Safety and Efficacy of Upfront Plerixafor + G-CSF vs. Placebo + G-CSF for Mobilization of CD34⁺ Hematopoietic Progenitor Cells in Patients ≥60 and <60 Years of Age with Non-Hodgkin’s Lymphoma or Multiple Myeloma

Abstract

The efficacy and safety of plerixafor + G-CSF in enhancing hematopoietic stem cell mobilization and collection has been demonstrated in two phase III studies involving patients with NHL or MM. In these pivotal studies, plerixafor + G-CSF significantly increased the proportion of patients achieving target stem cell yields, compared to placebo + G-CSF. In this analysis, we compare the efficacy and safety of plerixafor + G-CSF vs. placebo + G-CSF in patients enrolled in the two phase III studies, stratified by age: ≥60 years of age and <60 years of age. The proportion of older patients who achieved target stem cell yields were significantly higher in the plerixafor group than in placebo group (NHL: 50.9% vs. 25.4%, P<0.001; MM: 69.6% vs. 23.7%, P<0.001). In this older cohort, the median times to neutrophil and to platelet engraftment following autologous stem cell transplant were comparable between the plerixafor and placebo groups. Similar efficacy findings were observed in the younger age group. The most common adverse events (all grades) reported among older patients in the plerixafor group included diarrhea (41.3%), nausea (38.9%), fatigue (30.2%), and injection-site reaction (29.4%). The frequency of adverse events was similar between the older and the younger age groups. Taken together, our subanalysis demonstrate that plerixafor + G-CSF can be safely and effectively used in adult patients of all ages, including those ≥60 years, to support optimal stem cell mobilization for autologous stem cell transplantation.

Introduction

Non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) have considerable impact in the older patient population. In 2012, approximately 70,000 cases of NHL and 21,000 new cases of MM were diagnosed (1, 2). Since the median age at diagnosis is 66 years for NHL and 69 years for MM, more than half of newly diagnosed cases of these malignancies were made in patients ≥60 years of age(1, 2).

High-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has become the standard of care in patients with relapsed aggressive NHL and symptomatic MM (3, 4). In fact, NHL and MM are the most common hematologic malignancies indicated for HDT/ASCT (5). Significant gains in the rates of event-free survival (EFS) and overall survival (OS) have been shown in patients with diffuse large B-cell lymphoma treated with HDT/ASCT, compared with patients treated with conventional chemotherapy(6). In patients with MM, HDT/ASCT has been shown to significantly extend the period of time without symptoms, treatment, or treatment toxicity in older patients, compared with conventional chemotherapy(7). Thus, HDT/ASCT is an important treatment in patients with NHL and MM.

The success of HDT/ASCT is dependent on the collection of sufficient hematopoietic stem cells for transplantation. Approximately 10%-30% of patients with NHL and 15%-30% of patients with MM do not mobilize sufficient stem cells, either with cytokines alone or cytokines and chemotherapy, to meet the minimum requirements for ASCT(8-13). A number of patient and disease characteristics have been implicated as independent risk factors associated with poor stem cell mobilization: advanced patient age (≥60 years; prior chemotherapy (especially with alkylating agents, fludarabine, and lenalidomide); prior radiotherapy; time since first chemotherapy; extent of bone marrow involvement; histological subtype of NHL; and low platelet count at mobilization(8, 9, 14-19). The mobilization regimens frequently used are granulocyte-colony stimulating factor (G-CSF) alone or G-CSF with chemotherapy, either as part of salvage treatment, in cases of NHL, or solely for mobilization purposes. Chemotherapy is associated with significant side effects including: febrile neutropenia, infection or sepsis, the need for hospitalization and intravenous antibiotics, myelosuppression, bleeding, and the need for transfusions(20, 21). As such, chemotherapy + G-CSF as a mobilization regimen may not be an appropriate regimen for some patients at risk for poor mobilization, such as elderly patients, who may not tolerate the toxicities associated with the regimen.

