Bendamustine (Treanda®), Etoposide and Dexamethasone (BED) Followed by GCSF Effectively Mobilizes Autologous Peripheral Blood Hematopoietic Stem Cells

Abstract Abstract 4126 Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for patients with advanced or treatment refractory multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Stem cell proliferation and mobilization can be enhanced though the addition of myelosuppressive chemotherapy to GCSF administration. Chemotherapeutic agents without cross resistance to prior therapies may support peripheral blood stem cell (PBSC) collection and improve patient outcomes by exacting a more potent direct anti-tumor effect prior to ASCT. Bendamustine (Treanda®) is a synthetic chemotherapeutic agent that shares structural similarities to both purine analog and alkylating agents without significant cross resistance to other compounds in either drug class. Bendamustine appears to have low stem cell toxicity in vitro, is well tolerated, and has activity in MM and NHL. We hypothesized that bendamustine's activity in patients with disease resistant to first line therapies makes it a logical candidate for chemotherapy based PBSC mobilization. Methods: Patients were eligible if they had relapsed or refractory MM, B-cell NHL or T-cell NHL and were candidates for ASCT. Other criteria included: age >18 years, ANC >1,500/mm3, platelets >100,000/mm3, adequate renal and hepatic function, <3 prior myelotoxic regimens, <6 cycles of lenalidomide, no prior failed mobilization attempt, and no prior pelvic/spinal irradiation. Patients received 1 cycle of BED therapy [bendamustine (120 mg/m2 IV d 1, 2 - provided along with financial support for this study by Teva Pharmaceuticals), etoposide (200 mg/m2 IV d 1– 3), dexamethasone (40 mg PO d 1– 4), delivered as an outpatient, followed by filgrastim (10 mcg/kg/day; starting on d 5 through end of collection)]. Apheresis was initiated when peripheral blood CD34 cell counts were >5/μL. The primary endpoint was successful mobilization, defined as collection of >2.0 × 106CD34 cells/kg. Adverse events (AEs) were graded using the CTCAE v4.0. Results: Twenty patients (16 MM, 3 B-cell NHL, 1 NK/T-cell NHL) were treated. The median age was 59 years (range 43–70), and the median number of prior therapies was 1 (range 1–3) for MM and 2 (range 2–3) for NHL patients. All patients (20/20) were successfully mobilized. The median number of CD34+ cells collected was 19.11 × 106/kg (Mean 22.49; range 4.35 to 55.51 × 106). All MM patients collected >10 × 106 CD34+cells/kg. The median time from BED mobilization therapy to the first day of CD34 stem cell collection was 12 days (mean 12.05; range 10 to 20 days). The median number of days of apheresis was 1 (mean 1.45; range 1 to 4). A predictable pattern of leucocyte nadir and recovery was demonstrated (88% of patients started apheresis between days 10–12). One patient (5%) was given plerixafor and for 2 patients (10%) the dose of GCSF was increased to 16 mcg/kg twice daily. Among the 20 patients mobilized and collected, 12 have thus far undergone ASCT and 100% (12/12) have achieved an unsupported neutrophil count >500/μL at an average of 14.3 days after PBSC infusion and a platelet count >20K/μL at an average of 10 days. Serious AEs (SAEs) were observed in 5 patients and 1 patient died due to disease progression. No unexpected grade 3 or greater treatment related SAEs were seen. Disease response assessments are ongoing. The original protocol design involved 3 agents (bendamustine, dexamethasone and GCSF [BDG]). After the first 3 patients enrolled, the mobilization regimen was modified to include etoposide because BDG did not yield a predictable pattern of leucocyte nadir and recovery, thus complicating timing for apheresis (median time to collection 22 days). The first 3 patients were censored from the analysis, however all 3 patients were successfully mobilized and collected. Conclusions: The initial experience with PBSC mobilization after BED in this phase II study suggests the regimen is safe and effective, while the use of BDG does not yield predictable CD34 kinetics. Time to neutrophil and platelet engraftment after ASCT appears unimpaired when compared with other chemotherapy based mobilization regimens. Large numbers of stem cells were rapidly mobilized and resulted in short durations of apheresis. No patient with MM collected <10 × 106 CD34+ cells/kg (sufficient for 2 ASCTs). The regimen was very well tolerated and these findings suggest that the role of bendamustine in PBSC mobilization should be further explored. Disclosures: Green: Teva Pharmaceuticals: Research Funding. Holmberg:Millenium: Research Funding; Otsuka: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding. Budde:Teva Pharmaceuticals: Research Funding. Gopal:Teva Pharmaceuticals: Research Funding.

