Meta-analysis and systematic review of plerixafor for stem cell mobilization for autologous stem cell transplant (ASCT)

Autologous stem cell transplant (ASCT) is a core part of the treatment pathway for transplant-eligible patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). In order to perform an ASCT, it is necessary to collect hematopoietic stem cells (HSCs) from the peripheral blood. Granulocyte-colony stimulating factor (G-CSF) is often used to mobilize the HSCs and several studies have shown the addition of plerixafor can further improve this process.¹

The minimum number of CD34⁺ cells required for ASCT, as per the American Society for Blood and Marrow Transplantation recommendation, is ≥ 2 x 10⁶ CD34⁺ cells/kg, with an optimal number of ≥ 4 x 10⁶ CD34⁺ cells/kg.² It is difficult to mobilize HSCs in some patients, particularly those with NHL. The target collection for patients with MM is also higher as they often need to receive a second ASCT at a later timepoint.

Re-infusion with a higher number of CD34⁺ cells is associated with many benefits including; earlier engraftment post-transplantation and improved disease-free and overall survival (OS).¹ Additionally, if the collection process can be done in fewer apheresis sessions, this leads to better patient compliance, a reduction of apheresis-associated risks, and a shorter interval between mobilization and transplant.¹ Therefore, agents which increase the number of CD34⁺ cells collected are highly sought after.

Plerixafor is a novel bicyclam small-molecule that mobilizes stem cells into the blood stream, from the bone marrow, by reversibly binding to the CXCR4 chemokine receptor and antagonizing the chemokine stromal cell-derived factor 1-α interation.¹ Based on the results of two multicenter, randomized, placebo-controlled trials in patients with NHL and MM, the United States (US) Food & Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of plerixafor. Specifically, plerixafor is approved in combination with G-CSF for the collection of HSCs in patients with NHL and MM.^3-5

In 2015, Tim Hartmann and colleagues published a meta-analysis of two studies investigating the effect of combining plerixafor with G-CSF to mobilize HSCs. Hartmann et al., found that plerixafor increased stem cell collection in a shorter period of time, but were unable to determine the effects on survival or adverse events (AEs).⁶ Since then, no further analysis using additional studies has been published. Xiaoyang Yang, Affiliated Haikou Hospital of Xiangya Medical College, Haikou, CH, and colleagues, therefore, performed a systematic review and meta-analysis on current data focusing on the efficacy of plerixafor for HSC mobilization and safety, in patients with NHL or MM.¹

Study design¹

• Primary objective: quantitative analysis of successful optimal HSC mobilization
• Secondary objectives: analyze number of patients achieving minimal HSC mobilization, quantitative analysis of time to optimal and minimal HSC mobilization, number of CD34⁺ cells collected, number of patients subsequently transplanted, and AEs
• Database search sources: PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar
  • Inclusion criteria: patients with NHL or MM in first or second complete remission or partial remission who were eligible for ASCT but had not received any previous HSC mobilization attempts, or received an ASCT
    • Articles examined: 195
    • Articles excluded due to non-relevance: 186
    • Of the nine remaining articles, four were excluded as two were non-randomized, one had no control and one used a retrospective control group
• Five studies were included (Table 1)
  • Three studies were on patients with NHL and two studies in patients with MM
  • G-CSF protocol: G-CSF was given subcutaneously (SC) each morning for eight days
  • Plerixafor protocol: started on day four, patients received 240µg/kg of plerixafor or placebo, SC, daily in the evening, for up to four days or until target HSC collection (Table 1)
  • Apheresis: began on the morning of day five and continued for four days or until target HSC collection was reached

Table 1. Summary of studies used for analysis^1,7-11

	Year of publication	Disease	Treatment arm (N)	Control arm (N)	G-CSF protocol	Target HSC collection
DiPersio et al.,7	2009	NHL	150	148	10µg/kg	≥ 5 x 106 cells/kg
DiPersio et al.,8	2009	MM	148	154	10µg/kg	≥ 6 x 106 cells/kg
Ri et al.,9	2017	MM	7	7	400µg/m2/day	≥ 6 x 106 cells/kg
Zhu et al.,10	2017	NHL	50	50	10µg/kg	≥ 5 x 106 cells/kg
Matsue et al.,11	2018	NHL	16	16	400µg/m2/day	≥ 5 x 106 cells/kg

