High-dose chemotherapy along with autologous hematopoietic stem cell transplantation (HSCT) is a widely used effective therapeutic option for patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). HSCT has greatly evolved from its early days where the only source for the harvesting of hematopoietic stem cells (HSCs) was the bone marrow. A paradigm shift in HSC collection has been made possible with the use of granulocyte-colony stimulating factor (G-CSF) to increase the number of circulating CD34⁺ cells and improvements in collection devices, which allows for HSC collection in fewer apheresis sessions (1,2).

Successful HSCT is largely dependent on the adequate collection of CD34⁺ cells. The American Society for Blood and Marrow Transplantation recommends 4–5×10⁶ CD34⁺ cells/kg as the optimal number and ≥2×10⁶ CD34⁺ cells/kg as the minimum number of HSCs to support transplantation (3). A large number of cases, however, are hard-to-mobilize or require multiple mobilization attempts for successful HSCT. The number of patients who are ‘difficult mobilizers’ varies considerably, with an incidence ranging from 5 to 10% to approximately 30% (2,4,5). In general, greater mobilization issues have been found in patients with NHL compared to those suffering from MM (5).

Plerixafor, a novel bicyclam small-molecule, was initially developed for managing HIV infections. It reversibly binds to chemokine receptor CXCR4 and antagonizes the chemokine stromal cell-derived factor-1α (SDF-1α) interaction, thereby inducing the mobilization of stem cells into the bloodstream from the bone marrow (6,7). It has been approved in the US and EU for the collection of HSCs and autologous transplantation in patients with NHL and MM, when used in combination with G-CSF (8). A number of literature reviews describing the role of plerixafor in HSC mobilization have been published (2,9,10). However, to date, and at least to the best of our knowledge, level-1 evidence in the form of a systematic review and meta-analysis has been conducted only once (11). The published review analyses data from the first 2 randomized controlled trials (RCTs) were conducted by DiPersio et al in 2009 (12,13). With the addition of new studies (14,15) from different centers on the efficacy of plerixafor for HSCT, there is a need for an updated meta-analysis. Therefore, the aim of this study was to systematically search the published literature and analyze evidence on the efficacy of additional plerixafor for successful HSC mobilization in patients with NHL and MM, and to evaluate the safety of the drug.

This systematic review of the literature was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (16) and guidelines of the Cochrane Handbook for Systematic Reviews of Intervention (17).

In 2003, AMD3100, as plerixafor was formerly known, was studied by Liles et al (24) in healthy volunteers as a potential HSC mobilizer. The authors reported rapid generalized leukocytosis and an increase in the number of CD34⁺ cells in peripheral blood with a single dose of the drug. Later, in their study, serial administration of the drug at 80 µg/kg/day for 3 days resulted in a consistent, reversible increase in the number of CD34⁺ cells in peripheral blood with minimal toxicity. Their findings suggested the potential clinical application of plerixafor for HSCT. Their results were soon confirmed in patients with NHL and MM, where a significant increase in the CD34⁺ counts was noted (25). Phase 2 trials later established the superiority of plerixafor + G-CSF as compared to G-CSF alone for autologous HSC mobilization (26). Superior evidence in the form of RCTs by DiPersio et al (12,13) paved the way for the approval of plerixafor by FDA in December, 2008 (27). The drug was ratified for use in patients with NHL and MM for the mobilization of HSCs for autologous transplantation. Since then, a number of studies have evaluated the role of plerixafor in patients with NHL and MM. Single arm prospective trials or retrospective studies form the bulk of the research conducted (28–30). The results of our systematic review indicated that 5 RCTs evaluating the role of additional plerixafor to G-CSF have been published to date. Three of these were conducted on NHL (13–15) and 2 on patients with MM (12,19). The study end-points were more or less similar across trials which enabled the pooling of the data for the purposes of our meta-analysis.