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Bendamustine (Treanda®)-Based Regimens Are Effective In Mobilizing Peripheral Blood Hematopoietic Stem Cells For Autologous Transplantation

Blood ◽

10.1182/blood.v122.21.2033.2033 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2033-2033

Author(s):

Damian J. Green ◽

William I. Bensinger ◽

Leona Holmberg ◽

Theodore A. Gooley ◽

Brian G. Till ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

T Cell ◽

Disease Progression ◽

Peripheral Blood ◽

Median Number ◽

Cross Resistance ◽

Single Cycle ◽

Cd34 Cells ◽

Pbsc Mobilization

Abstract Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for patients with advanced or treatment refractory multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Stem cell proliferation and mobilization can be enhanced though the addition of myelosuppressive chemotherapy prior to GCSF administration. Chemotherapeutic agents without cross resistance to prior therapies may support peripheral blood stem cell (PBSC) collection and improve patient outcomes by exacting a more potent direct anti-tumor effect prior to ASCT. Bendamustine (Treanda®) is a synthetic chemotherapeutic agent that shares structural similarities to both purine analog and alkylating agents without significant cross resistance to other compounds in either drug class. Bendamustine appears to have low stem cell toxicity in vitro, is well tolerated, and has activity in MM and NHL, but the potential for the purine moiety to adversely impact stem cell reserve is unknown. We hypothesized that bendamustine’s activity in patients with disease resistant to first line therapies makes it a logical candidate for chemotherapy based PBSC mobilization and tested its impact on stem cell yield. Methods Patients were eligible if they had relapsed or refractory MM, B-cell NHL or T-cell NHL and were candidates for ASCT. Other criteria included: age >18 years, ANC >1,500/mm3, platelets >100,000/mm3, adequate renal and hepatic function, <3 prior myelotoxic regimens, <6 cycles of lenalidomide, no failed mobilization attempt, and no prior pelvic/spinal irradiation. Patients received 1 cycle of BED therapy [bendamustine (120 mg/m2 IV d 1, 2 - provided along with financial support for this study by Teva Pharmaceuticals), etoposide (200 mg/m2 IV d 1- 3), dexamethasone (40 mg PO d 1- 4), delivered as an outpatient, followed by filgrastim (initially 10 mcg/kg/d sc; starting on d 5 through end of collection)]. Apheresis was initiated when peripheral blood CD34 cell counts were >5/µL. The primary endpoint was successful mobilization, defined as collection of >2.0 x 106CD34 cells/kg. AEs were graded using the CTCAE v4.0. Results Thirty-seven patients (32 MM, 4B-cell NHL, 1 NK/T-cell NHL) were treated. The median age was 60 years (range 43-70). The median number of prior therapies was 1 (range 1-3) for MM and 2 (range 1-3) for NHL patients. All patients (37/37) were successfully mobilized. The median number of CD34+ cells collected was 19.43 x 106/kg (range 4.35 to 55.51 x 106). All MM patients collected >10 x 106 CD34+cells/kg. The median time from the start of BED mobilization therapy to the first day of CD34 stem cell collection was 12 days (range 9 to 20 days). The median number of apheresis days was 1 (range 1 to 4). A predictable pattern of leucocyte nadir and recovery was demonstrated (95% of patients started apheresis between days 9-13). Two patients (5%) were given plerixafor and for 2 patients (5%) GCSF was increased to 16 mcg/kg twice daily. Among the 37 patients mobilized and collected, 31 have thus far undergone ASCT and 100% (31/31) achieved an unsupported neutrophil count >500/µL at a median of 15 days (range 7-19) after PBSC infusion and a platelet count >20K/µL at a median of 11 days (range 8-14). Ten SAEs were observed in 8 patients and 1 patient died due to disease progression prior to ASCT. SAEs include: neutropenic fever (1, grade [GR] 3), bone pain (2, GR 3), renal insufficiency (1, GR 1), atrial fibrillation (1, GR 2), hypotension (1, GR 3), stroke (1, GR 2), and one patient accounted for 3 SAEs including GR 3 tumor lysis syndrome and sepsis and GR 5 disease progression. Among twenty-nine evaluable patients to date, responses include: CR= 4 PR=2, SD=19 and PD=4. The ORR to this single cycle of therapy was 21%. Conclusions PBSC mobilization with BED is safe and effective. BED is not an acute stem cell toxin. Large numbers of stem cells were rapidly mobilized and resulted in short durations of apheresis. No patient with MM collected <10 x 106 CD34+ cells/kg (sufficient for 2 ASCTs). Twenty-one percent of patients demonstrated a measurable response to a single cycle of BED therapy and an additional 65% of patients had stable disease. In patients who were transplanted, the time to neutrophil and platelet engraftment was comparable to other chemotherapy based mobilization regimens. The BED regimen was well tolerated and these findings suggest that the role of BED in PBSC mobilization should be further explored. Disclosures: No relevant conflicts of interest to declare.