Plerixafor is currently approved in the U.S. and Europe for use in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent ASCT in patients with NHL or MM (12, 22, 23). Plerixafor is a bicyclam molecule that reversibly binds to the CXCR4 chemokine receptor and blocks the binding to its ligand, stromal cell-derived factor-1α (SDF-1α) (24, 25). In two phase III, randomized, double-blind, placebo-controlled studies involving patients with NHL (3101 Study) and MM (3102 Study), plerixafor + G-CSF was shown to significantly increase the proportion of patients achieving optimal CD34⁺ stem cell yields for ASCT in fewer apheresis days, compared to placebo + G-CSF (12, 22). We hypothesized that plerixafor may be more poorly tolerated in older patients due to multiple medical co-morbidities and may not be as efficacious since older age is a known factor associated with poor mobilization. This report extends the 3101- and 3102-study analyses and compares the safety and efficacy of plerixafor + G-CSF vs. placebo + G-CSF in patients with NHL or MM ≥60 years of age and <60 years of age undergoing stem cell mobilization for ASCT.

Methods

Study design

This was a post-hoc analysis of patients ≥60 years of age and <60 years of age enrolled in the phase III 3101 and 3102 studies, both of which have been described previously(12, 22). Briefly, these were phase III, randomized, double-blind, placebo-controlled studies to evaluate the safety and efficacy of plerixafor + G-CSF vs. placebo + G-CSF in mobilizing CD34⁺ cells in patients 18-78 years of age with NHL (3101 study) or MM (3102 study). Patients received either G-CSF (10 μg/kg/day subcutaneously *SC+) + placebo or G-CSF + plerixafor (0.24 mg/kg SC). The schedule for stem cell mobilization/apheresis is described in Figure 1. Patients who failed to collect either ≥0.8 × 10⁶ CD34⁺ cells/kg after two days of apheresis or ≥2 × 10⁶ CD34⁺ cells/kg after four days of apheresis were eligible to enter an open-label rescue protocol as described previously(12, 22).

Figure 1.

Stem cell mobilization/apheresis schedule for phase III 3101 (NHL) and 3102 (MM) studies. G-CSF was administered each morning for four days prior to first evening dose of plerixafor and each morning of apheresis. Plerixafor was administered approximately 11 hours prior to initiation of apheresis. Apheresis was performed as 3 blood volumes ± 10% for up to four days. Events in shaded boxes were performed only if necessary.

Patient eligibility

Patients were eligible for enrollment into the 3101 and 3102 studies if they were in their first or second complete or partial remission, had completed their last cycle of chemotherapy >4 weeks before enrollment, had ECOG performance score of 0 or 1, and had normal laboratory values. Patients were not eligible if they had failed previous stem cell collection attempts, had prior stem cell transplantation, had received G-CSF within 14 days of the first dose of G-CSF on study, had >20% bone marrow involvement or received prior radioimmunotherapy (3101 study), or had received thalidomide, dexamethasone, lenalidomide, or bortezomib within seven days of the first dose of G-CSF (3102 study). These studies were conducted in accordance with Declaration of Helsinki and Good Clinical Practice guidelines and approved by the institutional review board or ethics committee of each participating institution. All patients provided written informed consent and could withdraw from the study at any time.

Mobilization and transplantation

Patients received G-CSF (10 μg/kg) SC daily for up to eight days. Beginning on the evening of Day 4 and continuing daily for up to four days, patients received either plerixafor (0.24 mg/kg) or placebo SC. Starting on Day 5, patients began daily apheresis (3.0 blood volume ± 10%) for up to four days or until sufficient CD34⁺ cells were collected (≥5 × 10⁶ cells/kg for patients with NHL and ≥6 × 10⁶ cells/kg for patients with MM). Within five weeks of last apheresis, patients received high-dose chemotherapy and underwent transplantation using collected CD34⁺ cells (minimum 2 × 10⁶ cells/kg) according to local practice guidelines.

Hematologic parameters for endpoint analysis

Peripheral blood CD34⁺ cell counts (cells/μL) were measured on the morning of Day 4, prior to G-CSF dosing, and on the morning of Day 5, 10-11 hours after plerixafor/placebo dosing. Fold-increase in peripheral blood CD34⁺ cell counts was calculated as the ratio of median absolute peripheral blood CD34⁺ cells/μL on Day 5 to that on Day 4. Neutrophil engraftment was defined as neutrophil count ≥0.5 × 10⁹/L for three days or ≥1.0 × 10⁹/L for one day. Platelet engraftment was defined as platelet count ≥20 × 10⁹/L without a transfusion for the preceding seven days. Graft durability was defined as maintenance of normal blood counts according to at least two of the following three criteria: platelet count >50 × 10⁹/L without transfusion for at least two weeks before the follow-up visit, hemoglobin level ≥10 g/dL with no erythropoietin support or transfusions for at least one month before the follow-up visit, absolute neutrophil count >1 × 10⁹/L with no G-CSF for at least one week before the follow-up visit.

