Bridger, Gary

Abstract Introduction: We previously reported that plerixafor + G-CSF was as safe as and more effective than placebo + G-CSF in mobilizing hematopoietic stem cell for autologous transplant in patients with non-Hodgkins lymphoma (NHL) through 100 days follow-up (DiPersio ASH 2007). We report herein the 12 months data. Methods: This was a phase 3, multicenter, randomized, double-blind, placebo-controlled study. NHL patients requiring an autologous hematopoietic stem cell transplant were eligible. Patients received G-CSF (10 μg/kg) subcutaneously daily for up to 8 days. Beginning on evening of Day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on morning of Day 5, patients began daily apheresis for up to 4 days or until ≥ 5 x 106 CD34+cells/kg were collected. We report herein the 12 months graft durability and hematology data. Results: As reported previously, 89/150 (59%) patients in the plerixafor group and 29/148 (20%) patients in the placebo group met the primary endpoint of collecting ≥ 5 x 106 CD34+ cells/kg in ≤ 4 days of apheresis, p < 0.001. 135 patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation. Median time to neutrophil and platelet engraftment was similar in both groups. There were no differences in graft durability through 12 months follow-up between the two groups. Two plerixa for treated patients had graft failure (one had pre-existing MDS and one developed AML). One plerixafor-treated patient had delayed platelet engraftment. The hematology profiles were similar between the two groups through 12 months follow-up, except that patients in the plerixafor group had significantly higher platelet count at 12 months than patients in the placebo group (p=0.026) (Table 1). During the 12 months follow-up, 14/135 (10.4%) patients in plerixafor group and 10/82 (12.2%) patients in the placebo group died. 7/14 in the plerixafor group and 5/10 in the placebo group died of disease progression. Plerixafor + G-CSF Placebo + G-CSF Hematology data presented as mean ± SD and n= number of patients with available data aAll patients who underwent transplantation bAll patients who underwent transplantation and had laboratory data at the study visit cP values were NS for all variables at all time points between groups except for platelet count at 12 months (p=0.026) Graft durability (n, %) 100 daysa 128/135 (94.8%) 78/82 (95.1%) 6 monthsb 120/123 (97.6%) 77/78 (98.7%) 12 monthsb 110/112 (98.2%) 65/65 (100.0%) Platelet (x 109/L) 100 days 183 ± 83 (n= 113) 169 ± 81 (n=63) 6 months 190 ± 78 (n=100) 180 ± 77 (n=64) 12 monthsc 209 ± 81 (n=50) 170 ± 78 (n=37) Neutrophils (x 109/L) 100 days 3.1 ± 1.7 (n=107) 3.2 ± 2.1 (n=61) 6 months 3.3 ± 1.4 (n=98) 3.8 ± 2.6 (n=64) 12 months 3.5 ± 1.4 (n=50) 4.2 ± 2.7 (n=38) Hemogloblin (mg/dL) 100 days 12.3 ± 1.5 (n=112) 12.3 ± 1.5 (n=63) 6 months 12.5 ± 1.5 (n=100) 12.4 ± 1.5 (n=64) 12 months 13.0 ± 1.4 (n=50) 12.7 ± 1.6 (n=37) Conclusions: The addition of plerixafor to G-CSF resulted in higher CD34+ cell collection in fewer days of apheresis and higher proportion of patients proceeding to transplant than G-CSF alone. Importantly, this 12 months report showed that transplants with cells collected with plerixafor resulted in graft durability rates that were similar to cells collected with G-CSF alone.