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Impact of the Use of Bendamustine Immediately before the Collection of Hematopoietic Stem Cells in Lymphoma. a Study By the Geltamo Group

Blood ◽

10.1182/blood-2021-150769 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1771-1771

Author(s):

Mariana Bastos-Oreiro ◽

Javier Anguita ◽

José Fernández ◽

Ana Pilar Gonzalez ◽

Raul Córdoba ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Research Funding ◽

Median Number ◽

Control Group ◽

First Line ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Number Of Cycles ◽

Pbsc Mobilization

Abstract Introduction: Bendamustine is a hybrid alkylating agent with high efficacy in different haematological malignancies, especially for lymphomas. Data about the capacity of peripheral blood stem cell (PBSC) mobilization or a possible stem cell toxicity after the use of bendamustine are unclear, with sufficient number of PBSC after bendamustine- rituximab (B-R) combination used in first line but with scarce information in relapse, especially with the use of bendamustine immediately before mobilization. The aim of this study was to evaluate the influence on PBSC mobilization of bendamustine as the last previous regimen used before the collection of PBSC. Methods: This is a retrospective, multicentre study, which includes patients from 8 different GELTAMO centres in Spain. Forty-eight lymphoma patients who received bendamustine followed immediately by stem cell mobilization (SCM) were included. A single-centre control group of consecutive patients was included, matched by histology, age and number of previous lines; HIV+ patients were excluded. Results: We included 83 patients, 45 in the bendamustine group and 38 in the control group. Table 1 shows patient´s characteristics. Both groups are adequately balanced. No patients received previous lenalidomide, and none patient had previous transplant. In the bendamustine group, the median number of cycles administered was 4 (range 2-6). In 8 patients of the bendamustine group and 12 in the control group the mobilization was programmed after first-line treatment. In the remaining cases, mobilizations were performed after 1 st or 2 nd relapse treatment. In most of the patients, the mobilization regimen was performed only with G-CSF, although 7 patients in the control and 3 patients in bendamustine groups received alternative regimens such as ESHAP, DHAP or ICE. Ten patients in the bendamustine group received plerixafor as part of the 1 st attempt mobilization regimen. Median number of apheresis with the first attempt of mobilization was 1.5 in the bendamustine group vs 1.3 in the control group. In bendamustine group 8 patients didn't go to apheresis due to a low pre-mobilization CD34+ cell count in peripheral blood, compared with 2 patients in control group. Median pre-mobilization CD34+ cells and median number of mobilized CD34 cells obtained was significative lower with in bendamustine group (Table 1). Moreover, 10 patients in this group didn't mobilized with 1 st attempt (and in 4 of them and neither with the second mobilization attempt), compared with only 2 in the control group. Mobilization failure in the bendamustine group was more frequent in certain lymphoma subtypes (among the 10 failures, HL and FL were the most frequent, 40%, p=0.07, and 50%, p=0.051 respectively), and was also associated with number of previous lines of therapy (HR 4,1; p= 0.041), since 90% of the failures were patients mobilized at relapse, and only 1 as 1st line consolidation. No relationship was found between stage, doses, or number of cycles of bendamustine administered. Conclusion: Our results show that the collection of sufficient numbers of PBSC could be affected by the use of bendamustine immediately prior to mobilization, especially in more pre-treated patients. We continue working on expanding our series to confirm these results. Figure 1 Figure 1. Disclosures Bastos-Oreiro: Kite: Speakers Bureau; Gilead: Honoraria; BMS-Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Salar: Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau.

