Additional plerixafor to granulocyte colony‐stimulating factors for haematopoietic stem cell mobilisation for autologous transplantation in people with malignant lymphoma or multiple myeloma
Abstract
Background
Autologous stem cell transplantation is widely used to restore functioning bone marrow in people with malignant lymphoma or multiple myeloma after myeloablative chemotherapy. Results of some clinical trials indicate that plerixafor in addition to granulocyte colony‐stimulating factors (G‐CSF) compared to G‐CSF only could lead to an increased mobilisation and release of CD34‐positive cells, facilitating effective apheresis.
Objectives
To evaluate the efficacy and safety of additional plerixafor to G‐CSF for haematopoietic stem cell mobilisation in people with malignant lymphoma or multiple myeloma.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1990 to September 2015), as well as conference proceedings (American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; American Society for Blood and Marrow Transplantation; European Group for Blood and Marrow Transplantation) for studies. Two review authors independently screened search results.
Selection criteria
We included randomised controlled trials (RCTs) comparing plerixafor in addition to G‐CSF compared to G‐CSF only for stem cell mobilisation in people with malignant lymphoma or multiple myeloma of all stages and ages. We included full text as well as abstracts and unpublished data if sufficient information on study design, participant characteristics, interventions, and outcomes was available. We excluded cross‐over trials, quasi‐randomised trials, and post‐hoc retrospective trials.
Data collection and analysis
Two review authors independently screened the results of the search strategies, extracted data, assessed quality, and analysed data according to standard Cochrane methods. We performed final interpretation with an experienced clinician.
Main results
We identified four RCTs fitting the inclusion criteria. However, two of these closed prematurely due to low recruitment and did not report results. The remaining two trials evaluated 600 participants with multiple myeloma or non‐Hodgkin lymphoma. In both studies the experimental group received G‐CSF plus plerixafor and the control group received G‐CSF plus placebo.
The meta‐analysis showed no evidence for differences between plerixafor and placebo group regarding mortality at 12 months (600 participants; risk ratio (RR) 1.00, 95% confidence interval (CI) 0.59 to 1.69; P = 1.00; moderate‐quality evidence) and adverse events during stem cell mobilisation and collection (593 participants; RR 1.02, 95% CI 0.99 to 1.06; P = 0.19; high‐quality evidence).
Regarding the outcome successful stem cell collection, the meta‐analysis showed an advantage for those participants randomised to the plerixafor group (600 participants; RR 2.42, 95% CI 1.98 to 2.96; P < 0.00001; high‐quality evidence).
As there was high heterogeneity between studies for the number of transplanted participants, we did not meta‐analyse these data. In the multiple myeloma study, 95.9% (142 participants) in the plerixafor arm and 88.3% (136 participants) in the placebo arm underwent transplantation (RR 1.09, 95% CI 1.02 to 1.16); in the non‐Hodgkin lymphoma trial, 90% (135 participants) in the plerixafor group versus 55.4% (82 participants) in the placebo group could be transplanted (RR 1.62, 95% CI 1.39 to 1.89). In both trials there was no evidence for a difference between participants in the plerixafor and placebo group in terms of time to neutrophil and platelet engraftment in transplanted participants.
None of the trials reported on the outcomes quality of life and progression‐free survival.
Authors' conclusions
The results of the analysed data suggest that additional plerixafor leads to increased stem cell collection in a shorter time. There was insufficient evidence to determine whether additional plerixafor affects survival or adverse events.
The two trials included in the meta‐analysis, both of which were conducted by the Genzyme Corporation, the manufacturer of plerixafor, were published several times. Two more RCTs examining the addition of plerixafor to a G‐CSF mobilisation regimen terminated early without publishing any outcome. The trials included nine and five participants, respectively. Another RCT with 100 participants was recently completed, but has not yet published outcomes. Due to the unpublished RCTs, it is possible that our review is affected by publication bias, even though two trials failed to recruit a sufficient number of participants to analyse any data.
PICOs
Plain language summary
Adding plerixafor to G‐CSF for stem cell mobilisation for autologous transplantation in people with certain cancers of the blood
Review question
We reviewed the existing literature regarding the efficacy and safety of additional plerixafor to granulocyte colony‐stimulating factors (G‐CSF) versus G‐CSF only for stem cell mobilisation in people with malignant lymphoma and multiple myeloma, cancers of the blood.
Background
Malignant lymphoma can be differentiated into Hodgkin and non‐Hodgkin lymphoma, and usually affects the lymph nodes and the lymphatic system. Multiple myeloma is a cancer of the bone marrow. An effective treatment option for non‐Hodgkin lymphoma and multiple myeloma is high‐dose chemotherapy followed by autologous stem cell transplantation. In autologous transplantation, stem cells are collected from the patient's blood prior to high‐dose chemotherapy, which must be mobilised from the bone marrow in the blood. A commonly used agent for stem cell mobilisation is G‐CSF. Recent studies have suggested that the addition of the new agent plerixafor, which was originally developed for the treatment of HIV infection, to G‐CSF could lead to higher stem cell harvest and thereby increase the probability of successful transplantation after chemotherapy.
Study characteristics
We searched several medical databases and identified four randomised controlled trials that met our inclusion criteria. Two of the four studies terminated early due to low recruitment (14 participants included) and did not release any results. We were therefore unable to include them in our statistical analysis. The two published analysed trials included 600 participants with multiple myeloma and non‐Hodgkin lymphoma. In both studies, the experimental group received G‐CSF plus plerixafor subcutaneously, and the control group received G‐CSF plus placebo. Both trials were sponsored by Genzyme, the manufacturer of plerixafor.
