Plerixafor Plus G-CSF Is An Effective Regimen to Mobilize Hematopoietic Stem Cells in NHL Patients with Circulating Peripheral Blood CD34+ Cells/μl < 10.

Abstract Abstract 33 Background: Circulating levels of peripheral blood (PB) CD34+ cells/μl are a strong predictor of hematopoietic stem cell (HSC) yields in patients with non-Hodgkin's lymphoma (NHL) undergoing autologous HSC transplantation (auto-HSCT), and are routinely monitored to optimize the timing and success of HSC collection after cytokine ± chemotherapy mobilization. The threshold PB CD34+ cell count to initiate apheresis varies from 5-20 cells/μl, depending on the institution. This analysis compared the efficacy of plerixafor + G-CSF to placebo + G-CSF for HSC mobilization in NHL patients with pre-apheresis PB CD34+ cells/μl <10. Methods: Data were obtained from a randomized, double-blind, phase 3 clinical trial comparing the safety and efficacy of plerixafor (0.24 mg/kg/day SC) + G-CSF (10 μg/kg/day) to placebo + G-CSF for mobilization and auto-HSCT in NHL patients. PB CD34+ cell count was measured on Day 4, before the first plerixafor/placebo dose, and on Day 5, 10-11 hours post study drug treatment. The proportion of patients collecting ≥2 × 106 (minimal) or ≥5 × 106 (optimal) CD34+ cells/kg, apheresis yields, and time to engraftment were compared between the plerixafor and placebo groups for patients with PB CD34+ cells/μl <10. Results: 77/150 (51%) patients and 73/148 (49%) patients in the plerixafor and placebo groups, respectively, had PB CD34+ cells/μl <10 on Day 4, prior to the first dose of study drug. Patient characteristics were similar between both groups. As shown in Table 1, addition of plerixafor to G-CSF resulted in a statistically significant increase in the absolute PB CD34+ cells/μl on Day 5 compared to G-CSF alone (p<0.001). The median fold increase in PB CD34+ cells from Day 4 to Day 5 was significantly higher in plerixafor-treated patients vs. placebo-treated patients: 6.0-fold vs. 1.6-fold (p<0.001). In these hard to mobilize patients, the median CD34+ cell yield after 2 days was significantly higher with plerixafor + G-CSF compared to placebo + G-CSF: 2.92 vs.0.94 × 106 cells/kg (p<0.001), respectively. The median CD34+ cell yield after 4 days was also significantly higher in the plerixafor vs. placebo groups: 3.96 vs.1.25 × 106 cells/kg (p<0.001). Plerixafor + G-CSF allowed a significantly greater proportion of patients with PB CD34+ cells/μl <10 to collect the minimal cell dose in 4 apheresis days: 77.9% vs. 34.2 % patients in the plerixafor and placebo group, respectively collected ≥2 × 106 CD34+ cells/kg in 4 days (p<0.001). The success rate of collecting the ≥5 × 106 CD34+ cells/kg in 4 days was 40.3% with plerixafor + G-CSF compared to only 9.6% with placebo + G-CSF (p<0.001). The proportion of patients collecting the optimal or minimal cell dose in 2 days was also significantly higher in the plerixafor vs. placebo group (p<0.001). The median time to platelet (19-21 days) and neutrophil (10-11 days) engraftment was similar in both groups. Similar, statistically significant increases in PB CD34+ cell collections were obtained when the efficacy of plerixafor + G-CSF was compared to placebo + G-CSF, in patients with a Day 4 PB CD34 cells/μl<20 (data not shown). Conclusions: Plerixafor + G-CSF allowed collection of the minimal transplantable cell dose in 78% patients with PB CD34+ cells/μl <10. These data show that adding plerixafor to G-CSF substantially reduces the risk of mobilization failure in patients with NHL predicted to be poor mobilizers based on low PB CD34+ cell counts. Thus, mobilization with plerixafor + G-CSF in patients with PB CD34+ cells/μl <10 increases stem cell collection efficiency allowing patients to pursue auto-HSCT with more optimal cell doses. Disclosures: Maziarz: Genzyme Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Micallef:Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bolwell:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Calandra:Genzyme Corporation: Consultancy, Equity Ownership. DiPersio:Genzyme Corporation: Honoraria.

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Mobilization with Plerixafor (Mozobil ®)Plus G-CSF Results in Superior Day 1 Collection of CD34+ Cells Compared to Placebo Plus G-CSF: Results From Two Randomized Placebo-Controlled Trials in Patients with Multiple Myeloma or Non-Hodgkin's Lymphoma.