Abstract Introduction: The impact of transplanted CD34+ cell dose on clinical outcomes remains controversial. The purpose of this study was to examine the relationship between CD34+ cell dose transplanted and platelet, neutrophil, and lymphocyte counts at 100 days, 6, and 12 months following autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Methods: Data were obtained from two phase 3 clinical studies that compared the safety and efficacy of plerixafor and G-CSF with placebo and G-CSF in mobilization of hematopoietic blood stem cells for autologous transplantation in NHL patients and in MM patients. The details of the study designs and preliminary safety and efficacy outcomes have been reported (DiPersio, ASH 2007). The following data were obtained from the two clinical study databases: number of CD34+ cells transplanted (first transplant only) as determined by a central laboratory, absolute neutrophil, platelet, red blood cell, and lymphocyte counts at 100 days, 6, and 12 months post-transplant. The proportions of patients who had platelet ≥150 x 109/L or neutrophil ≥2.5 x 109/L or lymphocyte ≥0.5 x 109/L at 100 days, 6, and 12 months were compared among these transplanted CD34+ cell dose categories regardless of mobilization treatment: 2–4 x 106 cells/kg, >4–6 x 106 cells/ kg, and > 6 x 106 cells/kg. Two separate analyses were performed, one for NHL patients and one for MM patients. Results: For the NHL study, 135/150 (90.0%) patients in the plerixafor group underwent transplantation after initial mobilization compared with 82/148 (55.4%) patients in the placebo group, p<0.001. The mean number of CD34+ cells transplanted was 6.06 ± 2.98 x 106 (median 5.41, range 1.79–17.6) for the plerixafor-treated patients and 4.09 ± 1.56 x 106 (median 3.85, range 1.98–8.7) for the placebo-treated patients, p<0.001. For the MM study, 142/148 (95.9%) patients in the plerixafor group and 136/154 (88.3%) patients in the placebo group underwent transplantation. The mean number of CD34+ cells transplanted was 5.84 ± 2.64 x 106 (median 5.34, range 1.9 to 16.7) for the plerixafor-treated patients and 4.37 ± 2.01 x 106 (median 3.98, range 1.8 to 16.9) CD34+ cells/kg for the placebo- treated patients. A significant linear trend with increasing proportion of patients with platelet count ≥150 x 109/L with increasing transplanted cell dose categories was observed at 100 days, 6, and 12 months for NHL patients and at 100 days for MM patients (Table 1). There were no apparent significant relationships between transplanted cell dose categories and other hematopoietic parameters. Table 1: Analysis of percentage of patients reaching a platelet count of ≥ 150 x 109/L by transplanted cell dose categories Transplant Cell Dose (CD34+ cells/kg) 2–4 x 106 ≥ 4–6 x 106 ≥ 6 x 106 P value* NHL Patients N=76 N=75 N=66 100 days 28 (48.3%) 42 (66.7%) 45 (81.8%) <0.001 6 months 31 (56.4%) 36 (66.7%) 42 (76.4%) 0.026 12 months 18 (56.3%) 21 (80.8%) 24 (82.8%) 0.020 MM Patients N=75 N=82 N=64 100 days 41 (68.3%) 57 (90.5%) 47 (88.7%) 0.004 6 months 48 (78.7%) 61 (89.7%) 51 (87.9%) 0.147 12 months 25 (73.5%) 33 (82.5%) 26 (81.3%) 0.435 For all transplanted cell dose categories, the proportions of patients are based on the number of patients with available data at each time point.*p-value for testing linear trend using Mantel-Haenszel Chi-square test Conclusions: Results from these ad hoc analyses confirm previous reports that transplanted cell dose may be associated with better long-term platelet recovery. Due to the small sample size in each transplanted cell dose category and the nature of ad hoc analyses, further studies are warranted to determine if the introduction of plerixafor will allow the mobilization and transplantation of higher quantity of CD34+ cells, which may positively influence long-term hematopoietic recovery.