Key results
We were able to conduct a meta‐analysis of the data of the two studies for the outcomes mortality at 12 months, successful stem cell collection, and adverse events.
We found no evidence for a difference between the plerixafor and placebo group for the outcomes mortality at 12 months and adverse events during stem cell mobilisation period.
The meta‐analysis showed an advantage for those participants randomised to plerixafor for the outcome successful stem cell collection. Furthermore, in both studies the time to collect a defined number of stem cells was significantly shorter in the plerixafor group compared to the placebo group.
In the study that enrolled people with multiple myeloma, 95.9% of the participants in the plerixafor arm and 88.3% in the placebo arm underwent transplantation. In the study that examined people with non‐Hodgkin lymphoma, 90% of the participants in the plerixafor group and only 55.4% in the placebo group could be transplanted. It seems that especially people with non‐Hodgkin lymphoma benefit from the addition of plerixafor in terms of successful transplantation, but there was no evidence for a difference for time to neutrophil and platelet engraftment in transplanted participants.
None of the trials reported on quality of life or progression‐free survival.
Quality of the evidence
The quality of the evidence was high for adverse events and successful stem cell collection and moderate for mortality at 12 months. The main limitation was a wide confidence interval.
Authors' conclusions
Summary of findings
| Plerixafor versus placebo for haematopoietic stem cell mobilisation for autologous transplantation in people with malignant lymphoma or multiple myeloma | ||||||
| Patient or population: People with haematopoietic stem cell mobilisation for autologous transplantation in malignant lymphoma or multiple myeloma | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Plerixafor | |||||
| Mortality (12 months) | Study population | RR 1 | 600 | ⊕⊕⊝⊝ | As overall survival has not been reported, we calculated mortality at 12 months | |
| 83 per 1000 | 83 per 1000 | |||||
| Quality of life | ‐ | ‐ | See comment | ‐ | ‐ | Not reported |
| Progression‐free survival | ‐ | ‐ | See comment | ‐ | ‐ | Not reported |
| Time to engraftment | ‐ | ‐ | See comment | ‐ | ‐ | Not reported with standard error or standard deviation, therefore no meta‐analysis possible |
| Number of transplanted participants | ‐ | ‐ | See comment | ‐ | ‐ | Due to high heterogeneity we did not pool the data |
| Successful stem cell collection | 270 per 1000 | 654 per 1000 (535 to 799) | RR 2.42 (1.98 to 2.96) | 600 | ⊕⊕⊕⊕ | ‐ |
| Adverse events (during stem cell mobilisation and collection) | Study population | RR 1.02 | 593 | ⊕⊕⊕⊕ | ‐ | |
| 939 per 1000 | 958 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to imprecision: wide confidence interval. | ||||||
Background
Description of the condition
Malignant lymphomas are malignancies of the lymph nodes and lymphatic system with possible involvement of other organs, and can be differentiated into non‐Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Multiple myeloma (MM) is a malignancy of the bone marrow and is classified among the plasma cell neoplasms by the World Health Organization (WHO).
Non‐Hodgkin lymphoma derives from B and T lymphocytes or natural killer (NK) cells at varying stages of maturation. The most common classification of NHL is the WHO system, which was last updated in 2008. It classifies the NHL in B‐cell neoplasms and T/NK‐cell neoplasms, whereby about 85% of the NHL descends from mature and progenitor B lymphocytes (Herold 2013; Jaffe 2009). A clinical approach is the classification to indolent NHL (approximately 70% of all NHLs) and aggressive NHL (approximately 30% of all NHLs) (Herold 2013). The annual incidence of NHL varies between different regions in the world. In North America, the incidence is estimated to be 13.7 per 100,000 inhabitants, while in the European Union, it is 8.3 per 100,000 inhabitants, with the global incidence amounting to 5.1 per 100,000 inhabitants. The worldwide mortality is 2.5% and is quite similar in the various global regions (GLOBOCAN 2008). The median age at diagnosis is around 60 years, and varies only slightly between the diverse types of NHL (Herold 2013).
Hodgkin lymphoma arises from germinal centre or post‐germinal centre B cells, and is associated with unique neoplastic cells called Reed‐Sternberg cells, which morphologically differentiate HL from NHL. The WHO classifies HL into two types: the classic (approximately 93% of all HLs) and the nodular lymphocyte predominant (approximately 7% of all HLs) (Gobbi 2013; Herold 2013). HL accounts for about 10% of all lymphomas and has an annual incidence of 2 to 3 per 100,000 inhabitants in Western countries (Jemal 2009; Sant 2010; Smith 2011). Hence, HL is a comparatively rare disease, but it is one of the most common malignancies in young adults. In industrialised countries, the age distribution of HL shows a first peak in the third decade and a second peak around the age of 60 (Herold 2013).
Multiple myeloma, one of the mature B‐cell neoplasms, is characterised by the accumulation of malignant plasma cells in the bone marrow compartment, the increased production of a monoclonal immunoglobulin, and bone destruction. MM may be preceded by a pre‐malignant state called monoclonal gammopathy of undetermined significance. Overall, MM accounts for approximately 10% of all haematologic malignancies and 1% of all cancers (Siegel 2012). The annual incidence is approximately 4 to 5 per 100,000 inhabitants in Western countries (Phekoo 2004; Sant 2010; Smith 2011). MM is an adult‐onset disease, with a median age at diagnosis of 66 and only 2% of people younger than 40 years of age (Kyle 2003). To date, no curative approach exists for MM, and depending on the therapy, the overall survival varies between a few months and some years. The 10‐year survival rate of young patients with ideal treatment is around 50% (Herold 2013).
