization approach was associated with significantly increased toxicity.
In other studies plerixafor was administered only to patients who were at high risk for mobilization failure. In general, collected cell counts of < 11.5 x 106 CD34+ cells/kg after at least 4-5 days of mobilization with G-CSF alone has been used as the cut-off marker. Plerixafor management in “just-in-time” approaches enables an optimal increased CD34+ yield in order to decrease mobilization failures as well as the number of apheresis days in addition to limiting costs. In the literature, three studies suggest that plerixafor does not substantially increase overall costs.
This study demonstrated that plerixafor was an effective drug for poor mobilizers: it synergized with G-CSF and improved the quantity and possibly the quality of collected PBSC. The successful remobilization rate was significantly increased (23%) when plerixafor was employed. We found that patients >50 years old who were previously mobilized using a steady-state protocol were at very high risk of PBSC mobilization failure and were good candidates for plerixafor use. More studies taking both clinical and economic data into account are needed to analyse the cost effectiveness of plerixafor’s use in rescue mobilization. This is why we will conduct a costeffectiveness analysis on this studies cohort with the objective of determining overall per-patient expenditures with or without plerixafor.