Abstract Introduction: We previously reported that plerixafor + G-CSF was as safe as and more effective than placebo + G-CSF in mobilizing hematopoietic stem cell for autologous transplant in patients with multiple myeloma (MM) through 100 days follow-up (DiPersio ASH 2007). We report herein the 12 months data. Methods: This is a phase 3, multi-center, randomized (1:1), double-blind, placebocontrolled study. Multiple myeloma patients requiring an autologous hematopoietic stem cell transplant, in first or second complete or partial remission were eligible. Patients received G-CSF (10μg/kg/day) subcutaneously for up to 8 days. Beginning on evening of Day 4 and continuing daily for up to 4 days, patients received either plerixafor (240μg/kg) or placebo subcutaneously. Starting on Day 5, patients began daily apheresis for up to 4 days or until ≥ 6 x 106 CD34+cells/kg were collected. We report herein the 12 months graft durability and hematology data. Results: As reported previously, the primary endpoint of collecting ≥ 6 x 106 CD34+ cells/kg in ≤ 2 days of apheresis was met in 106/148 (71.6%) patients in the plerixafor group and 53/154 (34.4%) patients in the placebo group, p<0.001. 142 (96%) patients in plerixafor group and 136 (88%) patients in placebo group underwent transplantation. Median time to PMN and PLT engraftment was similar in both groups. Through 12 months follow-up, there were no differences in graft durability and hematology profiles between groups (Table 1). Over the 12 months, 6/142 (4.2%) patients in the plerixafor group and 5/136 (3.7%) patients in the placebo group died. Of the patients who died, 2 patients in the plerixafor group and 2 patients in the placebo grouped died due to disease progression. Plerixafor + G-CSF Placebo + G-CSF Hematology data presented as mean ± SD and n=number of patients with available data P values were NS for all variables at all time points between groups aAll patients who underwent transplantation bAll patients who underwent transplantation and had laboratory data at the study visit Graft durability (n, %) 100 daysa 140/142 (98.6%) 133/136 (97.8%) 6 monthsb 133/135 (98.5%) 125/127 (98.4%) 12 monthsb 127/128 (99.2%) 119/120 (99.2%) Platelet (x 109/L) 100 days 226 ± 80 (n=90) 210 ± 88 (n=87) 6 months 218 ± 67 (n=95) 209 ± 89 (n=93) 12 months 204 ± 69 (n=53) 205 ± 80 (n=54) Neutrophils (x 109/L) 100 days 3.3 ± 2.3 (n=88) 3.0 ± 1.7 (n=80) 6 months 3.4 ± 1.6 (n=90) 3.5 ± 1.8 (n=88) 12 months 3.1 ± 1.1 (n=52) 3.6 ± 2.1 (n=52) Hemoglobin (mg/dL) 100 days 12.5 ± 1.5 (n=89) 12.6 ± 1.3 (n=86) 6 months 12.7 ± 1.4 (n=94) 12.7 ± 1.6 (n=92) 12 months 12.9 ± 1.8 (n=53) 13.1 ± 1.5 (n=54) Conclusions: The addition of plerixafor to G-CSF resulted in higher CD34+ cell collection in fewer days of apheresis than G-CSF alone. Importantly, this 12 months report showed that transplants with cells collected with plerixafor resulted in graft durability rates that were similar to cells collected with G-CSF alone.

Abstract AMD3100, Plerixafor (A)+G-CSF (G) have safely and effectively allowed aHSC mobilization in Phase I and II studies. This Phase III, multicenter, randomized, double-blind, placebo controlled study compared the safety and efficacy of A+G versus Placebo (P)+G to mobilize and transplant patients with NHL. Methods: Adult NHL patients requiring an aHSC transplant, in first or second CR or PR were eligible to participate. Patients received G (10μg/kg/day) subcutaneously (SQ) for 4 days. On the evening of Day 4, patients received either A (240μg/kg SQ) or P. Patients underwent apheresis on Day 5 after an AM dose of G and 10–11 hours after administration of study treatment. Patients continued to receive the evening dose of study treatment, followed by AM dose of G and apheresis for up to a total of 4 aphereses or until ≥5 x 106 CD34+cells/kg were collected. Only study cells were used for transplant. Patients who failed to mobilize ≥2 x 106 CD34+cells/kg could enter into a rescue arm of A+G, without unblinding of randomized treatment. The primary endpoint was the percentage of patients who achieved ≥5 x 106 CD34+cells/kg in 4 or less aphereses days. All patients will be followed for ≥12 months post-transplant. Results: 298 patients were enrolled and randomized. All patients have completed 100 days follow-up and are included in this intent-to-treat analysis. Baseline characteristics were similar between groups. The primary endpoint was met in 89/150 (59%) patients in the A+G group and 29/148 (20%) patients in the P+G group, p<0.0001. 130/150 (87%) patients in the A+G group and 70/148 (47%) patients in the P+G group collected ≥2 x 106 CD34+cells/kg in 4 or less aphereses days, p<0.0001. Kaplan-Meir Estimates of Time to Trget Collection of ≥ × 106 CD34 + cells/kg Kaplan-Meir Estimates of Time to Trget Collection of ≥ × 106 CD34 + cells/kg The figure shows that more patients in the A+G group reached target after 1 day of apheresis than patients in the P+G group after 4 days of apheresis. A+G rescue was successful in 33/52 rescue patients in the P+G group and 4/10 rescue patients in the A+G group. 135 patients (90%) in A+G group and 82 patients (55%) in P+G group underwent transplantation. Median time to engraftment was Day 10 for PMN and Day 20 for platelets in both groups. Through 100 days, grafts were durable in all but 2 A+G (133/135) patients and in all P+G (82) patients. A+G patients experienced a higher incidence of GI effects (mild to moderate) and injection site erythema than P+G patients. There were 2 drug related serious adverse events in the A+G group and 1 in the P+G group. Conclusions: In this study, the addition of AMD3100 to G-CSF is generally safe and well tolerated and is superior to G-CSF alone for aHSC mobilization in NHL patients. A+G patients were statistically significantly more likely to achieve target cell collection quicker and to achieve sufficient cells for successful transplant than P+G patients.