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Impact of Induction Treatment on Stem Cell Collection: A COVID Related Study

Blood ◽

10.1182/blood-2021-149812 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4848-4848

Author(s):

Brad Rybinski ◽

Ashraf Z. Badros ◽

Aaron P. Rapoport ◽

Mehmet Hakan Kocoglu

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Research Funding ◽

Median Number ◽

Cell Transplant ◽

Cd34 Cells ◽

Significant Difference ◽

Number Of Cycles ◽

Time Required ◽

Stem Cell Collection

Abstract Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant. Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of "lenalidomide containing regimen". In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles. Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829). 55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324). Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue. Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologous transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. Figure 1 Figure 1. Disclosures Badros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

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Stem Cell Dose and Time To Engraftment Does Not Predict Outcome After Autologous Stem Cell Transplantation For Relapsed Aggressive NHL

Blood ◽

10.1182/blood.v122.21.5542.5542 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5542-5542 ◽

Cited By ~ 1

Author(s):

Shane A Gangatharan ◽

John Kuruvilla ◽

Vishal Kukreti ◽

Armand Keating ◽

Manjula Maganti ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Entire Cohort ◽

Cell Dose ◽

Cd34 Cells

Abstract Introduction Autologous stem cell transplantation (ASCT) is the standard of care for relapsed aggressive lymphomas. Time to neutrophil and platelet engraftment is strongly correlated with CD34+ cell number infused but data are conflicting as to whether patients who receive greater numbers of CD34+ stem cells have improved outcomes. We sought to determine whether short term engraftment predicts progression-free survival (PFS) independent of other disease-specific prognostic factors. Methods From the Princess Margaret Cancer Centre transplant database, we identified patients undergoing ASCT for relapsed aggressive lymphoma between 2007-2011. Data were extracted on prognostic features at relapse/progression, stem cell collection, engraftment, and time to progression and death. All patients received platinum-based salvage chemotherapy and those with chemosensitivity were mobilised with cyclophosphamide, etoposide and filgrastim (minimum threshold 2x106 CD34 cells/kg) and proceeded to ASCT. Patients who failed initial mobilisation were remobilised using plerixafor. High-dose therapy consisted of etoposide 60mg/kg Day -4 and melphalan 180mg/m2 Day -3 with stem cells infused on Day 0. Filgrastim 300µg daily was started from Day +7 until neutrophil recovery to >1.0 x106/uL. Platelet engraftment was defined as an unsupported platelet count >20 x 109/L. Results 97 patients with DLBCL (n=66), transformed (n=24) and T-cell lymphoma (n=7) were reviewed. Median age was 54 (range 20-67), 61% were male and median IPI score on relapse was 2. Fifty one percent relapsed within 12 months of last therapy, and of the patients with B-cell lymphoma, 81% received rituximab prior to salvage chemotherapy. Median stem cell dose was 5.7x106 CD34+ cells/kg (range 1.69-17.82) with a median number of apheresis sessions to achieve this of 2 (range 1-4). Median time to neutrophils >0.5x106/uL was 11 days (range 9-14) and platelets >20x106/uL was 14 days (range 10-23). The Spearman correlation test confirmed a higher stem cell dose was significantly associated with shorter time to neutrophil (p=0.0014) and platelet engraftment (p=0.0003). From date of ASCT, median follow-up was 3.1 years in progression-free patients. For the entire cohort, PFS was 50% and overall survival (OS) was 74% at 3 years. On univariable analysis, patients with B-cell lymphoma with IPI score of 0-2 had a 3-year PFS of 59%, v 28% for those with IPI of 3-4 (p=0.03) (n=90). Patients with early relapse within 12 months of last therapy had inferior 3-year PFS, 42% v 59% for those with initial PFS > 1 year (p=0.08). Patients with B-cell lymphoma who received rituximab with primary chemotherapy had worse 3-year PFS: 47% v 69% (p=0.11). There were no associations of PFS with lymphoma subtype, dose of stem cells infused, number of apheresis sessions and neutrophil or platelet engraftment. Similarly, on univariable analysis of OS for the entire cohort, only secondary IPI (0-2 v 3-4) was significant, with 3-year OS 82% v 48%, respectively (p=0.01). Multivariable Cox regression analysis of outcomes for patients with B-cell lymphoma in a model including IPI score, time to relapse, prior rituximab, CD34+ cell dose and neutrophil and platelet engraftment times confirmed IPI was the only significant variable predicting PFS (HR 1.99, p=0.03) and OS (HR 3.2, p=0.006). Conclusions In this cohort of patients with aggressive lymphomas, CD34+ cell dose was correlated with time to neutrophil and platelet engraftment but was not predictive of PFS or OS. Secondary IPI score, relapse within 12 months, and for B-cell lymphomas previous use of rituximab were predictive of outcomes post ASCT. Disclosures: Kuruvilla: Roche: Honoraria. Kukreti:Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Keating:Roche: Honoraria. Crump:Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria.