Blood ◽

10.1182/blood.v114.22.3224.3224 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3224-3224 ◽

Cited By ~ 1

Author(s):

Brian J. Bolwell ◽

Auayporn P. Nademanee ◽

Patrick Stiff ◽

Edward Stadtmauer ◽

Richard T. Maziarz ◽

...

Keyword(s):

Placebo Group ◽

Board Of Directors ◽

Research Funding ◽

Cell Yield ◽

P Value ◽

Employment Equity ◽

Advisory Committees ◽

Cell Dose ◽

Cd34 Cells ◽

Equity Ownership

Abstract Abstract 3224 Poster Board III-161 Background While most centers use 2 × 106 CD34+ cells/kg as the minimal cell dose for autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT), infusion of higher CD34+ cell dose is associated with better outcomes in patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL). Recent evidence suggests a correlation between CD34+ cell yield on Day 1 of collection and total CD34+ cell yield as well as post-transplant outcomes. This analysis was designed to: 1) compare Day 1 collection between patients with NHL or MM mobilized with plerixafor plus G-CSF or placebo plus G-CSF; and 2) determine whether Day 1 CD34+ cell yields correlated with the total mobilization yield and number of apheresis days. Methods Data were obtained from two prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trials that compared the safety and efficacy of plerixafor (0.24 mg/kg/day SQ) plus G-CSF (10 μg/kg/day) with placebo plus G-CSF for mobilization of HSC for auto-HSCT in patients with NHL (3101 Study) or MM (3102 Study). Pearson correlation coefficient was used to evaluate the association of day 1 CD34+ cell collection with total CD34+ cell yield and the number of days of apheresis. Results In the NHL trial, 150 patients were mobilized with plerixafor plus G-CSF and 148 patients underwent mobilization with placebo plus G-CSF. More than half the patients (55.3%) in the plerixafor group collected ≥2 × 106 CD34+ cells/kg on Day 1 of apheresis (Figure 1A). In contrast, 19.6% patients in the placebo group collected ≥ 2 × 106 CD34+ cells/kg on Day 1 of apheresis (p< 0.001). In the MM study, 148 patients were mobilized with plerixafor plus G-CSF and 154 patients were mobilized with placebo plus G-CSF. More than half the patients (52.7%) in the plerixafor group collected ≥6 × 106 CD34+ cells/kg on the first day of collection compared to only 16.9% patients in the placebo group (p<0.001; Figure 1B). There was a strong positive correlation between day 1 collection and the total CD34+ cell yield in patients with NHL (r= 0.86, p-value= <0.0001) or MM (r= 0.87, p-value= <0.0001) in both the plerixafor and placebo groups. For NHL patients, the median Day 1 collection was higher in the plerixafor group compared to the placebo group: 2.66 × 106 vs. 0.77 × 106 CD34+ cells/kg (p<0.001) and this translated into higher total CD34+ cell yields in the two groups respectively: 5.69 × 106 vs. 1.98 × 106 CD34+ cells/kg (p<0.001). Similarly, for MM patients, the median CD34+ cells/kg collected on Day 1 was higher in the plerixafor group compared to the placebo group: 7.01 × 106 vs. 2.29 × 106 CD34+ cells/kg (p<0.001) and this translated into better overall collection in the plerixafor vs. placebo groups: 10.96 × 106 vs. 6.18 × 106 CD34+ cells/kg (p<0.001). A negative correlation was observed between CD34+ cells collected on Day 1 and the number of days of apheresis performed in patients with NHL (r= -0.67, p-value=<0.0001) or MM (r= -0.50, p-value= <0.0001) in both the plerixafor and placebo groups. Consequently, better Day 1 collection in plerixafor-treated NHL or MM patients translated into significantly fewer apheresis days to achieve the target collection compared to placebo treated patients. Conclusions These data support previous reports demonstrating a strong correlation between day 1 CD34+ cell collection and total CD34+ cell yield and apheresis days. These data also demonstrate that addition of plerixafor to G-CSF allows significantly more patients to achieve the target cell collection within 1 day of apheresis compared to G-CSF alone. These findings support the observation that mobilization with plerixafor plus G-CSF reduces the number of apheresis days required to achieve the minimal or optimal cell dose to proceed to transplantation. Disclosures Bolwell: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nademanee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stadtmauer:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Genzyme Corp.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Micallef:Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Gandhi:Genzyme Corporation: Employment, Equity Ownership. DiPersio:Genzyme: Honoraria.