Abstract AMD3100, Plerixafor (A)+G-CSF (G) have effectively allowed aHSC mobilization in Phase I and II studies. This Phase III, multicenter, randomized, double-blind, placebo controlled study compares the safety and efficacy of A+G Vs. placebo (P)+G to mobilize and transplant patients with MM. Methods: Adult MM patients requiring an aHSC transplant, in first or second CR or PR were eligible to participate. Patients were declared for single or tandem transplant with the second transplant occurring within 6 months from the first. Patients received G (10μg/kg/day) subcutaneously (SQ) for 4 days; on the evening of Day 4 they received either A (240μg/kg SQ) or P. Patients underwent apheresis on Day 5 after an AM dose of G and 10–11 hours after administration of study treatment. Patients continued to receive the evening dose of study treatment followed by AM dose of G and apheresis for up to a total of 4 apheresis or until ≥6 x 106 CD34+ cells/kg were collected. Patients who failed to collect ≥2 x 106 CD34+ cells/kg were eligible for rescue therapy with A+G, without unblinding of randomized treatment. Only study cells were used for transplant. The primary endpoint was the percentage of patients who achieved ≥6 x 106 CD34+ cells/kg in 2 or less apheresis days. All patients will be followed for ≥12 months post-transplant. Results: 302 patients were enrolled and randomized into the study. All have completed 100 days follow-up and are included in this intent-to-treat analysis. Baseline characteristics were similar between groups. The primary endpoint was met in 106/128 (72%) patients in the A+G group and 53/154 (34%) patients in the P+G group, p<0.0001. The figure shows that 54% of A+G patients reached target after 1 day of apheresis but 56% P+G patients required up to 4 days of apheresis to reach target. 7 patients in the P+G group required rescue therapy and all collected ≥2 x 106 CD34+ cells/kg after A+G rescue. 142 patients (96%) in A+G group and 136 patients (88%) in the P+G group underwent transplant. Tandem transplants were performed in 32 and 28 patients in A+G and P+G groups, respectively. Median time to engraftment was Day 11 for PMN and Day 18 for platelets in both groups. Grafts were durable in all patients in both group at ≥100 days post-transplant. Patients in the A+G group experienced more GI effects and injection site erythema than patients in the P+G group. These adverse events were generally mild. There were no drug related serious adverse events in either group. Conclusions: In this study, the addition of AMD3100 to G-CSF is generally safe and well tolerated and is superior to G-CSF alone for aHSC mobilization in MM patients. A+G patients were statistically significantly more likely to achieve target earlier than P+G patients and had successful transplant. Figure Figure

Abstract Background: AMD3100 (plerixafor)+G-CSF (A+G) was generally safe and more effective in mobilizing CD34+ hematopoietic stem cells compared to placebo+G-CSF (P+G) in a Phase III, multicenter, randomized, double-blind, placebo controlled study conducted in patients with non-Hodgkin’s lymphoma (NHL). In the intent-to-treat analysis, 78/148 (53%) patients in the P+G group and 20/150 (13%) patients in the A+G group failed to mobilize ≥ 2 x 106 CD34+ cells/kg, p<0.0001. Of these failure patients, 52 in the P+G group and 10 in the A+G group consented to enter into the rescue arm of the study. This abstract reports the outcomes of these rescue patients. Methods: Patients enrolled in the Phase III study who failed to mobilize ≥2 x 106 CD34+ cells/kg could enter into the rescue arm of the study and receive A+G. The patient’s treatment assignment in the study remained blinded. Following a rest period of ≥7 days, patients were given G (10 μg/kg/day) subcutaneously (SQ) for 4 days. In the evening around 10PM on Day 4, patients were given a dose of A (240 μg/kg SQ). On