Description of the intervention
High‐dose chemotherapy in combination with autologous stem cell transplantation is a widely used effective treatment option for people with NHL, HL, and MM (Naumann‐Winter 2012; Rancea 2013; Schaaf 2012). Stem cell transplantation is directed at restoring a functioning bone marrow in patients after myeloablative chemotherapy. In contrast to allogeneic transplantation with donor cells, in the autologous setting stem cells are collected from the patient and re‐infused after the high‐dose chemotherapy (Jantunen 2012).
Commonly used agents for stem cell mobilisation are granulocyte colony‐stimulating factors (G‐CSF). The patient receives G‐CSF for up to eight days, and as soon as sufficient CD34‐positive cells are detectable in the patient's peripheral blood, the stem cells are collected by stem cell harvest (apheresis) and stored for transplantation after the myeloablative therapy (Jantunen 2012). The two types of traditional mobilisation methods, G‐CSF with chemotherapy (chemo‐mobilisation) or without chemotherapy ('steady‐state'), lead to a failure rate of 5% to 40% of the cases, depending on definition, disease, and mobilisation agents used (Jantunen 2010). In contrast to G‐CSF mobilisation alone, chemo‐mobilisation leads to higher stem cell yield, a higher probability of getting grafts with a large number of CD34+ cells, the need for fewer apheresis procedures, and even to an antitumour effect. But chemo‐mobilisation is associated with higher toxicity and increased probability of complications (Bensinger 2009; Gertz 2010). Major risk factors for mobilisation failure are advanced age, the diagnosis of NHL, progressive disease, previous radiotherapy, bone marrow involvement or prior treatment with lenalidomide or purine analogues, thrombocytopenia, and the failure of previous mobilisation attempts (Basak 2011; Malard 2011).
Plerixafor is a new agent that apparently improves mobilisation and stem cell harvest, thereby reducing the required number of apheresis procedures (Jantunen 2010). It has mainly been studied in combination with G‐CSF mobilisation. Before its approval in Europe, plerixafor was only available at transplant centres in the compassionate use program. Positive results of this programme evaluating plerixafor in combination with G‐CSF in patients who had previously failed a mobilisation attempt (60% to 75%) strongly indicate the efficacy of this agent (Basak 2011; Hubel 2011). Based on promising data from phase II studies, randomised controlled trials (RCTs) were initiated comparing G‐CSF in combination with plerixafor to G‐CSF and placebo (AMD3100‐3102 MM; AMD3100‐3101 NHL).
How the intervention might work
Plerixafor (formerly AMD3100) was originally developed for the treatment of HIV infection. It inhibits the CXCR4 chemokine receptor that blocks the receptor binding of the stromal cell–derived factor‐1α. This interaction leads to the mobilisation of haematopoietic stem cells from the bone marrow into the peripheral blood, in mice as well as in humans (Broxmeyer 2005; Hatse 2003; Maziarz 2013). Moreover, plerixafor and G‐CSF are synergistic. Results of clinical trials indicate that plerixafor plus G‐CSF leads to an increased augmentation of mobilisation and release of CD34+ cells into the peripheral blood, facilitating effective apheresis (Bensinger 2009).
Why it is important to do this review
Even though a Health Technology Assessment (HTA) report of the Ludwig Boltzmann Institute has already evaluated the role of plerixafor (Hintringer 2010), this systematic review will be of high relevance because a new systematic literature search will be performed and recent research results will be included. At the time of publication of the HTA report in March 2010, at least two clinical trials were still ongoing. No new systematic literature search was run for the HTA report, and it only evaluated the evidence used during the European approval process in the European Public Assessment Report of the European Medicines Agency, already published in 2009.
Based on the published trials, plerixafor might be an effective mobilisation agent in the treatment of people with NHL, HL, and MM. A systematic review and meta‐analysis will provide the conclusive evidence to clarify the role of this agent and will also examine differences of treatment effectiveness caused by population group or chemotherapy agents. Evidence for the best therapeutic options is needed for decision‐making at both the level of the individual patient and the healthcare system.
Objectives
To evaluate the efficacy and safety of additional plerixafor to G‐CSF for haematopoietic stem cell mobilisation in people with malignant lymphoma or multiple myeloma.
Methods
Criteria for considering studies for this review
Types of studies
We included only RCTs. We excluded cross‐over trials and quasi‐randomised trials. We included full text as well as abstracts and unpublished data if sufficient information on study design, participant characteristics, interventions, and outcomes was available.
Types of participants
We examined people with histologically confirmed diagnosis of NHL, HL, or MM requiring high‐dose chemotherapy followed by autologous stem cell transplantation, without age or gender restriction. We considered all stages and subtypes of malignant lymphoma or multiple myeloma, including people newly diagnosed, relapsed, or with resistant disease.
Types of interventions
We evaluated additional plerixafor compared to placebo or no additional therapy for stem cell mobilisation.
Apart from the experimental/control intervention, participants in both groups had been intended to receive identical treatment for stem cell mobilisation (for example G‐CSF) and supportive care.