Results¹

• Results of the efficacy of plerixafor + G-CSF versus control (G-CSF only) are shown in Table 2
• Patients receiving plerixafor had a better minimal (≥ 2 x 10⁶ CD34⁺ cells/kg) HSC mobilization compared to control
• Statistically significant improvement seen in both NHL and MM subgroups

Table 2. Efficacy results of plerixafor + G-CSF versus placebo (G-CSF alone)¹

* Target number of HSCs was ≥ 5 x 106 cells/kg for patients with NHL and ≥ 6 x 106 cells/kg for patients with MM. Minimal HSC mobilization was defined as ≥ 2 x 106 cells/kg
Efficacy measure*	RR	95% CI	p value
Successful mobilization of HSCs to target number of cells in ≤ four apheresis days (plerixafor, n= 364 vs control, n= 368)	2.59	1.40–4.81	< 0.0001
Successful minimal HSC mobilization in ≤ four apheresis days (plerixafor, n= 371 vs control, n= 375)	1.46	1.01–2.12	0.04
Patients who ultimately underwent ASCT	1.19	1.02–1.39	0.03
Mean total number of CD34+ cells collected (pooled analysis of three studies)	Mean difference (MD): 4.21	2.85–5.57	< 0.00001

• Number of days to reach optimal or minimal HSC mobilization:
  • Data not pooled for quantitative analysis as these were given as median values
  • Qualitative analysis showed plerixafor reduced the number of days to reach optimal and minimal HSC collection

Safety¹

• Meta-analysis of pooled data of patients experiencing one or more treatment-related AE showed no significant increase in AEs with the use of plerixafor
  • RR: 1.03, 95% CI, 0.99–1.06, p= 0.16
• Plerixafor was generally well-tolerated with all AEs being mild–moderate (Table 3)
• No treatment-related deaths occurred

Table 3. Number of AEs by study included in analysis^1,7-11

		Number of AEs		Most frequent AEs associated with plerixafor
	Year of publication	Treatment (n= 371)	Control (n= 368)
DiPersio et al.,7	2009	146/150	138/145	Gastrointestinal (GI) or injection site reactions
DiPersio et al.,8	2009	140/147	140/151
Ri et al.,9	2017	6/7	4/7	Headaches, diarrhea and back pain
Zhu et al.,10	2017	32/51	31/49	GI-related disorders and headaches
Matsue et al.,11	2018	13/16	12/16

Limitations of analysis

• Lack of randomized controlled trials available for inclusion in analysis
• Not all trials were rated as high-quality based on the quality assessment tool used
• Data on engraftment, progression-free survival (PFS) and OS were not available
• Heterogeneity was significant
• Time period, locations and samples of trials were variable, but balanced between arms

Long term survival

Post-transplant outcomes such as PFS and OS are also important considerations for clinicians. Two of the studies used in this analysis (DiPersio et al., 2009⁷ and DiPersio et al., 2009⁸) have recently reported long-term results (Table 4).¹²

Table 4. Long-term survival analysis from two studies by DiPersio et al.,^7,8 evaluating the addition of plerixafor to G-CSF for stem cell mobilization¹²

	Indication	N	OS (%)	95% CI	5-year PFS	95% CI
Plerixafor arm	NHL	123	64	56–71	50%	44–67
Control arm	NHL	44	56	44–67	43%	31–54
Plerixafor arm	MM	91	64	54–72	17%	10–24
Control arm	MM	72	64	53–73	30%	21–40

Conclusion

The meta-analysis and systematic review found that the addition of plerixafor led to an increased HSC collection, in less time, with no associated increase in AEs in patients with NHL and MM. However, this analysis did have limitations, and so randomized controlled trials with a larger sample size are required to confirm the efficacy of this strategy.¹ Long-term survival analyzes concluded that using plerixafor in combination with G-CSF did not affect 5-year survival in patients with NHL or MM.¹²