Day 5, all patients returned to clinic to receive a morning dose of G before apheresis. Patients continued to receive the evening dose of A followed by morning dose of G and apheresis the next day for up to a total of 4 aphereses or until ≥5 x 106 CD34+ cells/kg were collected. Pooled cells were allowed for transplantation. Results: After rescue therapy, 33/52 (63%) patients who previously failed P+G and 4/10 (40%) patients who previously failed A+G collected ≥2 x 106 CD34+ cells/kg. Seven of the 33 patients who previously failed with P+G collected ≥ 5 x 106 CD34+ cells/kg. Six of the ten A+G patients and 46/52 P+G patients were transplanted. Median time to PMN engraftment was Day 10 and Day 11 for the A+G and P+G groups, respectively. Median time to platelet engraftment was Day 22 and Day 20 for the A+G and P+G groups, respectively. One patient in the P+G group never had platelet counts > 50,000 and was counted as a failure to engraft, even though the patient was clinically stable through 6 months post-transplant. In the re-mobilized group, 9 patients died (2 patients were never transplanted and 7 patients had disease progression). Grafts were durable for ≥100 days in all 6 rescued A+G patients and all 41 rescued P+G patients who engrafted. The predominant adverse events were mild gastrointestinal effects (diarrhea, nausea, vomiting, and abdominal pain) and injection site reactions. There were no drug-related serious adverse events reported in these re-mobilized patients. Conclusions: The addition of AMD3100 to G-CSF successfully mobilized sufficient stem cells for transplant in 63% of NHL patients who previously failed mobilization with G-CSF alone. The high success rate is consistent with the Compassionate Use Protocol experience. AMD3100 was generally well tolerated. The 40% success rate in the patients who previously failed AMD3100+G-CSF suggests that re-mobilization with the same combination is a potentially useful strategy for similar patients.

Purpose This study evaluates the safety and efficacy of plerixafor (AMD3100), a CXCR4 antagonist, in mobilizing hematopoietic stem cells for autologous stem-cell transplantation in non-Hodgkin's lymphoma (NHL) patients. Patients and Methods This is a phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study. Patients with non-Hodgkin's lymphoma requiring an autologous hematopoietic stem-cell transplantation in first or second complete or partial remission were eligible. Patients received granulocyte colony-stimulating factor (G-CSF; 10 μg/kg) subcutaneously daily for up to 8 days. Beginning on evening of day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until ≥ 5 × 10 6 CD34+ cells/kg were collected. The primary end point was the percentage of patients who collected ≥ 5 × 10 6 CD34+ cells/kg in 4 or fewer apheresis days. Results This report presents all data for all patients (n = 298) through 12 months follow-up. Eighty-nine (59%) of 150 patients in the plerixafor group and 29 (20%) of 148 patients in the placebo group met the primary end point (P < .001). One hundred thirty-five patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation after initial mobilization. Median time to engraftment was similar in both groups. The most common plerixafor-associated adverse events were GI disorders and injection site reactions. Conclusion Plerixafor and G-CSF were well tolerated and resulted in a significantly higher proportion of patients with non-Hodgkin's lymphoma achieving the optimal CD34+ cell target for transplantation in fewer apheresis days, compared with G-CSF alone.

Abstract This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 μg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 × 106 CD34+ cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 × 106 CD34+ cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34+ cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.