Types of outcome measures
Primary outcomes
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Overall survival
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Successful stem cell collection
Secondary outcomes
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Progression‐free survival
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Proportion of participants achieving the optimal CD34+ cell target for transplantation
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Time to engraftment in transplanted participants
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Number of transplanted patients
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Quality of life, if measured with reliable and valid instruments
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Adverse events
Search methods for identification of studies
We used search strategies based on those described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We did not use any language constraints.
Electronic searches
We searched the following electronic databases:
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Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, September 2015) (see Appendix 1)
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MEDLINE (1990 to September 2015, for search strategy see Appendix 2)
Searching other resources
We searched conference proceedings of the following annual meetings that were not included in CENTRAL for abstracts:
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American Society of Hematology (2005 to 2014)
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American Society of Clinical Oncology (2005 to 2015)
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European Hematology Association (2005 to 2015)
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American Society for Blood and Marrow Transplantation (2005 to 2014)
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European Group for Blood and Marrow Transplantation (2005 to 2014)
We electronically searched the metaRegister of Controlled Trials (http://www.isrctn.com/page/mrct) for ongoing trials.
We handsearched the references of all identified trials, relevant review articles, and current treatment guidelines.
Data collection and analysis
Selection of studies
Two review authors (TH, NS) independently screened the results of the search strategies for eligibility by reading the abstracts. In cases of disagreement, we obtained the full‐text publication. If we could not reach consensus, we consulted a third review author, in accordance with Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We documented the study selection process in a flow chart as recommended in the PRISMA statement (Moher 2009), showing the total numbers of retrieved references and the numbers of included and excluded studies.
Data extraction and management
Two review authors independently extracted the data according to the guidelines proposed by Higgins 2011. Where required, we contacted authors of individual studies for additional information. We used a standardised data extraction form containing the following items:
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General information: author, title, source, publication date, country, language, duplicate publications.
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Quality assessment: sequence generation, allocation concealment, blinding (participants, personnel, outcome assessors), incomplete outcome data, selective outcome reporting, other potential sources of bias.
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Study characteristics: trial design, aims, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, subgroup analysis, statistical methods, power calculations, treatment cross‐overs, compliance with assigned treatment, length of follow‐up, time point of randomisation.
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Participant characteristics: underlying disease, stage of disease, histological subtype, additional diagnoses, age, gender, ethnicity, number of participants recruited/allocated/evaluated, participants lost to follow‐up, type of treatment (multi‐agent chemotherapy (intensity of regimen, number of cycles), additional radiotherapy).
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Interventions: type, duration, and intensity of plerixafor.
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Outcomes: overall survival, progression‐free survival, proportion of participants achieving the optimal CD34+ cell target for transplantation, time to engraftment, quality of life, adverse events.
Assessment of risk of bias in included studies
Two review authors (TH, NS) independently assessed the risk of bias for each study using the following criteria outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).
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Sequence generation
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Allocation concealment
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Blinding (participants, personnel, outcome assessors)
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Incomplete outcome data
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Selective outcome reporting
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Other potential sources of bias
We made a judgement for every criterion, using one of three categories.
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'Low risk': if the criterion was adequately fulfilled in the study, i.e. the study was at a low risk of bias for the given criterion.
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'High risk': if the criterion was not fulfilled in the study, i.e. the study was at high risk of bias for the given criterion.
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'Unclear': if the study report provided insufficient information to allow for a judgement of 'Yes' or 'No', or if the risk of bias was unknown for the given criterion.
Measures of treatment effect
We used intention‐to‐treat data. For binary outcomes, we calculated risk ratios with 95% confidence intervals for each trial. For time‐to‐event outcomes, we extracted hazard ratios from published data according to Parmar and Tierney (Parmar 1998; Tierney 2007). We calculated continuous outcomes as standardised mean differences.
Dealing with missing data
As suggested in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), we had to take into account many potential sources of missing data: at study level, at outcome level, and at summary data level. Firstly, it was important to distinguish between 'missing at random' and 'not missing at random'. We contacted the original investigators to request missing data. If we were unable to obtain missing data, we made explicit assumptions of any methods used, for example, that we assumed the data to be missing at random or that we assumed the missing values to have a particular value, such as a poor outcome. We imputed missing data for participants who were lost to follow‐up after randomisation (dichotomous data) assuming poor outcome ('worst‐case scenario') for missing participants. We performed sensitivity analysis to assess how sensitive results were to reasonable changes in the assumptions that we made. We addressed the potential impact of missing data on the findings of the review in the discussion.
Assessment of heterogeneity
We assessed heterogeneity of treatment effects between trials by using a Chi2 test with a significance level at P less than 0.1. We used the I2 statistic to quantify possible heterogeneity (I2 greater than 30%, moderate heterogeneity; I2 greater than 75%, considerable heterogeneity) (Deeks 2011). We explored potential causes of heterogeneity by sensitivity and subgroup analyses.
Assessment of reporting biases
In meta‐analyses with at least 10 trials included for one outcome, we would have explored potential publication bias by generating a funnel plot and statistically tested this by using a linear regression test (Sterne 2011). We would have considered a P value of less than 0.1 to be significant for this test. However, as we analysed two trials only, we did not generate a funnel plot.