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Plerixafor (Mozobi ®)Plus G-CSF Is More Effective Than Placebo Plus G-CSF in Mobilizing CD34+ Hematopoietic Stem Cells in Patients with Multiple Myeloma Who Have Low (<20 cells/μl) Peripheral Blood CD34+ Cell Count.

Blood ◽

10.1182/blood.v114.22.3230.3230 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3230-3230 ◽

Cited By ~ 1

Author(s):

Auayporn P. Nademanee ◽

Edward Stadtmauer ◽

Ivana N Micallef ◽

Patrick Stiff ◽

Sachin Marulkar ◽

...

Keyword(s):

Placebo Group ◽

Cell Count ◽

Board Of Directors ◽

Research Funding ◽

Fold Increase ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cell Counts ◽

Cd34 Cells ◽

Equity Ownership

Abstract Abstract 3230 Poster Board III-167 Background Pre-apheresis peripheral blood (PB) CD34+ cells of < 20 cells/μl is a significant risk factor for poor hematopoietic stem cell (HSC) mobilization and collection in patients with multiple myeloma (MM) undergoing autologous HSC transplantation (auto-HSCT). PB CD34+ cells are routinely monitored to optimize the timing and success of HSC collection after mobilization with cytokines ± chemotherapy. This analysis was designed to compare the efficacy of plerixafor + G-CSF to placebo + G-CSF for mobilization in patients with MM who had pre-apheresis PB CD34+ cell counts < 20 cells/μl. We hypothesized that the addition of plerixafor to G-CSF would improve the stem cell yield in these patients with baseline CD34+ cells < 20 cells/μl. Methods Data were obtained from a prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trial that compared the safety and efficacy of plerixafor (0.24 mg/kg/day SC) + G-CSF (10 μg/kg/day) to placebo + G-CSF for mobilization and auto-HSCT in patients with MM. PB CD34+ cell count was measured on Day 4, prior to first plerixafor/placebo dose, and on Day 5, 10-11 hours post study treatment. The proportion of patients achieving the minimal (≥2 × 106 CD34+ cells/kg) or optimal (≥6 × 106 CD34+ cells/kg) cell doses in 2 apheresis days, apheresis yields, and time to engraftment were compared between the plerixafor and placebo groups for PB CD34+ cell count <10 cells/μl (PB<10) and <20 cells/μl (PB<20). Results In the plerixafor group (n=148), 27 (18%) and 56 (38%) patients had Day 4 PB CD34+ cells/μl <10 and <20 which was as expected identical to the 30 (19%) and 60 (39%) patients in the placebo group, respectively (n=154). Patient characteristics were similar in both groups. Plerixafor + G-CSF resulted in a statistically significant increase in the absolute PB CD34+ cells/ml on Day 5 compared to placebo + G-CSF (p<0.001; Table 1). For patients with PB <10, the median fold increase in PB CD34+ cells in the plerixafor (n = 27) vs. placebo (n = 30) groups was 9.6 vs. 2 (p<0.001). Similarly, for patients with PB <20 the median fold increase in PB CD34+ cells in the plerixafor (n = 56) vs. placebo (n = 60) groups was 6.6 vs. 2 (p<0.001).The median CD34+ cell yield after 2 aphereses was significantly higher in the plerixafor vs. placebo group: 5.44 vs.1.68 × 106 cells/kg (p<0.001; PB<10) and 7.06 vs. 3.27 × 106 cells/kg (p<0.001; PB <20). The proportion of patients achieving ≥2 × 106 CD34+ cells/kg in 2 aphereses was significantly higher in the plerixafor group compared to the placebo group: 92.6% vs. 43.3 % in patients with PB<10 (p<0.001), and 94.6% vs. 66.7% in patients with PB<20 (p<0.001). Similarly, the proportion of patients achieving ≥6 × 106 CD34+ cells/kg in 2 apheresis days was significantly higher in the plerixafor vs. placebo group: 40.7% vs. 3.3 % in patients with PB<10 (p<0.001), and 55.4% vs. 15% in patients with PB<20 (p<0.001). The median time to platelet (19-20 days) and neutrophil (11 days) engraftment was similar in both groups. Conclusions These data demonstrate that in patients with MM who are predicted to fail mobilization based on low PB CD34+ cell count, the addition of plerixafor to G-CSF allows for 2-day collection of the minimal and optimal cell dose in a greater proportion of patients compared to G-CSF alone. Thus, addition of plerixafor to G-CSF can decrease the risk of poor mobilization in patients with MM who have PB CD34+ cell counts < 20 or even < 10 cells/μl. Disclosures Nademanee: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stadtmauer:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Micallef:Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Calandra:Genzyme Corporation: Consultancy, Equity Ownership. DiPersio:Genzyme: Honoraria.