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Non Interventional Prospective Clinical Study on Peripheral Blood Stem Cell Mobilization in Patients with Relapsed Lymphomas

Blood ◽

10.1182/blood.v124.21.3852.3852 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3852-3852

Author(s):

Gwendolyn van Gorkom ◽

Herve Finel ◽

Sebastian Giebel ◽

David Pohlreich ◽

Avichai Shimoni ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Clinical Study ◽

Research Funding ◽

Median Number ◽

Stem Cell Mobilization ◽

Prospective Clinical Study ◽

Cd34 Cells ◽

Relapsed Lymphoma ◽

Cell Mobilization

Abstract Introduction: Autologous stem cell transplantation (ASCT) is the standard of care for many patients with relapsed chemosensitive lymphoma. Peripheral blood stem cells have become the main source for the ASCT worldwide, because of its advantages over bone marrow. Several risk factors have been identified for poor stem cell mobilization, and diagnosis of lymphoma is one of the most important ones, with an inadequate stem cell harvest reported in 4 to 25% of the cases. Even though stem cell mobilization in relapsed lymphoma patients can be relatively difficult, mobilization strategies have not been standardized and there is a significant variation amongst centers. The aim of this non-interventional prospective clinical study was to review the mobilization strategies used by EBMT centers in relapsed lymphoma and to evaluate the failure rates. Methods: All EBMT centers were invited to participate in this non-interventional prospective clinical study that was started in 2010 and ended in 2014. Centers were requested to collect data on all consecutive patients with relapsed lymphoma considered to be candidates for an ASCT and were 18 years of age or older. Data collected included age, sex, diagnosis, number of prior chemotherapy regimens, mobilization regimen, collected CD34+ cells and marrow harvests. Results: In total, 275 patients with relapsed lymphoma from 30 EBMT centers were registered for this study. There were 158 males and 117 females with a median age of 51 (range 18 – 77) years; 181 patients (66%) with non-Hodgkin’s lymphoma (NHL) (DLBCL 28%, FL 17%, MCL 6%, PTL, 3%, other 12%) and 94 patients (34%) with Hodgkin’s lymphoma (HL). The median number of chemotherapy lines received before this relapse was one (range 1 – 8). 263 patients (96%) were mobilized with chemotherapy + G-CSF being DHAP (43%) and ESHAP (11%) the most frequent protocols, and 12 patients (4%) were mobilized with G-CSF alone. Thirteen patients (5%) who were mobilized with chemotherapy + G-CSF, received additional PLX in the first mobilization. These were all patients that were mobilized with chemotherapy as part of the mobilization regimen. Thirty patients (11%) failed to mobilize adequate stem cells (<2 x 10⁶ CD34+ cells/kg) during first mobilization despite the use of PLX in four patients. The median number of stem cells collected at first mobilization was 5.6 x 10⁶ CD34+ cells/kg (range: 0 – 82). In 255 patients (92.7%) only one mobilization course was given, 18 patients (6.5%) had two mobilization courses, 2 patients (0.7%) underwent three mobilization courses. Three patients had a mobilization failure after only G-CSF; they all were successfully harvested in a second attempt after chemotherapy + G-CSF. Five of the patients failing the first mobilization with chemotherapy + G-CSF received PLX at second mobilization, but only three succeeded. One patient failed both first and second mobilization and received PLX at third mobilization without success. 22 patients (8%) still had an inadequate amount of stem cells in the end. Of those, only 4 patients (1.5%) underwent bone marrow harvest. Conclusion: In the EBMT centers participating in this study, a primary mobilization strategy based on the combination of salvage chemotherapy plus G-CSF was used for virtually all patients with relapsed lymphoma. PLX was used in only 5% of the mobilization procedures during the time period analyzed. With 11% after the first mobilization attempt and 8% after several attempts, the failure rate was relatively low. Disclosures van Gorkom: Sanofi: Research Funding. Sureda:Takeda Pharmaceuticals International Co.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics, Inc.: Research Funding.