Data synthesis
Where we considered the data sufficiently similar to be combined, we pooled results by applying meta‐analyses using the fixed‐effect model, and used the random‐effects model as a sensitivity analysis. If the trials were clinically too heterogeneous to combine, we performed subgroup analyses only without calculating an overall estimate. We performed analyses according to the recommendations of The Cochrane Collaboration and used the Cochrane statistical package Review Manager 5 for analysis (Deeks 2011; Review Manager (RevMan)).
We created a 'Summary of findings' table on absolute risks in each group with the help of GRADEpro 2014 and used it to summarise the evidence of overall survival, quality of life, progression‐free survival, time to engraftment, and adverse effects. At variance with the protocol, we added the second primary outcome, 'successful stem cell collection', and 'number of transplanted participants' to the summary of findings Table for the main comparison, as both are clinically important outcomes for transplanted patients. For clinical interpretation, we calculated numbers needed to treat for an additional beneficial outcome and numbers needed to treat for an additional harmful outcome, with corresponding 95% confidence intervals.
Subgroup analysis and investigation of heterogeneity
We considered performing subgroup analyses using the following characteristics:
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Age (< 60 years, ≥ 60 years)
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Gender (male, female)
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Underlying disease (NHL, MM, HL)
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Therapy (first‐line, relapse therapy) of underlying disease
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Dosage of plerixafor
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Additional drugs for mobilisation (e.g. G‐CSF)
However, as only two trials provided data, we did not perform these analyses.
Sensitivity analysis
We considered performing sensitivity analyses using the following quality criteria:
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Quality components with regard to low and high risk of bias
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Fixed‐effect modelling versus random‐effects modelling
Again, as only two trials provided data, we did not perform these analyses.
Results
Description of studies
Results of the search
The search strategies resulted in a total of 855 potentially relevant references. After screening the titles and abstracts of these publications, we excluded 829 references at initial stage. After evaluating the full‐text publications of the remaining 26 references, we excluded four studies (six references) that did not match our methodological demands and a further five studies that were still ongoing. Finally, we included 15 references of four trials that fulfilled the methods criteria. However, only two of these trials provided data and were included in the meta‐analysis. One trial was stopped early after including nine participants, without providing any reasons and without publishing outcomes (NCT01301963). The study investigator did not respond to email. Another trial was reported as being completed in 2009, but no details have been published (NCT00665314). We contacted the study investigator via email, but he was not able to provide the missing data. The study flow diagram in Figure 1 provides an overview of the searching process.
Study flow diagram.
Included studies
One trial included people with MM (AMD3100‐3102 MM), whereas the second trial analysed the effect of plerixafor on people with NHL (AMD3100‐3101 NHL). The third trial evaluated people with MM with at least two cycles of lenalidomide from July 2011 to June 2013 and included nine participants (NCT01301963). The fourth trial evaluated the safety and efficacy of the addition of plerixafor to a G‐CSF mobilisation regimen in people with lymphoma (NHL and HL) and MM (NCT00665314); the study period lasted from November 2007 to June 2009 with an enrolment of five participants. The third and fourth trial did not provide any outcome, even after we had contacted the study investigators via email. Therefore we have only described them further in the Characteristics of included studies section.
Design
AMD3100‐3101 NHL and AMD3100‐3102 MM were multicentre, randomised (1:1), double‐blind, placebo‐controlled studies.
Sample sizes
AMD3100‐3102 MM randomised 302 participants; 148 entered the plerixafor arm and 154 the placebo arm. AMD3100‐3101 NHL allocated 150 participants to the plerixafor arm and 148 to the placebo arm.
Locations
The participants in AMD3100‐3102 MM were treated at 38 sites in the USA, one site in Canada, and one site in Germany. AMD3100‐3101 NHL was conducted at 32 sites, but detailed information on the countries was not provided.
Participants
In AMD3100‐3102 MM, participants had a median age of 58.2 (± 8.4) in the plerixafor arm and 58.4 (± 8.6) in the placebo arm. The amount of male participants was 67.6% in the plerixafor arm and 69.5% in the placebo arm. In the plerixafor arm, 61.5% of participants had a MM at stage III at initial diagnosis. In the placebo arm, 58.4% of participants were at stage III.
In AMD3100‐3101 NHL, the median age of the participants in the plerixafor arm was 56 years (29 to 75) with 66.7% male participants. In the placebo group, the median age was 59 years (22 to 75) with 68.9% male participants. In the plerixafor arm, 34.0% of the participants had a first complete remission, 20.0% a second complete remission, 17.3% a first partial remission, and 28.7% a second partial remission. In the placebo arm, 29.7% of the participants had a first complete remission, 19.6% a second complete remission, 12.8% a first partial remission, and 36.5% a second partial remission. The current remission status of two placebo participants was unknown.
Interventions
In both trials the participants received G‐CSF, 10 μg/kg subcutaneously daily in the mornings for up to eight days. In the evening of day four, participants in both trials received plerixafor, 240 μg/kg or placebo subcutaneously for up to four days. The apheresis began at day five in both trials. In AMD3100‐3102 MM, apheresis continued daily for up to four days or until more than or equal to 6 x 106 CD34+ cells/kg were collected. In AMD3100‐3101 NHL, apheresis continued daily for up to four days or until more than or equal to 5 x 106 CD34+ cells/kg were collected.
Outcomes
Both trials analysed overall survival throughout a 12 months' follow‐up. The studies defined different endpoints to analyse successful stem cell collection and the proportion of participants achieving the optimal CD34+ cell target for transplantation. Both trials also examined the number of days to successful neutrophil and platelet engraftment, as well as adverse events. Neither study evaluated quality of life.