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Plerixafor (Mozobil ®)Plus G-CSF Is Effective in Mobilizing Hematopoietic Stem Cells in Patients with Concurrent Thrombocytopenia Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.3229.3229 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3229-3229 ◽

Cited By ~ 1

Author(s):

Ivana N Micallef ◽

Eric Jacobsen ◽

Paul Shaughnessy ◽

Sachin Marulkar ◽

Purvi Mody ◽

...

Keyword(s):

Stem Cell ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Platelet Counts ◽

Cd34 Cells ◽

Low Platelet Count ◽

Equity Ownership

Abstract Abstract 3229 Poster Board III-166 Introduction Low platelet count prior to mobilization is a significant predictive factor for mobilization failure in patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) undergoing autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT; Hosing C, et al, Am J Hematol. 2009). The purpose of this study is to assess the efficacy of HSC mobilization with plerixafor plus G-CSF in patients with concomitant thrombocytopenia undergoing auto-HSCT. Methods Patients who had failed successful HSC collection with any mobilization regimen were remobilized with plerixafor plus G-CSF as part of a compassionate use program (CUP). Mobilization failure was defined as the inability to collect 2 ×106 CD34+ cells/kg or inability to achieve a peripheral blood count of ≥10 CD34+ cells/μl without having undergone apheresis. As part of the CUP, G-CSF (10μg/kg) was administered subcutaneously (SC) every morning for 4 days. Plerixafor (0.24 mg/kg SC) was administered in the evening on Day 4, approximately 11 hours prior to the initiation of apheresis the following day. On Day 5, G-CSF was administered and apheresis was initiated. Plerixafor, G-CSF and apheresis were repeated daily until patients collected the minimum of 2 × 106 CD34+ cells/kg for auto-HSCT. Patients in the CUP with available data on pre-mobilization platelet counts were included in this analysis. While patients with a platelet count <85 × 109/L were excluded from the CUP, some patients received waivers and were included in this analysis. Efficacy of remobilization with plerixafor + G-CSF was evaluated in patients with platelet counts ≤ 100 × 109/L or ≤ 150 × 109/L. Results Of the 833 patients in the plerixafor CUP database, pre-mobilization platelet counts were available for 219 patients (NHL=115, MM=66, HD=20 and other=18.). Of these, 92 patients (NHL=49, MM=25, HD=8 and other=10) had pre-mobilization platelet counts ≤ 150 × 109/L; the median platelet count was 115 × 109/L (range, 50-150). The median age was 60 years (range 20-76) and 60.4% of the patients were male. Fifty-nine patients (64.1%) collected ≥2 × 109 CD34+ cells/kg and 13 patients (14.1%) achieved ≥5 × 106 CD34+ cells/kg. The median CD34+ cell yield was 2.56 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 68.5%. The median time to neutrophil and platelet engraftment was 12 days and 22 days, respectively. Similar results were obtained when efficacy of plerixafor + G-CSF was evaluated in 29 patients with platelet counts ≤ 100 × 109/L (NHL=12, MM=10, HD=3 and other=4). The median platelet count in these patients was 83 × 109/L (range, 50-100). The median age was 59 years (range 23-73) and 60.4% of the patients were male. The minimal and optimal cell dose was achieved in 19(65.5%) and 3(10.3%) patients, respectively. The median CD34+ cell yield was 2.92 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 62.1%. The median time to neutrophil and platelet engraftment was 12 days and 23 days, respectively. Conclusions For patients mobilized with G-CSF alone or chemotherapy ±G-CSF, a low platelet count prior to mobilization is a significant predictor of mobilization failure. These data demonstrate that in patients with thrombocytopenia who have failed prior mobilization attempts, remobilization with plerixafor plus G-CSF allows ∼65% of the patients to collect the minimal cell dose to proceed to transplantation. Thus, in patients predicted or proven to be poor mobilizers, addition of plerixafor may increase stem cell yields. Future studies should investigate the efficacy of plerixafor + G-CSF in front line mobilization in patients with low platelet counts prior to mobilization. Disclosures Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacobsen:Genzyme Corporation: Research Funding. Shaughnessy:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Mody:Genzyme Corporation: Employment, Equity Ownership. van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.1176.1176 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1176-1176 ◽

Cited By ~ 19

Author(s):

Julie Kanter ◽

Mark C. Walters ◽

Matthew M. Hsieh ◽

Lakshmanan Krishnamurti ◽

Janet Kwiatkowski ◽

...