Statistical analysis

In the current multivariate analysis, the proportion of patients achieving minimum an ideal targets of ≥2 × 10⁶ CD34⁺ cells/kg in ≤4 days of apheresis and ≥5 × 10⁶ CD34⁺ cells/kg in ≤4 days of apheresis (NHL 3101 study) or ≥6 × 10⁶ CD34⁺ cells/kg in ≤2 days of apheresis and ≥6 × 10⁶ CD34⁺ cells/kg in ≤4 days of apheresis (MM 3102 study), the proportion of patients proceeding to ASCT, the number of days to neutrophil and platelet engraftment, and the frequencies of adverse events (all grades) were compared between the plerixafor and placebo groups for patients ≥60 years of age and patients <60 years of age. Age 60 was chosen as the cut-off of older versus younger patients in this analysis, since age older than 60 years is a prognostic factor in patients with diffuse large B-cell lymphoma in the international prognostic index (IPI).

To evaluate whether plerixafor negates the negative impact of age in mobilization, multivariate logistic regression analyses was done in which the dependent variable was the primary endpoint for each study. Regression analyses were conducted separately for each treatment group (G-CSF + Plerixafor and G-CSF + placebo), in each study. Gender, stage at diagnosis, prior radiotherapy were also included as factors in the analyses. Age as a continuous variable and age by decade (<45, 45-54, 55-64, 65-74, ≥75) were both analyzed.

The statistical analyses for the 3101 and 3102 studies have been described previously(12, 22). Briefly, the intent-to-treat analyses, which included all randomized patients, were used to establish efficacy. Patients proceeding to rescue were censored from the safety analyses. For continuous outcomes, p-values were calculated using Wilcoxon rank sum test; for dichotomous outcomes, p-values were calculated using chi-square test. The proportion of patients reaching target stem cell collection was also calculated using Kaplan-Meier estimates. A p-value of <0.05 was considered statistically significant and all analysis was performed using SAS version 8.2 or above (SAS Institute, Cary, NC).

Results

Patients

A total of 600 patients were enrolled in the phase III 3101 (NHL) and 3102 (MM) studies(12, 22). Of the 298 patients enrolled in the 3101 study, 124 patients (42%) were ≥60 years of age. Of the 302 patients enrolled in the 3102 study, 145 patients (48%) were ≥60 years of age. The median age of NHL patients and MM patients included in the older age group was 65 years (range 60-75 years) and 64 years (range 60-75 years), respectively. Baseline characteristics of the older and younger patient cohorts are described in Table 1. Baseline characteristics between the plerixafor + G-CSF and placebo + G-CSF groups for both age categories were similar.

Table 1.

Baseline characteristics of patients <60 and ≥60 years of age in the 3101 and 3102 studies.

	3101 Study (NHL)				3102 Study (MM)
	<60 years		≥60 years		<60 years		≥60 years
	Plerixafor + G-CSF (n = 93)	Placebo + G-CSF (n = 81)	Plerixafor + G-CSF (n = 57)	Placebo + G-CSF (n = 67)	Plerixafor + G-CSF (n = 79)	Placebo + G-CSF (n = 78)	Plerixafor + G-CSF (n = 69)	Placebo + G-CSF (n = 76)
Median age at enrollment (range), years	50.0 (29-59)	53.0 (22-59)	65.0 (60-75)	65.0 (60-75)	53.0 (28-59)	54.0 (28-59)	64.0 (60-75)	64.5 (60-75)
Median time since diagnosis, months	10.0	11.0	17.0	13.0	6.5	6.0	7.0	7.0
Median time since progression/relapse, months (n)	4.0 (40)	4.0 (45)	4.0	4.0	5.0 (8)	4.0 (3)	3.0	4.0
Stage of disease at diagnosis, n (%)
I	5 (5.4)	6 (7.4)	11 (19.3)	4 (6.0)	13 (16.5)	8 (10.3)	15 (21.7)	11 (14.5)
II	9 (9.7)	17 (21.0)	6 (10.5)	15 (22.4)	11 (13.9)	24 (30.8)	17 (24.6)	17 (22.4)
III	23 (24.7)	28 (34.6)	6 (10.5)	16 (23.9)	54 (68.4)	42 (53.8)	37 (53.6)	47 (61.8)
IV	50 (53.8)	27 (33.3)	34 (59.6)	31 (46.3)	0 (0)	0 (0)	0 (0)	0 (0)
Missing	6 (6.5)	3 (3.7)	0 (0)	1 (1.5)	1 (1.3)	4 (5.1)	0 (0)	1 (1.3)