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Comparative efficacy of reduced or standard doses of lenograstim for peripheral blood stem cell mobilization and transplantation: A randomized study in patients undergoing autologous peripheral stem cell transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.7099 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 7099-7099

Author(s):

M. Ozturk ◽

F. Arpaci ◽

S. Ataergin ◽

A. Ozet ◽

T. Cetin ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Dose Group ◽

Low Dose ◽

Peripheral Blood Stem Cell ◽

Standard Dose ◽

Randomized Study ◽

Median Number ◽

Cd34 Cells ◽

Pbsc Mobilization

7099 Background: 10 microg/kg/day of filgrastim and lenograstim have been recommended for mobilization of CD34+ cells without associated chemotherapy. However,in our previous randomized study we demonstrated that a 7.5 microg/kg/day dose of lenograstim has been as efficacious as 10 microg/kg/day of filgrastim. In this study, we investigated whether a reduced dose of lenograstim is equavalent to standard dose for autologous peripheral blood stem cell (PBSC) mobilization and transplantation. Methods: A total of 49 consecutive patients were randomized to either low dose (7.5 microg/kg/day, n = 24) or standard dose (10 microg/kg/day, n = 25) of lenograstim. These two groups were similar in regard to disease, sex, body weight, body surface area, conditioning regimens, previous chemotherapy cycles and radiotherapy. Each dose of lenograstim was administered for 4 consecutive days. The first PBSC apheresis was done on the 5th day. In the posttransplant period, lenograstim was given at 5 microg/kg/day until leukocyte engraftment. Results: Successful mobilization with the first apheresis, was achieved in 10/24 (42%) patients in low dose group versus 14/25 (56%) patients in standard dose group. No significant difference was seen in the median number of CD34+cells mobilized, as well as the median number of apheresis, median volume of apheresis, percentage of CD34+ cells, and CD34+ cell number. Leukocyte and platelet engraftments, the number of days requiring G-CSF and parenteral antibiotics, the number of transfusions were similar in both groups in the posttransplant period. Conclusions: Lenograstim 7.5 microg/kg/day is as efficious as Lenograstim 10 microg/kg/day for autologous PBSC mobilization and transplantation. No significant financial relationships to disclose.

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Mobilization of Peripheral Blood Stem Cells with Rituximab Plus ESHAP Combination Regimen in B-Cell NHL - Preliminary Results.

Blood ◽

10.1182/blood.v108.11.5443.5443 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5443-5443

Author(s):