Keyword(s):

Gene Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Globin Gene ◽

Advisory Committees ◽

Cell Dose ◽

Cd34 Cells ◽

Equity Ownership

Abstract β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms and long-term complications of severe sickle cell disease (SCD). LentiGlobin Drug Product (DP) is a gene therapy product containing autologous CD34+ cells transduced with the BB305 lentiviral vector. BB305 encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed in fetal hemoglobin (γ-globin). In two ongoing studies, subjects with transfusion-dependent β-thalassemia (Studies HGB-204 and HGB-205) or SCD (Study HGB-205) receiving LentiGlobin DP have demonstrated sustained expression of 3-9 g/dL therapeutic hemoglobin (HbAT87Q) and have shown marked improvements in clinical symptoms 1 year post-treatment. Study HGB-206 is a multi-center, Phase 1/2 safety and efficacy study of LentiGlobin DP in adults with severe SCD. We previously (ASH 2015) presented results from 2 subjects, who had 3 and 6 months of follow-up after LentiGlobin treatment. We now present data from 7 treated subjects, 4 of whom have ≥6 months of follow-up data. Subjects (≥18 years of age) with severe SCD (history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were screened for eligibility. Following bone marrow harvest (BMH), CD34+ cells were transduced with the BB305 vector. Subjects underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. Safety assessments include adverse events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL). After infusion, subjects are monitored for hematologic engraftment, vector copy number (VCN), HbAT87Q expression, and other laboratory and clinical parameters. As of July 2016, 7 subjects with severe SCD (median age: 26 years, range 18-42 years) have received LentiGlobin DP in this study. All subjects successfully underwent BMH, with a median of 2 harvests required (range 1-4). Fifteen Grade 3 AEs in 5 subjects were attributed to BMH: pain (n=10), anemia (n=3) and VOC (n=2); all resolved with standard measures. Table 1 summarizes cell harvest, DP characteristics, and lab results. The median LentiGlobin DP cell dose was 2.1x10e6 CD34+ cells/kg (range 1.6-5.1) and DP VCN was 0.6 (0.3-1.3) copies/diploid genome. Median post-infusion follow-up as of July 2016 is 7.1 months (3.7-12.7 months). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 22 days (17-29 days). The toxicity profile observed from start of conditioning to latest follow-up was consistent with myeloablative conditioning with single-agent busulfan. To date, there have been no DP-related ≥Grade 3 AEs or serious AEs, and no evidence of clonal dominance or RCL. The BB305 vector remains detectable at low levels in the peripheral blood of all subjects infused, with median VCN 0.08 (0.05-0.13, n=7) at last measurement. All subjects express HbAT87Q, with a median of 0.4g/dL (0.1-1.0 g/dL, n=7) at 3 months; most subjects demonstrated modest increases over time, and the 2 subjects with the longest follow-up expressed 0.31 and 1.2 g/dL HbAT87Q at 9 months. All 4 subjects with ≥6 months of follow-up experienced multiple VOCs in the 2 years prior to study entry (2-27.5 VOCs annually). Since LentiGlobin DP infusion, 3 of these 4 subjects have had fewer VOCs, although this trend may be confounded by the short follow-up, the effects of transplant conditioning, and/or post-transplant RBC transfusions. The decrease in VCN between DP and peripheral cells contrasts with previous reports of successful LentiGlobin gene therapy in ongoing studies HGB-204 and HGB-205. The relatively low in vivo VCN in this study appears to result in the lower HbAT87Q expression seen to date. We are exploring multiple hypotheses as to the etiology of the VCN drop between DP and peripheral blood, including the adverse impact of sickle marrow pathology on HSCs, the adequacy of myeloablation, and the magnitude of the transduced cell dose. We will provide an update on study data and ongoing efforts to increase in vivo VCN in patients with SCD, such as increasing the transduced cell dose through alternate HSC procurement methods or enhancing the DP VCN through manufacturing improvements. Disclosures Kanter: Novartis: Consultancy. Walters:Bayer HealthCare: Honoraria; AllCells, Inc./LeukoLab: Other: Medical Director ; ViaCord Processing Laboratory: Other: Medical Director ; Leerink Partners, LLC: Consultancy; Kiadis Pharma: Honoraria; bluebirdBio, Inc: Honoraria. Kwiatkowski:Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy; Sideris Pharmaceuticals: Consultancy; Apopharma: Research Funding; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Kuypers:Children's Hospital Oakland Research Institute: Employment; bluebird bio: Consultancy. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Eli Lily: Research Funding.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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Lower Hematopoietic Progenitor Cell Counts and Yields at Subsequent Donations Is Influenced By a Shorter Inter-Donation Interval between the First and Subsequent Mobilizations