Mobilization efficacy

In both age groups, patients treated with plerixafor had a greater median increase in peripheral blood CD34⁺ cells/μl between Day 4 and Day 5, compared with patients treated with placebo (≥60 years: NHL: 5.5-fold vs. 1.6-fold; MM: 4.9-fold vs. 1.6-fold ; <60 years: NHL: 4.9-fold vs. 1.4-fold; MM: 4.7-fold vs. 1.7-fold). In both age groups, a significantly greater proportion of patients receiving plerixafor met the primary endpoint of collecting ≥5 × 10⁶ CD34⁺ cells/kg within four days (NHL) or ≥6 × 10⁶ CD34⁺ cells/kg within two days (MM) of apheresis, compared with patients receiving placebo (≥60 years: NHL: 50.9% vs. 25.4%, P<0.001; MM: 69.6% vs. 23.7%, P<0.001; <60 years: NHL: 64.5% vs. 14.8%, P<0.0001; MM: 73.4% vs. 44.9%, P<0.001) (Table 2). A greater proportion of patients receiving plerixafor achieved target stem cell collection (NHL: ≥5 × 10⁶ CD34⁺ cells/kg; MM: ≥6 × 10⁶ CD34⁺ cells/kg) on each day of apheresis, compared with patients receiving placebo, regardless of age group (Figures 2 and 3). However, patients in the NHL (but not MM) plerixafor + G-CSF group that were <60 years did meet target stem cell collection more frequently than those ≥60 years (71.4 vs. 56.1% at Day 5), although the approximate same proportion met the minimum stem cell collection requirements regardless of age group (Figure 2). In addition, significantly more patients receiving plerixafor met the secondary endpoint of collecting a minimum of ≥2 × 10⁶ CD34⁺ cells/kg within four days of apheresis (NHL) or a target of ≥6 × 10⁶ CD34⁺ cells/kg within four days of apheresis (MM), compared to patients receiving placebo, regardless of age group (≥60 years: NHL: 84.2% vs. 49.3%, P<0.001; MM: 75.4% vs. 42.1%, P<0.001; <60 years: NHL: 88.2% vs. 45.7%, P<0.0001; MM: 75.9% vs. 60.3%, P = 0.035) (Table 2). Median total stem cell yields were also significantly greater for patients in the plerixafor group, compared with those in the placebo group, regardless of age group (≥60 years: NHL: 5.07 vs. 1.92 × 10⁶ cells/kg, P<0.0001; MM: 10.14 vs. 5.64 × 10⁶ cells/kg, P<0.0001; <60 years: NHL: 6.65 vs. 1.97 × 10⁶ cells/kg, P<0.0001; MM: 11.01 vs. 6.98 × 10⁶ cells/kg, P = 0.001) (Table 2). Of the 124 patients ≥60 years with NHL, 33 (26.6%) proceeded to the rescue protocol, including 5 of 57 (8.8%) patients in the plerixafor group and 28 of 67 (41.8%) patients in the placebo group. A smaller proportion of patients <60 years with NHL proceeded to the rescue protocol: 29 of 174 (16.7%) overall, including 5 of 93 (5.4%) in the plerixafor group and 24 of 81 (29.6%) in the placebo group. A total of seven patients with MM proceeded to the rescue protocol, including two (2.6%) patients ≥60 years of age in the placebo group and five (6.4%) patients <60 years of age in the placebo group.

Table 2.

Efficacy endpoints in patients <60 and ≥60 years of age in the 3101 and 3102 studies.