Conflict of interest
Both trials were supported and sponsored by the Genzyme Corporation.
Excluded studies
After a detailed evaluation of the selected full‐text publications, we excluded four studies, of which two were post‐hoc retrospective analyses (Maziarz 2013; Stiff 2011), one was a non‐randomised open‐label rescue protocol (Micallef 2009), and in one trial the study design was amended during the treatment period (Flomenberg 2005). For more details, see Characteristics of excluded studies.
Risk of bias in included studies
There was low risk of bias in AMD3100‐3101 NHL and AMD3100‐3102 MM; however, in NCT01301963 and NCT00665314 we considered the potential risk of bias as high since neither study has published outcomes nor reported reasons for stopping early. For detailed information, see the 'Risk of bias' table in Characteristics of included studies, Figure 2, and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
We judged random sequence generation as 'low risk' for all four trials because participants were randomly assigned. In AMD3100‐3102 MM, randomisation was stratified by study centre, baseline platelet count, and type of transplantation planned. No information was available for allocation concealment for AMD3100‐3101 NHL, NCT01301963, and NCT00665314.
Blinding
AMD3100‐3101 NHL and AMD3100‐3102 MM were double‐blind, placebo‐controlled studies, therefore we rated performance and detection bias as 'low risk'. NCT01301963 was an open‐label study, and in NCT00665314 only participants were blinded, therefore we rated performance and detection bias as 'high risk' for both trials.
Incomplete outcome data
We judged attrition bias as 'low risk' for AMD3100‐3101 NHL and AMD3100‐3102 MM because all participants who withdrew from the studies or entered rescue procedure were documented in detail in the patients' flow charts. We rated attrition bias as 'high risk' for NCT00665314, as the study investigator could not provide the missing data, and as 'unclear risk' for NCT01301963, as the study investigator did not respond to email.
Selective reporting
The study protocols were available and all outcomes were reported in detail for AMD3100‐3101 NHL and AMD3100‐3102 MM (www.clinicaltrials.gov); therefore we judged reporting bias as 'low risk'. We rated reporting bias as 'high risk' for NCT00665314, as the study investigator could not provide the missing data, and as 'unclear risk' for NCT01301963, as the study investigator did not respond to email.
Other potential sources of bias
AMD3100‐3101 NHL and AMD3100‐3102 MM were supported by the Genzyme Corporation, the manufacturer of plerixafor. We therefore rated the risk of other bias as 'unclear'. We rated other bias as 'high risk' for NCT00665314, as the study investigator could not provide the missing data, and as 'unclear risk' for NCT01301963, as the study investigator did not respond to email.
Effects of interventions
The trial NCT01301963 was prematurely closed and no analysis was being done on collected data. Nine participants were randomised in this trial. The trial NCT00665314, which had an enrolment of five participants, was completed in 2009 and also did not report any results.
Primary outcomes
Overall survival
No hazard ratios for overall survival were reported, therefore we analysed mortality at 12 months for the 600 included participants. The meta‐analysis did not show a statistically significant difference between participants treated with G‐CSF plus plerixafor and G‐CSF plus placebo (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.59 to 1.69; P = 1.00). For more details, see Analysis 1.1.
Successful stem cell collection
In AMD3100‐3102 MM, the primary endpoint was the proportion of participants collecting more than or equal to 6 x 106 CD34+ cells/kg in two or fewer apheresis days. In AMD3100‐3101 NHL, the primary endpoint was the percentage of participants who collected more than or equal to 5 x 106 CD34+ cells/kg in four or fewer apheresis days. The meta‐analysis showed a significant advantage for those participants randomised to plerixafor (RR 2.42, 95% CI 1.98 to 2.96; P < 0.00001), with important heterogeneity (I2 = 67%). Reasons for the heterogeneity could be different underlying condition or different targeted stem cell number. For detailed information, see Analysis 1.2.
Furthermore, in both trials the time required to reach the primary endpoint was significantly shorter in the plerixafor group (AMD3100‐3102 MM: P < 0.001; AMD3100‐3101 NHL: P < 0.0001).
Secondary outcomes
Progression‐free survival
Not reported.
Proportion of participants achieving the optimal CD34+ cell target for transplantation
In AMD3100‐3102 MM, 95.3% of 148 participants in the plerixafor arm and 88.3% in the placebo arm achieved the secondary endpoint, which was defined as the number of participants collecting more than or equal to 2 x 106 CD34+ cells/kg in two or fewer apheresis days (RR 1.08, 95% CI 1.01 to 1.15).
In AMD3100‐3101 NHL, statistically significantly more participants in the plerixafor group (86.7%) compared to the control arm (47.3%) met this endpoint (RR 1.83, 95% CI 1.53 to 2.20).
Due to the high heterogeneity between the trials, we did not pool these data. For more details, see Analysis 1.3.
Time to engraftment in transplanted participants
Time to engraftment could be measured only for those participants that were transplanted. As there was high heterogeneity between studies, we did not meta‐analyse these data for transplantation. In addition, as only the median time to engraftment was reported, without the publishing of standard error or standard deviation, we could not meta‐analyse the data for engraftment.