Min Kyoung Kim ◽

Shin Kim ◽

Seong Sook Lee ◽

Sun Jin Sym ◽

Dae Ho Lee ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

B Cell ◽

Peripheral Blood ◽

B Cell Lymphoma ◽

Hematopoietic Progenitor Cell ◽

High Dose ◽

Optimal Response ◽

Cd34 Cells ◽

Pbsc Mobilization

Abstract Objectives: The mobilization chemotherapy should be directed toward the dual objectives of good antilymphoma activity and adequate PBSC mobilization. Previously, we reported the ESHAP plus G-CSF is an effective mobilization regimen in patients with relapsed and high risk NHL. The purpose of this study is to assess the efficacy and feasibility of autologous stem cell collection after mobilization with Rituximab plus ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) combination therapy in B-cell Non-Hodgkin’s lymphoma. Patients and Methods: CD20 + B-cell NHL patients with either high risk, relapsed or refractory patients were eligible for the study. The regimen consisted of: Rituximab 375mg/m2 given on day 1, standard ESHAP therapy (etoposide 40mg/m2 IV/2hr day 2–5, methylprednisolone 500mg/m2 days 2–6, cytarabine 2g/m2 IV/3hr on day 5 and cisplatin 25mg/m2 CIV days 2–5). In all patients, the collection of PBSC was performed during recovery after giving G-CSF (10μ/kg/day) started on day 7. The first harvest was started only if the peripheral blood hematopoietic progenitor cell (HPC) count exceeded 5/μl. Results: Fifty-five mobilization procedures performed on 20 patients with a median of three apheresis (range 2–5) per patient. Median age was 37 years (range 15–65). At the time of PBSC mobilization, Seventeen patients were considered to be responsive (CR, PR and sensitive relapse). Aphereses were started on day 16 (range 13–18). The number of total MNCs (×106/kg) collected was 5.4 (range, 1.4–14.5) and the number of CD34+cells (× 106/kg) was 10.6 (range, 4.9–52.6). The median days of G-CSF usage was 11(range 9–15). Most non-hematologic adverse events were mild and reversible. Nineteen patients (95%) were achieved optimal response, which was defined as ≥ 5 × 106 CD34 cells/kg. In all, sixteen of the patients underwent high-dose chemotherapy. The median time to ANC ≥ 0.5 × 109/L was 10 days (range, 8–17). The median days to platelets ≥ 20 × 109/L was 12 (range, 7–27). Conclusion: Addition of Rituximab to ESHAP chemotherpy does not show any adverse effect in autologous stem cell mobilization and collection. R-ESHAP regimen is effective as a combined mobilization and second-line regimen for patients with pretreated B-cell lymphoma. Figure 1. Days to achieve optimal response Figure 1. Days to achieve optimal response

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Impact of Rituximab on Peripheral Blood Stem Cell Mobilization and Collection Following ACVBP Regimen in Poor Risk Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Large Cohort of Patients from Two Prospective GELA Trials.

Blood ◽

10.1182/blood.v112.11.2314.2314 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2314-2314

Author(s):

Francois Lefrere ◽

Dominique bastit-Barrau ◽

Suzanne Mathieu ◽

Alain Bohbot ◽

Philippe Bourrin ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Peripheral Blood Stem Cell ◽

B Cell Lymphoma ◽

Median Number ◽

Blood Stem Cell ◽

Poor Risk ◽

Cd34 Cells ◽

Risk Patients ◽

Pbsc Mobilization

Abstract <>The ACVBP regimen is commonly used in young poor-risk patients with DLBCL candidates to first line consolidative high-dose therapy followed by autologous stem cells transplantation in GELA trials. The combination with the monoclonal anti-CD20 antibody rituximab (R-ACVBP) is now routinely used, as induction treatment and to mobilize peripheral blood stem cell (PBSC). The aim of the present study was to assess the impact of rituximab on PBSC mobilization and collection in patients with newly diagnosed DLBCL receiving ACVBP chemotherapy. We reviewed the data from two prospective controlled trials. The first, conducted between 1999 and 2003, involved patients presenting with 2 or 3 adverse prognostic factors on the basis of the age-adjusted IPI (aa-IPI), treated by ACVBP (LNH 98B-3) (ASCO2007:8018). In the second trial (LNH 03-3B), conducted between 2004 and 2007, similar patients received the same initial inductive chemotherapy combined to rituximab (375mg/m2 at D1). 137 and 91 patients in the ACVBP and the R-ACVBP groups are here analyzed, respectively. Clinical and biological characteristics at diagnosis of the two groups of patients were similar (aa-IPI 2 and aa-IPI 3: 75% and 25%, respectively). The conditions for G-CSF administration and stem cell collections were identical. PBSC mobilizations were performed following the third or fourth cycle of (R)-ACVBP. The median delay between day 1 of chemotherapy and the first hemapheresis was identical for both groups. First hemapheresis was performed with a median peripheral white blood cell concentration of 16.2 x 109/l and 16.6 x 109/l for ACVBP and R-ACVBP groups, respectively. The median peak number of peripheral blood CD34+ cells observed the same day of first hemapheresis in ACVBP and R-ACVBP group was 69 x 106/l and 63 x 106/l, respectively (p = 0.5). The median number of CD34+ cells collected were 7.1 x 106 and 6.0 x 106 CD34 cells/kg for ACVBP and R-ACVBP groups (p = 0.12) while the median number of hemapheresis to target a minimal number of 3 x 106 CD34 cells/kg was identical, of one, in both groups. Failure of stem cell collection , defined as less than 3 x 106 CD34 cells/kg harvested, was observed in 8% and 4% of the patients who received ACVBP or R-ACVBP , respectively (p = 0.13). We conclude that rituximab combined to ACVBP regimen does not impair PBSC mobilization and collection.