	3101 Study (NHL)
	<60 years			≥60 years
	Plerixafor + G- CSF (n = 93)	Placebo + G- CSF (n = 81)	P value*	Plerixafor + G- CSF (n = 57)	Placebo + G- CSF (n = 67)	P value†
Primary endpoint: % achieving ≥5 × 106 CD34+ cells/kg within 4 days	64.5	14.8	<0.0001	50.9	25.4	<0.001
Secondary endpoint: % achieving ≥2 × 106 CD34+ cells/kg within 4 days	88.2	45.7	<0.0001	84.2	49.3	<0.001
Median total CD34+ × 106 cells/kg collected (range)	6.6 (0.4-29.2)	2.0 (0.06-15.0)	<0.0001	5.1 (0.03-14.58)	1.9 (0.06-12.0)	<0.0001
% proceeding to transplant	88.2	56.8	<0.0001	87.7	52.2	<0.001
	3102 Study (MM)
	<60 years			≥ 60 years
	Plerixafor + G- CSF (n = 79)	Placebo + G- CSF (n = 78)	P value*	Plerixafor + G- CSF (n = 69)	Placebo + G- CSF (n = 76)	P value†
Primary endpoint: % achieving ≥6 × 106 CD34+ cells/kg within 2 days	73.4	44.9	<0.001	69.6	23.7	<0.001
Secondary endpoint: % achieving ≥6 × 106 CD34+ cells/kg within 4 days	75.9	60.3	0.035	75.4	42.1	<0.001
Median total CD34+ × 106 cells/kg collected (range)	11.0 (1.7-104.6)	7.0 (0.3-42.7)	0.001	10.1 (0.7-41.6)	5.6 (0.1-18.1)	<0.0001
% proceeding to transplant	93.7	88.5	0.252	98.6	88.2	0.014

^*P values for comparisons between patients receiving plerixafor + G-CSF vs. placebo + G-CSF in the <60 years group

^†or ≥60 years group

Figure 2.

Kaplan-Meier estimate of the proportion of NHL patients (3101 study) <60 years of age (top) and ≥60 years of age (bottom) reaching target (left) and minimum (right) stem cell collection.

Figure 3.

Kaplan-Meier estimate of the proportion of MM patients (3102 study) <60 years of age (top) and ≥60 years of age (bottom) reaching target (left) and minimum (right) stem cell collection.

Since age is a known factor associated with poor mobilization, further analyses was done to evaluate whether plerixafor negates the negative impact of age in mobilization. In the NHL study, for both treatment groups, age either as a continuous variable and age by decade (<45, 45-54, 55-64, 65-74, ≥75) were not associated (p >0.05) with a difference in mobilization. However, in the MM study, increasing age was associated with poorer mobilization in the placebo group but not in the plerixafor group. In the placebo group, a significantly less proportion of patients achieved the endpoint with advancing decades (< 45, 60%; 45-54, 42%; 55-64, 36%; 65-74, 19% and ≥75, 0). Similar results were observed with age as a continuous variable or age by decades.

Transplantation and engraftment

A significantly greater proportion of patients ≥60 years old with NHL or MM receiving plerixafor proceeded to transplant, compared with those receiving placebo (NHL: 87.7% vs. 52.2%, P<0.001; MM: 98.6% vs. 88.2%, P=0.014) (Table 2). While the addition of plerixafor also allowed a greater proportion of patients <60 years old to proceed to transplant, compared with placebo, this difference was statistically significant only for patients with NHL (NHL: 88.2% vs. 56.8%, P<0.0001; MM: 93.7% vs. 88.5%, P = 0.252) (Table 2). Regardless of mobilization treatment received and age group, every patient on the NHL study who underwent transplantation achieved successful neutrophil engraftment. Only one transplanted patient on the MM study did not achieve neutrophil engraftment, whereas four transplanted patients on the NHL study and two patients on the MM study did not achieve successful platelet engraftment (Table 3). The median time to platelet and neutrophil engraftment was similar between patients who received plerixafor or placebo in both studies, regardless of age group (Table 3). Graft durability, measured at 100 days, 6 months, and 12 months post-transplant, was also comparable between the plerixafor and placebo arms in the NHL and MM groups. In total, there were four graft failures at one year: one NHL patient in the <60 group who received plerixafor, one MM patient in the <60 group who received placebo, one NHL patient in the ≥60 group who had received plerixafor, and one MM patient in the ≥60 group who had received plerixafor. The NHL patient in the <60 group died of disease progression at 319 days post-ASCT; graft was durable up to that time. The MM patient in the <60 group had disease progression and did not meet laboratory criteria for graft durability at one year. Both the NHL patient and the MM patient in the ≥60 group did not meet laboratory criteria for graft durability but met clinical criteria for graft durability at one year, as assessed by study investigators. There were no significant differences in mean platelet, neutrophil, or hemoglobin recovery at 3, 6, and 12 months between the plerixafor and placebo groups in patients with NHL or MM.

Table 3.