Blood ◽

10.1182/blood-2019-123492 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1962-1962

Author(s):

Sandhya R. Panch ◽

Brent R. Logan ◽

Jennifer A. Sees ◽

Bipin N. Savani ◽

Nirali N. Shah ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Time Interval ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Peripheral Blood Cd34 ◽

Cell Counts ◽

Cd34 Cells

Introduction: Approximately 7% of unrelated hematopoietic stem cell (HSC) donors are asked to donate a subsequent time to the same or different recipient. In a recent large CIBMTR study of second time donors, Stroncek et al. incidentally found that second peripheral blood stem cell (PBSC) collections had lower total CD34+ cells, CD34+ cells per liter of whole blood processed, and CD34+ cells per kg donor weight. Based on smaller studies, the time between the two independent PBSC donations (inter-donation interval) as well as donor sex, race and baseline lymphocyte counts appear to influence CD34+ cell yields at subsequent donations. Our objective was to retrospectively evaluate factors contributory to CD34+ cell yields at subsequent PBSC donation amongst NMDP donors. Methods. The study population consisted of filgrastim (G-CSF) mobilized PBSC donors through the NMDP/CIBMTR between 2006 and 2017, with a subsequent donation of the same product. evaluated the impact of inter-donation interval, donor demographics (age, BMI, race, sex, G-CSF dose, year of procedure, need for central line) and changes in complete blood counts (CBC), on the CD34+ cell yields/liter (x106/L) of blood processed at second donation and pre-apheresis (Day 5) peripheral blood CD34+ cell counts/liter (x106/L) at second donation. Linear regression was used to model log cell yields as a function of donor and collection related variables, time between donations, and changes in baseline values from first to second donation. Stepwise model building, along with interactions among significant variables were assessed. The Pearson chi-square test or the Kruskal-Wallis test compared discrete variables or continuous variables, respectively. For multivariate analysis, a significance level of 0.01 was used due to the large number of variables considered. Results: Among 513 PBSC donors who subsequently donated a second PBSC product, clinically relevant decreases in values at the second donation were observed in pre-apheresis CD34+ cells (73.9 vs. 68.6; p=0.03), CD34+cells/L blood processed (32.2 vs. 30.1; p=0.06), and total final CD34+ cell count (x106) (608 vs. 556; p=0.02). Median time interval between first and second PBSC donations was 11.7 months (range: 0.3-128.1). Using the median pre-apheresis peripheral blood CD34+ cell counts from donation 1 as the cut-off for high versus low mobilizers, we found that individuals who were likely to be high or low mobilizers at first donation were also likely to be high or low mobilizers at second donation, respectively (Table 1). This was independent of the inter-donation interval. In multivariate analyses, those with an inter-donation interval of >12 months, demonstrated higher CD34+cells/L blood processed compared to donors donating within a year (mean ratio 1.15, p<0.0001). Change in donor BMI was also a predictor for PBSC yields. If donor BMI decreased at second donation, so did the CD34+cells/L blood processed (0.74, p <0.0001). An average G-CSF dose above 960mcg was also associated with an increase in CD34+cells/L blood processed compared to donors who received less than 960mcg (1.04, p=0.005). (Table 2A). Pre-apheresis peripheral blood CD34+ cells on Day 5 of second donation were also affected by the inter-donation interval, with higher cell counts associated with a longer time interval (>12 months) between donations (1.23, p<0.0001). Further, independent of the inter-donation interval, GCSF doses greater than 960mcg per day associated with higher pre-apheresis CD34+ cells at second donation (1.26, p<0.0001); as was a higher baseline WBC count (>6.9) (1.3, p<0.0001) (Table 2B). Conclusions: In this large retrospective study of second time unrelated PBSC donors, a longer inter-donation interval was confirmed to be associated with better PBSC mobilization and collection. Given hematopoietic stem cell cycling times of 9-12 months in humans, where possible, repeat donors may be chosen based on these intervals to optimize PBSC yields. Changes in BMI are also to be considered while recruiting repeat donors. Some of these parameters may be improved marginally by increasing G-CSF dose within permissible limits. In most instances, however, sub-optimal mobilizers at first donation appear to donate suboptimal numbers of HSC at their subsequent donation. Disclosures Pulsipher: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Bellicum: Consultancy; Amgen: Other: Lecture; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Honoraria. Shaw:Therakos: Other: Speaker Engagement.