The minimum number of CD34⁺ cells likely to result in successful engraftment is generally considered to be ≥2×10⁶ cells/kg, whereas the ‘optimal’ number of HSCs for transplantation is 4–6×10⁶ CD34⁺ cells/kg (31). It has been found that the re-infusion of higher number of CD34⁺ cells is associated with earlier engraftment following transplantation, with better disease-free and overall survival than lower cell doses (32). As a result, many transplant centers strive to harvest the optimal number of HSCs rather than the minimal dose. The primary efficacy end-point in the majority of the included trials of this review was the collection of optimal HSCs in 4 or less apheresis days. The results of our meta-analysis revealed that patients receiving additional plerixafor were 2.59-fold more likely to achieve optimal HSC collection in 4 or less apheresis days. Similarly, patients in the plerixafor group were 1.46-fold more likely to mobilize minimal HSCs (≥2×10⁶ cells/kg in 4 or less apheresis days) as compared to those receiving G-CSF only. There was slight variation in the primary efficacy end-point in NHL and MM studies, with NHL studies reporting the mobilization of ≥5×10⁶ cells/kg, while MM studies reporting the mobilization of ≥6×10⁶ cells/kg as the optimal number of HSCs for harvest. A higher primary endpoint is set for the collection of HSCs in patients with MM as they frequently require a second transplantation. A subgroup analysis was therefore carried out for NHL and MM, which demonstrated the effectiveness of plerixafor in both conditions. An important aspect to note is that only one study (12) was available evaluating the collection of optimal HSCs in 4 or less apheresis days for MM. The study by Ri et al (19) reported the collection of ≥6×10⁶ cells/kg in 2 or less apheresis days and was not pooled with the other study of DiPersio et al (12) for this variable.

In addition to the optimal collection of HSCs, another critical goal of stem cell mobilization is to collect cells in minimum number of days so as to reduce treatment stress and financial burden of the patient and also ensure optimal utilization of medical resources. Despite the fact that pooled analysis was not possible for the number of days needed for HSC mobilization with or without plerixafor, all studies included in this review reported the rapid mobilization with the drug. The median number of days for both optimal and minimal HSC mobilization was less with the addition of plerixafor. The more rapid collection of HSCs may lead to better patient compliance, reduce apheresis-associated risks and may shorten the interval between mobilization and transplant (15). The superior efficacy of plerixafor + G-CSF was also observed in the total number of CD34⁺ cells collected and the number of patients who eventually underwent HSCT.

The safety profile of plerixafor was tested in all included studies. Based on our analysis and the investigation of individual trials, plerixafor is generally well-tolerated and there is no significant increase in treatment-related adverse events with the addition of the drug. In both the trials of DiPersio et al (12,13), the majority of adverse events were gastrointestinal (GI) disorders or injection site reactions. Ri et al (19) reported increased headaches, diarrhea and back pain with the addition of plerixafor. Zhu et al (14) and Matsue et al (15) reported GI-related disorders and headaches to be more common in the plerixafor arm than the control arm. All adverse events reported were mild to moderate and there were no treatment-related deaths reported in any of the included studies.

As plerixafor tends to mobilize relatively different cell populations as compared to other methods of mobilizing CD34⁺ cells, post-transplant outcomes, such as hematopoietic and immune recovery and progression-free survival (PFS) are important variables of concern to clinicians (2). In total, 2 of the 5 included trials reported that engraftment and short-term outcomes at 12 months were similar with plerixafor + G-CSF and plerixafor + placebo. Importantly, the long-term results of these 2 studies have been published recently (33). The results indicated that the probability of overall survival and PFS evaluated over a period of 5 years did not differ significantly in patients with NHL or MM treated with plerixafor or the placebo. There is however, a need for more such long-term studies in order to validate the safety and efficacy of plerixafor for long-term PFS.

Some limitations of our review and meta-analysis need to be elaborated. Firstly, the paucity of RCTs limited the number of studies for inclusion in our review. Secondly, not all trials included were high quality studies. In total, 2 of the 5 included studies were sored as ‘medium quality’ based on the quality assessment tool. Thirdly, data on engraftment, long-term overall survival and PFS were not available from all included studies. Fourthly, as with any meta-analysis, heterogeneity as measured with I² statistic was significant in all our investigations. The time period, locations and samples of individual trials are quite variable across studies, but are usually balanced between the two arms of the meta-analysis. Nevertheless, our systematic review and meta-analysis is a significant update from the last review published on the subject by Hartmann et al in 2015 (11). Data from a 3 additional trials were available and added for quantitative analysis. The results of this study indicate that addition of plerixafor to G-CSF leads to increased HSC collection in a shorter period of time with no concomitant increase in adverse events. Further RCTs with a larger sample size evaluating short-term efficacy, as well as long-term survival would help to further strengthen evidence on this subject.