Neutrophil and platelet engraftment in patients <60 and ≥60 years of age.

	3101 Study (NHL)				3102 Study (MM)
	<60 years		≥60 years		<60 years		≥60 years
	Plerixafor + G-CSF (n = 85)	Placebo + G-CSF (n = 47)	Plerixafor + G-CSF (n = 50)	Placebo + G-CSF (n = 35)	Plerixafor + G-CSF (n = 74)	Placebo + G-CSF (n = 69)	Plerixafor + G-CSF (n = 68)	Placebo + G-CSF (n = 67)
Median infused CD34+ cell dose/kg (range)	5.9 (2.1-17.6)	3.6 (2.0-8.7)	5.1 (2.0-13.5)	4.3 (2.2-8.3)	5.3 (2.0-16.7)	4.0 (1.8-16.9)	5.6 (1.2-16.1)	3.9 (1.8-15.4)
Median time to neutrophil engraftment (range), days	10 (8-14)	11 (8-13)	10 (8-30)	10 (9-13)	11 (2-17)	11 (9-21)	11 (9-29)	11 (9-21)
Median time to platelet engraftment (range), days	20 (9-104)	20 (15-97)	20 (9-69)	21 (13-98)	19 (1-57)	19 (1-95)	18 (1-92)	18 (1-45)

Note: Every patient on 3103 achieved successful neutrophil engraftment. Only one patient on 3102 did not achieve neutrophil engraftment, whereas four patients on 3103 and two patients on 3102 did not achieve successful platelet engraftment.

Safety

The frequencies of adverse events (AEs) reported in patients ≥60 years of age were comparable to those reported in patients <60 years of age. Adverse events, regardless of relationship to study drug, occurring in >10% patients are reported in Table 4. In both age groups, more patients in the plerixafor arm experienced injection site erythema (<60 years: 25.0% vs. 4.4%; ≥60 years: 29.4% vs. 5.6%), diarrhea (<60 years: 38.4% vs. 15.7%; ≥60 years: 41.3% vs. 23.1%), nausea (<60 years: 37.8% vs. 27.7%; ≥60 years: 38.9% vs. 24.5%), and vomiting (<60 years: 15.1% vs. 7.5%; ≥60 years: 12.7% vs. 10.5%) than in the placebo arm. The frequencies of all other AEs were similar between the plerixafor and placebo arms for both age groups as were the frequencies of Grade 3 or greater AEs, with the exception of gastrointestinal disorders, which occurred with a greater frequency (8.7% vs. 1.9%) in the plerixafor <60 group than placebo (Table 4). No serious renal complications were observed in the plerixafor arm, however patients with compromised renal function were ineligible for study.

Table 4.

Adverse reactions occurring in ≥10% of patients <60 and ≥60 years of age in the 3101 and 3102 studies.

