Research Article Wiley Periodicals, Inc. 1017

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1 Research Article Safety and efficacy of upfront plerixafor 1 versus placebo 1 for mobilization of CD34 1 hematopoietic progenitor cells in patients 60 and <60 years of age with non-hodgkin s lymphoma or multiple myeloma Ivana N. Micallef, 1 * Patrick J. Stiff, 2 Edward A. Stadtmauer, 3 Brian J. Bolwell, 4 Auayporn P. Nademanee, 5 Richard T. Maziarz, 6 Angela M. Partisano, 7 Sachin Marulkar, 8 and John F. DiPersio 9 The efficacy and safety of plerixafor 1 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 1 significantly increased the proportion of patients achieving target stem cell yields, compared to placebo 1. In this analysis, we compare the efficacy and safety of plerixafor 1 versus placebo 1 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 was 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 1 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. Am. J. Hematol. 88: , VC 2013 Wiley Periodicals, Inc. Introduction Non-Hodgkin s lymphoma (NHL) and multiple myeloma (MM) have considerable impact in the older patient population. In 2012, 70,000 cases of NHL and 21,000 new cases of MM were diagnosed [1,2]. As 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 VC 2013 Wiley Periodicals, Inc. American Journal of Hematology 1017 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 () alone or 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 1 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. 1 Mayo Clinic, Rochester, Minnesota; 2 Loyola University, Chicago, Illinois; 3 University of Pennsylvania, Philadelphia, Pennsylvania; 4 Cleveland Clinic, Cleveland, Ohio; 5 City of Hope, Duarte, California; 6 Oregon Health and Science University, Portland, Oregon; 7 Sanofi Oncology, Cambridge, Massachusetts; 8 Genzyme, a Sanofi company, Cambridge, Massachusetts; 9 Washington University, St. Louis, Missouri Conflict of interest: INM: Consultancy, Sanofi (formerly Genzyme) and Advisory Board; PJS: None; EAS: Consultancy: Sanofi (formerly Genzyme); BJB: None; APN: Consultancy: Allos Therapeutics; RTM: Reasearch funding and Honoraria: Sanofi (formerly Genzyme); AP: Employment and Ownership interest: Sanofi (formerly Genzyme; SM: Employment and Ownership interest: Sanofi (formerly Genzyme); JFD: None. *Correspondence to: Ivana N. Micallef, Department of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN Micallef.Ivana@mayo.edu Received for publication 17 April 2013; Revised 24 July 2013; Accepted 25 July 2013 Am. J. Hematol. 88: , Published online 1 August 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: /ajh

2 Figure 1. Stem cell mobilization/apheresis schedule for phase III 3101 (NHL) and 3102 (MM) studies. was administered each morning for 4 days before first evening dose of plerixafor and each morning of apheresis. Plerixafor was administered 11 hr before initiation of apheresis. Apheresis was performed as 3 blood volumes 6 10% for up to 4 days. Events in shaded boxes were performed only if necessary. Plerixafor is currently approved in the U.S. and Europe for use in combination with 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-1a (SDF-1a) [24,25]. In two phase III, randomized, double-blind, placebo-controlled studies involving patients with NHL (3101 Study) and MM (3102 Study), plerixafor 1 was shown to significantly increase the proportion of patients achieving optimal CD34 1 stem cell yields for ASCT in fewer apheresis days, compared to placebo 1 [12,22]. We hypothesized that plerixafor may be more poorly tolerated in older patients due to multiple medical comorbidities and may not be as efficacious since older age is a known factor associated with poor mobilization. This report extends the and 3102-study analyses and compares the safety and efficacy of plerixafor 1 versus placebo 1 in patients with NHL or MM 60 years of age and <60 years of age undergoing stem cell mobilization for ASCT. Materials and 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 1 versus placebo 1 in mobilizing CD34 1 cells in patients years of age with NHL (3101 study) or MM (3102 study). Patients received either [10 lg/kg/day subcutaneously (SC)] 1 placebo or 1 plerixafor (0.24 mg/kg SC). The schedule for stem cell mobilization/apheresis is described in Fig. 1. Patients who failed to collect either CD34 1 cells/kg after 2 days of apheresis or CD34 1 cells/kg after 4 days of apheresis were eligible to enter an open-label rescue protocol as described previously [12,22]. 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 within 14 days of the first dose of on study, had >20% bone marrow involvement or received prior radioimmunotherapy (3101 study), or had received thalidomide, dexamethasone, lenalidomide, or bortezomib within 7 days of the first dose of (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 (10 lg/kg) SC daily for up to 8 days. Beginning on the evening of Day 4 and continuing daily for up to 4 days, patients received either plerixafor (0.24 mg/kg) or placebo SC. Starting on Day 5, patients began daily apheresis (3.0 blood volume 6 10%) for up to 4 days or until sufficient CD34 1 cells were collected ( cells/kg for patients with NHL and cells/kg for patients with MM). Within 5 weeks of last apheresis, patients received high-dose chemotherapy and underwent transplantation using collected CD34 1 cells (minimum cells/kg) according to local practice guidelines. Hematologic parameters for endpoint analysis Peripheral blood CD34 1 cell counts (cells/ml) were measured on the morning of Day 4, before dosing, and on the morning of Day 5, hr after plerixafor/placebo dosing. Fold-increase in peripheral blood CD34 1 cell counts was calculated as the ratio of median absolute peripheral blood CD34 1 cells/ll on Day 5 to that on Day 4. Neutrophil engraftment was defined as neutrophil count /L for 3 days or /L for 1 day. Platelet engraftment was defined as platelet count /L without a transfusion for the preceding 7 days. Graft durability was defined as maintenance of normal blood counts according to at least two of the following three criteria: platelet count > /L without transfusion for at least 2 weeks before the follow-up visit, hemoglobin level 10 g/dl with no erythropoietin support or transfusions for at least 1 month before the follow-up visit, absolute neutrophil count > /L with no for at least 1 week before the follow-up visit. Statistical analysis In the current multivariate analysis, the proportion of patients achieving minimum an ideal targets of CD34 1 cells/kg in 4 daysof apheresis and CD34 1 cells/kg in 4 days of apheresis (NHL 3101 study) or CD34 1 cells/kg in 2 days of apheresis and CD34 1 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 ( 1 Plerixafor and 1 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 American Journal of Hematology