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Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽

10.1182/blood-2019-128467 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4451-4451

Author(s):

Sarah A. Holstein ◽

Sarah Cooley ◽

Parameswaran Hari ◽

Sundar Jagannath ◽

Catherine R Balint ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Nk Cell ◽

Single Infusion ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

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Updated Interim Results of the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Patients with Relapsed or Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) (CC-5013-CLL-009 Study)

Blood ◽

10.1182/blood.v120.21.3925.3925 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3925-3925 ◽

Cited By ~ 2

Author(s):

Clemens Wendtner ◽

Michael Hallek ◽

Graeme Fraser ◽

Anne-Sophie Michallet ◽

Peter Hillmen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Median Number ◽

Advisory Committees ◽

Starting Dose ◽

Purine Analog ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.

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Diacylglycerol Enhances Hematopoietic Stem/Progenitor Cell Development and Engraftment Via MAP Kinase Activation

Blood ◽

10.1182/blood.v122.21.174.174 ◽

2013 ◽

Vol 122 (21) ◽

pp. 174-174

Author(s):

Vera Binder ◽

Pulin Li ◽

Francesca Barrett ◽

Alex Leung ◽

Leonard I. Zon

Keyword(s):

Cord Blood ◽

Map Kinase ◽

Board Of Directors ◽

Marrow Transplantation ◽

Fluorescent Protein ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Equity Ownership ◽

Marrow Cells

Abstract Hematopoietic stem and progenitor cells (HSPCs) are exposed to a variety of intrinsic and extrinsic factors regulating all processes needed during development, and for successful engraftment after transplantation. In order to decipher the molecular pathways that may promote engraftment of HSPCs after marrow transplantation, we performed a competitive transplantation screen using chemical genetics in zebrafish. Green fluorescent protein-labeled kidney marrow cells (equivalent to mammalian bone marrow cells) were treated ex vivo with single compounds of a chemical library of known biologically active compounds, and administered by retro-orbital venous injection to lethally irradiated recipient zebrafish. About 500 chemicals were screened. Untreated kidney marrow cells labeled with a red fluorescent protein were used as competitors. Imaging-based assessment of short-term engraftment demonstrated that 1,2-Didecanoylglycerol, a membrane permeable but non-physiologic analogue of diacylglycerol (DAG), significantly improved engraftment compared to competitor cells. Follow-up by FACS analysis showed a 3.5 fold increase of long-term repopulating units after DAG treatment. To interrogate whether DAG treatment not only affects HSPCs under transplant conditions, but also during normal embryonic development, we treated zebrafish embryos within the time window of HSC formation in the dorsal aorta. DAG treatment increased expression of the HSPC markers Runx1 and c-myb in the AGM (Aorto-Gonad-Mesonephros). Treatment after HSC specification also led to an upregulation of HSPC markers in the caudal hematopoietic tissue (equivalent to fetal liver in mammals). These data suggest that DAG affects not only HSC formation, but also migration and engraftment of HSPCs as hematopoiesis transitions from the AGM to the CHT during development. To determine whether HSPCs respond to DAG in a cell autonomous manner, and to identify the underlying molecular mechanism, we treated human CD34+ cells from umbilical cord blood with DAG and performed RNA-seq analysis. Ingenuity Pathway Analysis of the 395 differentially expressed genes (q-value < 0.05) implicated the MAP kinase pathway as an upstream regulator. Human Phosphokinase array analysis of treated CD34+ showed ERK 1/2 activation. DAG is known to activate Protein Kinase C (PKC) with subsequent Raf kinase phosphorylation, which has the potential to activate ERK. Co-treatment of CD34+ cells with DAG and the ERK inhibitor PD98059 blocked upregulation of downstream ERK-targets (e.g. AREG, CSF2, EGR1, HMOX, SERPINE1, DUSP4, DUSP6), whereas the PI3K family inhibitor LY294002 and the p38 MAP kinase inhibitor SB202190 did not alter the effect of DAG on expression of these genes. This demonstrates that DAG activates ERK and its downstream targets. Our competitive marrow transplantation-based chemical screen has led to the discovery of 1,2-Didecanoylglycerol as a novel modulator of HSPC development and engraftment after transplantation. This discovery may be of clinical relevance to marrow or cord blood hematopoietic stem cell transplantation. Disclosures: Zon: FATE Therapeutics, Inc: Consultancy, Equity Ownership, Founder Other, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties; Stemgent, Inc: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Stocks, Stocks Other; Scholar Rock: Consultancy, Equity Ownership, Founder, Founder Other, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.