	3101 and 3102 Studies (NHL and MM)
	<60 years				≥60 years
	Plerixafor + G-CSF (n = 172)		Placebo + G-CSF (n = 159)		Plerixafor + G-CSF (n = 126)		Placebo + G-CSF (n = 143)
	All Grades (%)	Grades ≥3 (%)	All Grades (%)	Grades ≥3 (%)	All Grades (%)	Grades ≥3 (%)	All Grades (%)	Grades ≥3 (%)
Blood and lymphatic system disorders	14.0	8.7	15.1	5.7	16.7	9.5	11.9	8.4
Febrile neutropenia	9.3	7.0	6.3	4.4	11.1	7.1	5.6	4.9
Cardiac disorders	7.6	1.2	7.5	1.3	9.5	1.6	13.3	3.5
Gastrointestinal disorders	69.2	8.7	49.1	1.9	73.8	7.1	58.0	9.1
Diarrhea	38.4	3.5	15.7	0.0	41.3	2.4	23.1	2.1
Nausea	37.8	2.9	27.7	0.6	38.9	4.0	24.5	3.5
Vomiting	15.1	2.3	7.5	0.6	12.7	3.2	10.5	1.4
General disorders and Administration site conditions	77.3	14.5	67.9	7.5	74.6	10.3	60.8	7.0
Catheter site pain	11.6	-	17.6	-	11.1	-	8.4	-
Fatigue	29.1	1.2	27.0	0.0	30.2	0.0	24.5	0.0
Injection site erythema	25.0	-	4.4	-	29.4	-	5.6	-
Mucosal inflammation	15.7	10.5	10.7	6.3	15.1	8.7	8.4	5.6
Oedema peripheral	7.6	-	6.9	-	11.9	-	11.9	-
Pain	9.9	0.6	11.3	0.0	4.8	0.0	5.6	0.0
Pyrexia	13.4	2.3	13.8	0.6	6.3	0.8	7.7	1.4
Infections and infestations	28.5	14.0	22.0	11.9	22.2	13.5	18.9	9.8
Injury, poisoning, and procedural complications *	12.2	1.2	10.7	1.9	9.5	3.2	6.3	0.7
Investigations †	12.2	1.2	14.5	1.9	11.9	0.0	15.4	1.4
Metabolism and nutrition disorders	29.1	2.3	28.9	3.1	33.3	4.8	30.1	3.5
Hypokalemia	16.3	0.6	15.7	1.3	16.7	1.6	18.2	1.4
Hypomagnesemia	9.9	0.0	10.7	0.6	9.5	0.0	8.4	0.7
Musculoskeletal and connective tissue disorders	66.9	2.9	62.9	3.1	55.6	0.0	63.6	1.4
Arthralgia	15.7	-	12.6	-	9.5	-	11.9	-
Back pain	19.8	0.6	20.8	1.3	17.5	0.0	23.1	0.0
Bone pain	36.0	1.7	39.0	0.6	27.8	0.0	30.1	0.0
Nervous system disorders	50.6	2.9	51.6	1.3	45.2	3.2	35.7	0.7
Dizziness	9.3	0.0	7.5	0.0	11.9	0.8	4.9	0.0
Headache	26.2	0.6	25.8	1.3	17.5	0.0	16.1	0.7
Paraesthesia	20.3	-	23.9	-	20.6	-	18.2	-
Psychiatric disorders	20.9	1.7	10.1	0.0	13.5	1.6	11.9	0.7
Respiratory, thoracic and mediastinal disorders	18.6	1.2	23.3	3.1	21.4	6.3	14.7	1.4
Skin and subcutaneous tissue disorders	23.8	0.6	15.1	0.6	23.8	0.0	16.8	0.7
Vascular disorders	12.2	1.7	13.2	1.3	17.5	4.0	10.5	2.1

^*Injury, poisoning, and procedural complications included: ankle fracture, delayed engraftment, drug toxicity, hip fracture, incorrect route of drug administration, lung injury, procedural hypertension, procedural pain, subdural hematoma, and transfusion-related acute lung injury.

^†Investigations included: alanine aminotransferase, aspartate aminotransferase, blood potassium, blood uric acid, gamma-glutamyltransferase, hepatic enzymes, liver function test, and platelet count.

Plerixafor-related AEs were reported in 108 (62.8%) patients <60 years old and 86 (68.3%) patients ≥60 years old and commonly included injection site erythema (<60 years: 23.3%; ≥60 years: 27.0%), nausea (<60 years: 15.7%; ≥60 years: 19.8%), and diarrhea (<60 years: 27.3%; ≥60 years: 28.6%). Serious AEs (SAEs) considered to be related to study drug profile were observed in two plerixafor-treated patients in the <60 years age group: one patient reported thrombocytopenia (Grade 4) and another experienced Grade 2 dizziness and hypotension. The former was a 54-year-old female NHL patient who had a platelet count of 35×10³/μL 24 hours post-apheresis; one week later, her platelet count was 51×10³/μL. Fourteen days post-apheresis, the patient continued to be thrombocytopenic with platelet counts of 27×10³/μL and 22×10³/μL that later decreased to 13×10³/μL. In the second case, a 50-year-old female NHL patient had her blood pressure (BP) drop from a baseline of 110/62mmHg to 104/62 mmHg shortly after plerixafor injection. Subsequently, her BP dropped to 72/42 mmHg and she became diaphoretic, flushed, and nauseous. After bolus of IV fluids, her BP increased to 85/55 mmHg. The next day, the patient’s BP had decreased to 88/56 mmHg and then back to 101/68 mmHg after IV fluids. No drug-related SAEs were reported in patients ≥60 years of age.

Among patients of all ages in both studies, four patients (1.3%) in the plerixafor group discontinued treatment because of an adverse event. However, only of two of these patients’ AEs were considered to be treatment related: one patient experienced diarrhea and fatigue and the other abdominal pain, diarrhea, nausea, eye swelling, and paraesthesia. Five patients (1.7%) within the placebo group also discontinued treatment due to AEs, which included nausea, vomiting, pyrexia, non-cardiac chest pain, and atrial fibrillation.