3 TABLE I. 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 (n 5 93) (n 5 81) (n 5 57) (n 5 67) (n 5 79) (n 5 78) (n 5 69) (n 5 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) Median time since progression/relapse (months) (n) 4.0 (40) 4.0 (45) (8) 4.0 (3) 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) TABLE II. Efficacy Endpoints in Patients <60 and 60 years of Age in the 3101 and 3102 Studies 3101 Study (NHL) <60 years 60 years (n 5 93) (n 5 81) P a (n 5 57) (n 5 67) P b Primary endpoint: % achieving CD34 1 cells/kg within 4 days < <0.001 Secondary endpoint: % achieving CD34 1 cells/kg within 4 days < <0.001 Median total CD cells/kg collected (range) 6.6 ( ) 2.0 ( ) < ( ) 1.9 ( ) < % proceeding to transplant < < Study (MM) <60 years 60 years (n 5 79) (n 5 78) P a (n 5 69) (n 5 76) P b Primary endpoint: % achieving < <0.001 CD34 1 cells/kg within 2 days Secondary endpoint: % achieving <0.001 CD34 1 cells/kg within 4 days Median total CD cells/kg collected (range) 11.0 ( ) 7.0 ( ) ( ) 5.6 ( ) < % proceeding to transplant P values for comparisons between patients receiving plerixafor 1 versus placebo 1 in: a the <60 years group or b the 60 years group. 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 chisquare 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 years) and 64 years (range years), respectively. Baseline characteristics of the older and younger patient cohorts are described in Table I. Baseline characteristics between the plerixafor 1 and placebo 1 groups for both age categories were similar. Mobilization efficacy In both age groups, patients treated with plerixafor had a greater median increase in peripheral blood CD34 1 cells/ml 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 CD34 1 cells/kg within 4 days (NHL) or CD34 1 cells/kg within 2 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 < ; MM: 73.4 vs. 44.9%, P < 0.001) (Table II). A greater proportion of patients receiving plerixafor achieved target stem cell collection (NHL: CD34 1 cells/kg; MM: CD34 1 cells/kg) on each day of apheresis, compared with patients receiving placebo, regardless of age group (Figs. 2 and 3). However, patients in the NHL (but not MM) plerixafor 1 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 (Fig. 2). In addition, significantly more patients receiving plerixafor met the secondary endpoint of collecting a minimum of CD34 1 cells/kg within 4 days of apheresis (NHL) or a target of CD34 1 cells/kg within 4 days of apheresis (MM), compared to patients receiving placebo, regardless of age group (60 years: American Journal of Hematology 1019

4 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. 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 < ; MM: 75.9 vs. 60.3%, P ) (Table II). 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 cells/kg, P < ; MM: vs cells/ kg, P < ; <60 years: NHL: 6.65 vs cells/kg, P < ; MM: vs cells/kg, P ) (Table II). Of the 124 patients 60 years with NHL, 33 (26.6%) proceeded to the rescue protocol, including five of 57 (8.8%) patients in the plerixafor group and American Journal of Hematology