Number of transplanted patients
In AMD3100‐3102 MM, 142 participants (95.9%) in the plerixafor arm and 136 (88.3%) in the placebo arm underwent transplantation (RR 1.09, 95% CI 1.02 to 1.16). Median time to engraftment was 11 days for neutrophils and 18 days for platelets in both groups. One participant in the plerixafor arm and one participant in the control arm died 10 and 13 days after transplantation, respectively. Nevertheless, using clinical and laboratory data we identified no graft failures.
In AMD3100‐3101 NHL, 135 participants (90%) in the plerixafor group and 82 (55.4%) in the control group underwent transplantation (RR 1.62, 95% CI 1.39 to 1.89). The median time was 10 days for neutrophil engraftment and 20 days for platelet engraftment in each arm. All participants in both groups who underwent transplantation had successful neutrophil engraftment. For platelet engraftment, the study reported two graft failures in the plerixafor arm but none in the placebo arm.
For more details, see Analysis 1.4.
Quality of life
Not reported.
Adverse events
For the period from participants' randomisation to the day before high‐dose chemotherapy (period one), the meta‐analysis did not show a statistically significant difference between the plerixafor and placebo group in terms of adverse events (RR 1.02, 95% CI 0.99 to 1.06; P = 0.19).
Only AMD3100‐3101 NHL reported serious adverse events in period one. Eight serious adverse events occurred in the plerixafor arm and 10 in the placebo arm (RR 0.77, 95% CI 0.31 to 1.90; P = 0.58).
The meta‐analysis of adverse events that led to discontinuation of study treatment did not show a statistically significant difference between the plerixafor and control group (RR 0.79, 95% CI 0.21 to 2.91; P = 0.72).
Adverse events leading to study withdrawal also did not show a statistically significant result (RR 1.17, 95% CI 0.38 to 3.58; P = 0.78).
For detailed information, see Analysis 1.5, Analysis 1.6, Analysis 1.7, and Analysis 1.8.
Discussion
Summary of main results
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As no hazard ratios for overall survival were provided, we analysed mortality at 12 months. No evidence for differences between plerixafor and control arm regarding mortality emerged in the meta‐analysis.
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The meta‐analysis of adverse events in study period one (stem cell mobilisation) did not show a statistically significant difference between the plerixafor and placebo group.
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Regarding the primary endpoint of successful stem cell collection, the meta‐analysis showed a significant advantage for those participants randomised to plerixafor, with important heterogeneity. Reasons for the heterogeneity could be different underlying condition or different targeted stem cell number. In AMD3100‐3102 MM, the primary endpoint was defined as the proportion of participants collecting more than or equal to 6 x 106 CD34+ cells/kg in two or fewer apheresis days. In AMD3100‐3101 NHL, the primary endpoint was the percentage of participants who collected more than or equal to 5 x 106 CD34+ cells/kg in four or fewer apheresis days. It is common practice to define a higher primary endpoint of collected stem cells for MM patients, as they often need a second transplantation. In both studies, the time to reach the primary endpoint was significantly shorter in the plerixafor group compared to the control group.
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In AMD3100‐3102 MM, 95.9% of participants in the plerixafor arm and 88.3% in the placebo arm underwent transplantation. By contrast, in AMD3100‐3101 NHL, 90% of participants in the plerixafor group but only 55.4% in the control group underwent transplantation.
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In both trials, there was no evidence for a difference between participants in the plerixafor and the control group in terms of time to neutrophil and platelet engraftment.
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None of the trials reported quality‐of‐life events or progression‐free survival.
Overall completeness and applicability of evidence
The following aspects should be considered when interpreting the results of this meta‐analysis.
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Trial NCT01301963, terminated in June 2013, did not analyse and publish collected data due to low enrolment (nine participants). The study investigator did not respond to email. Study NCT00665314, completed in June 2009 with randomisation of five participants, did not report any outcomes. Genzyme, the responsible party, was not able to provide the missing data.
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Trial NCT01767714 (classified as an ongoing study), completed in November 2014 with enrolment of 100 participants, has not to this date reported any outcomes, however the trial could publish results in the near future, which may affect the results of this review. The collaborator of the study, Genzyme, did not respond to email.
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The two analysed studies, AMD3100‐3101 NHL and AMD3100‐3102 MM, have been published several times.
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Besides mortality at 12 months, number of collected stem cells, and adverse events, the studies did not provide much clinical data (e.g. quality of life).
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Both trials were conducted by the same study director and were supported by the Genzyme Corporation, the manufacturer of plerixafor.
Quality of the evidence
The risk of bias in AMD3100‐3101 NHL and AMD3100‐3102 MM was low as they were randomised, double‐blind, placebo‐controlled studies. We rated the risk of performance, detection, attrition, and reporting bias as low for both trials. The quality of allocation concealment (selection bias) in AMD3100‐3101 NHL remained unclear as the publication provided no information. We judged the risk of selection bias in AMD3100‐3102 MM as low. Due to the sponsorship of the Genzyme Corporation, we rated the risk of other bias as unclear for both trials.
We could conduct a meta‐analysis for mortality at 12 months, successful stem cell collection, and adverse events. We rated the quality of the evidence for mortality after one year as moderate due to the wide confidence interval and imprecision. We judged the quality of evidence for successful stem cell collection and adverse events during study period one (stem cell mobilisation) as high.