Discussion

The subgroup analyses reported here describe the efficacy and safety of plerixafor + G-CSF vs. placebo + G-CSF in patients ≥60 years of age and <60 years of age enrolled in the 3101(22) and 3102(12) studies. Plerixafor + G-CSF was found to significantly increase the proportion of patients who achieved ≥5 × 10⁶ CD34⁺ cells/kg within four days (NHL) or ≥6 × 10⁶ CD34⁺ cells/kg within two days (MM) of apheresis, compared to patients receiving placebo + G-CSF in both age groups. Furthermore, plerixafor + G-CSF also significantly increased the proportion of patients who achieved minimum stem cell harvest of ≥2 × 10⁶ CD34⁺ cells/kg within four days of apheresis (NHL) or target stem cell harvest of ≥6 × 10⁶ CD34⁺ cells/kg within four days of apheresis (MM), compared with patients receiving placebo + G-CSF in both age groups. Collectively, these data suggest that stem cell mobilization with plerixafor + G-CSF is superior to G-CSF alone in patients ≥60 and <60 years of age.

Stem cell mobilization is particularly challenging in elderly patients. Increasing patient age has been found to be significantly correlated with a lower probability of successful stem cell mobilization and lower total stem cell yields in both MM and NHL patients, likely because of a greater prevalence of unfavorable factors affecting stem cell yield, such as mobilization regimen and duration of chemotherapy(8, 18, 26). Indeed we observed that NHL patients ≥60 years in this study met target stem cell collection less often than those <60 years of age. Issues such as the method and criteria used to identify patients most likely to fail mobilization, the choice of mobilization regimen, and the timing of mobilization and re-mobilization, if necessary, become pronounced in the elderly patient population, because of the increased likelihood of mobilization failure and decreased physical ability to tolerate certain mobilization regimens(27, 28). As such, options to induce a good clinical outcome in these older patients, such as re-mobilization efforts or modified dosing, need to be carefully considered in the clinical management of this group.

In the 3101 and 3102 studies the most commonly reported adverse reactions in the plerixafor group for both age categories were diarrhea, nausea, fatigue, and injection-site reaction. Furthermore, no unexpected adverse events were observed in older patients, a particularly relevant point given the increased prevalence of comorbidities in the geriatric cancer patient population (29). For example, no serious renal complications were observed in the plerixafor arm, which can sometimes be a concern in elderly patients in this disease setting. Thus, plerixafor + G-CSF significantly increased the proportion of patients that could proceed to ASCT without any added toxicity over G-CSF alone. This is an important consideration, particularly for elderly patients, who are less able to tolerate the side effects associated with chemotherapy-based mobilization regimens. Although our study does not compare the efficacy and safety of plerixafor + G-CSF vs. chemotherapy-based mobilization regimens, our findings coupled with data from the literature(30) could suggest that plerixafor + G-CSF, with its high efficacy and low toxicity, may be a more appropriate mobilization regimen for elderly patients than chemotherapy-based regimens.

Despite the observation that elderly patients may experience greater difficulty in mobilization, studies of elderly patients with NHL or MM have found outcomes following HDT/ASCT to be comparable between older and younger patients(31, 32). Elderly NHL patients (≥60 years) did not have a significantly higher rate of treatment-related mortality or a lower rate of 4-year event-free survival following HDT/ASCT, compared with a younger matched cohort(31). Patients with MM ≥70 years who had undergone HDT/ASCT showed response rates, median time to progression, and median overall survival that were not significantly different from those of a younger matched cohort(32). In light of these study results, our findings suggest that patients with NHL and MM who are mobilized with plerixafor + G-CSF and more likely to proceed to ASCT can expect to experience outcomes from HDT/ASCT that are similar to those of younger patients.

Taken together, these results demonstrate that plerixafor + G-CSF is an effective and well-tolerated stem cell mobilization regimen in patients ≥60 years. The efficacy of plerixafor + G-CSF for stem cell mobilization was superior to G-CSF alone in both younger and older patients. Furthermore, treatment with plerixafor + G-CSF in older patients did not increase the frequency or range of adverse events, compared to G-CSF alone. Based on these data, the upfront use of plerixafor with G-CSF should be considered an option for stem cell mobilization in patients ≥60 years of age with NHL or MM who are candidates for autologous stem cell transplantation.