5 TABLE III. 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 (n 5 85) (n 5 47) (n 5 50) (n 5 35) (n 5 74) (n 5 69) (n 5 68) (n 5 67) Median infused CD34 1 cell dose/kg (range) Median time to neutrophil engraftment (range) (days) Median time to platelet engraftment (range) (days) 5.9 ( ) 3.6 ( ) 5.1 ( ) 4.3 ( ) 5.3 ( ) 4.0 ( ) 5.6 ( ) 3.9 ( ) 10 (8 14) 11 (8 13) 10 (8 30) 10 (9 13) 11 (2 17) 11 (9 21) 11 (9 29) 11 (9 21) 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. 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. 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 ) (Table II). 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 < ; MM: 93.7 vs. 88.5%, P ) (Table II). 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 III). 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 III). 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 1 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 1 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 1 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. 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. AEs, regardless of relationship to study drug, occurring in >10% patients are reported in Table IV. 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 IV). No serious renal complications were observed in the plerixafor arm; however, patients with compromised renal function were ineligible for study. 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 /ll 24-hr postapheresis; 1 week later, her platelet count was /ll. Fourteen days postapheresis, the patient continued to be thrombocytopenic with platelet counts of and /ll that later decreased to /ll. In the second case, a 50-year-old female NHL patient had her blood pressure (BP) drop from a baseline of 110/62 104/62 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/ American Journal of Hematology 1021

6 TABLE IV. 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 (n 5 172) (n 5 159) (n 5 126) (n 5 143) Blood and lymphatic system disorders Febrile neutropenia Cardiac disorders Gastrointestinal disorders Diarrhea Nausea Vomiting General disorders and administration site conditions Catheter site pain Fatigue Injection-site erythema Mucosal inflammation Edema peripheral Pain Pyrexia Infections and infestations Injury, poisoning, and procedural complications a Investigations b Metabolism and nutrition disorders Hypokalemia Hypomagnesemia Musculoskeletal and connective tissue disorders Arthralgia Back pain Bone pain Nervous system disorders Dizziness Headache Paresthesia Psychiatric disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Vascular disorders a 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. b Investigations included: alanine aminotransferase, aspartate aminotransferase, blood potassium, blood uric acid, gamma-glutamyltransferase, hepatic enzymes, liver function test, and platelet count. 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 paresthesia. Five patients (1.7%) within the placebo group also discontinued treatment due to AEs, which included nausea, vomiting, pyrexia, noncardiac chest pain, and atrial fibrillation. Discussion The subgroup analyses reported here describe the efficacy and safety of plerixafor 1 versus placebo 1 G- CSF in patients 60 years of age and <60 years of age enrolled in the 3101 [22] and 3102 [12] studies. was found to significantly increase the proportion of patients who achieved CD34 1 cells/kg within 4 days (NHL) or CD34 1 cells/kg within 2 days (MM) of apheresis, compared to patients receiving placebo 1 G- CSF in both age groups. Furthermore, plerixafor 1 also significantly increased the proportion of patients who achieved minimum stem cell harvest of CD34 1 cells/kg within 4 days of apheresis (NHL) or target stem cell harvest of CD34 1 cells/kg within 4 days of apheresis (MM), compared with patients receiving placebo 1 G- CSF in both age groups. Collectively, these data suggest that stem cell mobilization with plerixafor 1 is superior to 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 remobilization, 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 remobilization 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 1022 American Journal of Hematology

7 injection-site reaction. Furthermore, no unexpected AEs 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 1 significantly increased the proportion of patients that could proceed to ASCT without any added toxicity over 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 1 versus chemotherapy-based mobilization regimens, our findings coupled with data from the literature [30] could suggest that plerixafor 1, 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 OS 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 1 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 1 is an effective and well-tolerated stem cell mobilization regimen in patients 60 years. The efficacy of plerixafor 1 for stem cell mobilization was superior to alone in both younger and older patients. Furthermore, treatment with plerixafor 1 in older patients did not increase the frequency or range of AEs, compared to alone. Based on these data, the upfront use of plerixafor with should be considered an option for stem cell mobilization in patients 60 years of age with NHL or MM who are candidates for ASCT. Acknowledgments The studies included in this manuscript (3101 and 3102) [12,22] and the development of this manuscript was supported by Genzyme Corporation. The authors thank Anna Lau for providing editorial assistance. References 1. SEER. Available at: Accessed November SEER. Available at: Accessed November NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin s Lymphoma v NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma v Pasquini M. CIBMTR summary slides part 1. CIBMTR Newslett 2006;12: Philip T, Guglielmi C, Hagenbeek A, et al. Autologous Bone Marrow Transplant as compared with salvage chemotherapy in relapses of chemotherapysensitive non-hodgkin s lymphoma. N Engl J Med 1995;333: Fermand JP, Katsahian S, Divine M, et al. 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