There was a low risk of publication bias, but we did not downgrade the quality of evidence because although two trials, which were terminated early, did not report results, they were stopped early due to low recruitment, and included 14 participants only. We therefore judged potential risk of publication bias as low. The first of these two trials, NCT01301963, was conducted and sponsored by the Case Comprehensive Cancer Center in Ohio, USA and was terminated in 2013. On clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/results/NCT01301963?sect=X01256#all), the investigators stated that they had recruited nine participants, but due to low enrolment (10% of anticipated participants), they were doing no analysis on data collected in this study. We contacted principal investigator Hien Duong, MD, to obtain the collected data, but he did not respond. The second trial NCT00665314 was terminated in 2009; study sponsor and collaborator Genzyme stated via email that the low enrolment (five participants) was probably due to the compassionate use programme for plerixafor that had started at the same time. Genzyme was not able to provide more information on the outcomes.
Potential biases in the review process
We tried to avoid bias by performing all relevant processes in duplicate. We are not aware of any obvious deficiencies in our review process. However, the small number of trials included in this analysis could lead to publication bias, as we could not generate a funnel plot. As stated above, there is a low risk of publication bias, because of three studies that were completed and have not yet published results.
Agreements and disagreements with other studies or reviews
Sheppard 2012 conducted a systematic review of RCTs of haematopoietic stem cell mobilisation strategies for autologous transplantation for haematologic malignancies. They analysed 28 articles including AMD3100‐3101 NHL and AMD3100‐3102 MM as well as studies with chemotherapy mobilisation strategies. Due to the different methodological quality of the trials, they were not able to compare the studies via meta‐analysis and draw definitive conclusions. Regarding AMD3100‐3101 NHL and AMD3100‐3102 MM, Sheppard 2012 stated that primary mobilisation failure in the control groups could be a result of a too‐low G‐CSF dose. Sheppard 2012 recommended a risk‐adapted, cost‐effective approach for the use of plerixafor. Duong 2011 and Abhyankar 2012 described a risk‐based algorithm for the use of plerixafor based on analysing the CD34+ cell count on the first day of collection. Duong 2011 identified participants with a day one CD34+ cell yield of <= 0.7 x 106 CD34+ cells/kg as being at risk for mobilisation failure. Costa 2011 described a cost‐based algorithm to decide whether to add plerixafor on the basis of the CD34+ cell count on the fourth day of G‐CSF application.
Giralt 2014 discussed recommendations for optimal stem cell mobilisation strategies. With reference to AMD3100‐3101 NHL and AMD3100‐3102 MM, they agreed that plerixafor‐containing strategies reduce mobilisation failure rates. They recommend using plerixafor for remobilisation attempts or for predictable poor mobilisers.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Plerixafor versus placebo, Outcome 1 Mortality at 12 months.
Comparison 1 Plerixafor versus placebo, Outcome 2 Successful stem cell collection.
Comparison 1 Plerixafor versus placebo, Outcome 3 Proportion of participants achieving the optimal CD34+ cell target for transplantation.
Comparison 1 Plerixafor versus placebo, Outcome 4 Number of transplanted patients.
Comparison 1 Plerixafor versus placebo, Outcome 5 Adverse events (during study period 1).
Comparison 1 Plerixafor versus placebo, Outcome 6 Serious adverse events (during period 1).
Comparison 1 Plerixafor versus placebo, Outcome 7 Adverse events leading to discontinuation of study treatment.
Comparison 1 Plerixafor versus placebo, Outcome 8 Adverse events leading to study withdrawal.
| Plerixafor versus placebo for haematopoietic stem cell mobilisation for autologous transplantation in people with malignant lymphoma or multiple myeloma | ||||||
| Patient or population: People with haematopoietic stem cell mobilisation for autologous transplantation in malignant lymphoma or multiple myeloma | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Plerixafor | |||||
| Mortality (12 months) | Study population | RR 1 | 600 | ⊕⊕⊝⊝ | As overall survival has not been reported, we calculated mortality at 12 months | |
| 83 per 1000 | 83 per 1000 | |||||
| Quality of life | ‐ | ‐ | See comment | ‐ | ‐ | Not reported |
| Progression‐free survival | ‐ | ‐ | See comment | ‐ | ‐ | Not reported |
| Time to engraftment | ‐ | ‐ | See comment | ‐ | ‐ | Not reported with standard error or standard deviation, therefore no meta‐analysis possible |
| Number of transplanted participants | ‐ | ‐ | See comment | ‐ | ‐ | Due to high heterogeneity we did not pool the data |
| Successful stem cell collection | 270 per 1000 | 654 per 1000 (535 to 799) | RR 2.42 (1.98 to 2.96) | 600 | ⊕⊕⊕⊕ | ‐ |
| Adverse events (during stem cell mobilisation and collection) | Study population | RR 1.02 | 593 | ⊕⊕⊕⊕ | ‐ | |
| 939 per 1000 | 958 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to imprecision: wide confidence interval. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality at 12 months Show forest plot | 2 | 600 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.59, 1.69] |
| 2 Successful stem cell collection Show forest plot | 2 | 600 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.42 [1.98, 2.96] |
| 3 Proportion of participants achieving the optimal CD34+ cell target for transplantation Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4 Number of transplanted patients Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5 Adverse events (during study period 1) Show forest plot | 2 | 593 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.99, 1.06] |
| 6 Serious adverse events (during period 1) Show forest plot | 1 | 295 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.31, 1.90] |
| 7 Adverse events leading to discontinuation of study treatment Show forest plot | 2 | 593 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.21, 2.91] |
| 8 Adverse events leading to study withdrawal Show forest plot | 2 | 593 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.38, 3.58] |