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Correlation of Cytokines Levels and Adhesion Molecules Expression with Stem Cell Mobilization Efficacy in Healthy Donors

Blood ◽

10.1182/blood.v112.11.3466.3466 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3466-3466

Author(s):

Daniel Lysák ◽

Alexandra Jungová ◽

Jindra Vrzalová ◽

Luboš Holubec ◽

Vladimir Koza

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adhesion Molecules ◽

Peripheral Blood ◽

Odds Ratio ◽

Healthy Donors ◽

Cd34 Cells ◽

Cell Mobilization ◽

Poor Mobilizers ◽

Pbsc Mobilization

Abstract Peripheral blood stem cells (PBSC) are standard source of hematopoietic stem cells for allogeneic transplantations. Mobilization of PBSC in healthy donors is induced by a short term administration of G-CSF. The biological basis of the mobilization procedure in not completely discovered. Several factors were identified influencing the mobilization efficacy however their predictive potential for detection of poor mobilizers is limited. We performed a prospective study to evaluate differences in cytokines levels and adhesion molecules expression between good and poor mobilizers. The aim was to find out whether some of these factors can predict mobilization efficacy. Sixty healthy donors (25 related, 35 unrelated) were included in the study. The median age was 39 years (26–67). All donors were treated with G-CSF 10 μg/kg/day (filgrastim, Neupogen) for 5 days. Aphereses were started on day+5. Blood levels of certain cytokines (SDF-1, ICAM, VCAM, MMP-9, IL-6, IL-8, fractalkine, TNFα, VEGF, E-selectin) were tested before G-CSF application (day+0) and at first apheresis (day+5). Adhesion molecules expression (CD11a, CXCR4, CD44, CD117, CD26, CD49d) on CD34+ cells was measured at day +5. Cytokines were assayed by multiplex xMAP or ELISA technology. CD34 positive cells and adhesion molecules were evaluated with the flow cytometry using standard protocols. In response to the G-CSF stimulation the following cytokines significantly increased: ICAM (p<0.0001), VCAM (p<0.0001), MMP-9 (p=0.0039) IL-6 (p=0.0133), TNFα (p<0.0001) and E-selectine (p<0.0001). SDF-1 (p=0.0001), IL-8 (p=0.0013) decreased and fractalkine and VEGF remained unchanged. There was a positive correlation of day+5 SDF-1 (p=0.0011) and VCAM (p<0.0001) levels with CD34+ count at day+5. As for IL-6 borderline negative correlation (p=0.0861) between day+0 cytokine level and day+5 CD34+ count was found. Afterwards the donors were divided into two groups according to the CD34+ count at day +5. The cut-off of 40.0 CD34+ cells/μl was used for distinguishing of poor mobilizers. Twenty two percent (13 donors) mobilized below and 78 % (47 donors) above the cut-off. Between good and poor mobilizers there were significant differences of ICAM levels at day+0 (p=0.0369) and day+5 (p=0.0023), VCAM at day+5 (p=0.117) and IL-8 at day+5 (p=0.0473). Using logistic regression ICAM and IL-6 measured at day+0 (before stimulation) were tested as predictors of mobilization efficacy. The ICAM level below cut-off of 100 ng/mL implies approx. 5× higher risk of poor mobilization (odds ratio 4.8, p=0.0206). Conversely the IL-6 level above cut-off of 32 pg/mL means approx. 16× higher risk of poor mobilization (odds ratio 15.6, p=0.0112). Immunophenotyping of CD34+ cells suggested an inverse relationship of CD34+ counts with two adhesion molecules expression: CD11a (p=0.0002), CXCR4 (p=0.0075). However the expression of all tested antigens was similar in both donors groups. G-CSF stimulated PBSC mobilization results in increased plasma levels of some cytokines mostly evident for ICAM, VCAM, TNFα and decreased levels of SDF-1 and IL-8. In cases of ICAM and IL-6 the kinetics of these changes correlates with the quality of PBSC mobilization in peripheral blood. Their levels measured before G-CSF mobilization might serve as predictive factor for mobilization efficacy and graft quality. Contribution of adhesion molecules to stem cell mobilization is less clear and their practical utilization for mobilization course management is low.

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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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