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Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Blood ◽

10.1182/blood.v126.23.737.737 ◽

2015 ◽

Vol 126 (23) ◽

pp. 737-737

Author(s):

Paul G. Richardson ◽

Marcie Riches ◽

Nancy A. Kernan ◽

Joel A. Brochstein ◽

Shin Mineishi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Final Analysis ◽

Occlusive Disease ◽

Sinusoidal Obstruction Syndrome ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), is a rare and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Severe cases, historically defined by multi-organ dysfunction (MOD), may be associated with mortality rates of >80%. There is no FDA-approved treatment for VOD/SOS. Defibrotide (DF) has a proposed mechanism of action that includes stabilization of endothelial cells and restoration of thrombo-fibrinolytic balance. Earlier analyses of a pivotal phase 3 trial of DF in VOD/SOS plus MOD (Richardson et al. Blood. 2009;114:Abstract 654) underpinned approval of DF in the EU to treat severe hepatic VOD/SOS after HSCT. Additional data were obtained at the request of US health authorities. Here we present the final analysis: day +100 survival (primary endpoint) and complete response (CR; secondary). Methods This was a multicenter, open-label, phase 3 historical control (HC) study assessing DF. Eligible patients met Baltimore VOD/SOS criteria (total bilirubin ≥2.0 mg/dL with ≥2 of: hepatomegaly, ascites, or 5% weight gain) by day +21 post-HSCT, plus MOD (renal [trebling of creatinine levels, reduced creatinine clearance, or dialysis] and/or pulmonary [oxygen saturation ≤90%, need for oxygen supplementation/ventilator dependence]) by day +28 post-HSCT. Exclusion criteria included severe graft-versus-host disease (GvHD) of liver or gut, clinically significant bleeding, or need for ≥2 pressors. HC patients were reviewed for inclusion/exclusion criteria in a sequential review of medical charts starting 6 months prior to use of DF at each site; a blinded medical review committee made the final determination of HCs unequivocally meeting criteria for VOD/SOS with MOD. DF dose was 25 mg/kg/d in 4 divided 2-hour IV infusions q6h; recommended treatment duration was ≥21 days. Primary endpoint was day +100 survival. CR by day +100 was a secondary endpoint. Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival (ie, ventilator and/or dialysis dependency at entry, age ≤/>16 years, transplant type, and prior HSCT). Analyses included patients treated with DF and HCs. Results There were 102 patients in the DF group and 32 cases selected as HCs. Baseline characteristics were similar in the DF and HC groups: mean age (26 and 25 years; 43% and 44% ≤16 years), allogeneic graft (88% and 84%), prior HSCT (13% and 9%), ventilator- and/or dialysis-dependent at study entry (33% and 22%), myeloablative conditioning (87% and 94%), and the most common underlying diseases (acute leukemias: 45% and 47%), respectively. In the DF-treated group, common GvHD medications included tacrolimus (49%), methotrexate (41%), and cyclosporine (38%); in the HC group, common medications were cyclosporine (72%) and methotrexate (63%). Survival at day +100 in the DF and HC groups was 38% and 25%, respectively. The propensity-stratified difference in survival was 23.0% (95.1% CI, 5.2-40.8, P = .0109). Respective observed CR rates by day +100 were 25.5% and 12.5%, and the propensity-stratified difference in CR was 19.0% (95.1% CI, 3.5-34.6, P = .0160). Comparing the earlier EU and final analyses, the survival rates at day +100 in each group did not vary; however, the propensity adjusted final analysis provided a different level of statistical significance. Day +100 CR rates in the original analysis were slightly lower in both arms at 24% and 9% due to increased data capture to investigate CR; the P value was essentially unchanged. For the DF group, 45% had an adverse event (AE) at least possibly related to study drug, and 21% had a serious AE at least possibly related to study drug. In this very sick population, percentages of patients with ≥1 AE leading to death were similar between DF and HC patients (64% and 69%), as were hemorrhagic AEs (64%, 75%) and hypotension (39%, 50%). Conclusions Based on observed study data and using a propensity-adjusted rate difference estimator, patients treated with DF had a 23% reduction in risk of death by day +100 and 19% improvement in CR rate. Overall incidence of hemorrhage and fatal AEs were similar between groups with AEs consistent with those expected in this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Marizomib, pmalidomide, and low dose dexamethasone in RR MM. Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. . Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Guinan:Gentium SpA/Jazz Pharmaceuticals: Other: My institution received fees for research.. Martin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Steinbach:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Krishnan:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Jazz: Consultancy; Millenium: Speakers Bureau. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding. Rodriguez:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Doyle:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. D'Agostino:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Massaro:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Iacobelli:Gentium SpA: Employment. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Gentium SpA: Other: Personal fees during conduct of the study.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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