Temporal Changes in Plerixafor Administration Do Not Impact Hematopoietic Stem Cell Mobilization Efficacy: Results of a Prospective Clinical Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2988-2988
Author(s):  
R. Donald Harvey ◽  
Sagar Lonial ◽  
Heather Renfroe ◽  
Rajni Sinha ◽  
Christopher R Flowers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Published Data ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Dosing Interval ◽  
Cell Counts ◽  
Cd34 Cells

Abstract Abstract 2988 Objectives: Plerixafor (AMD3100, Mozobil) with filgrastim (G-CSF, Neupogen) is approved for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and multiple myeloma (MM). Plerixafor pharmacokinetics (PK) and pharmacodynamics (PD) are well described, with linear, dose-dependent PK following subcutaneous (SC) administration, peak concentrations 30–60 mins post-injection and an elimination half-life (t1/2) of 5.3 hr. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, peak CD34+ cell counts occur 10–14 hours following administration, however, data is limited in the 14–24 hr timeframe. Plerixafor labeling requires SC dosing approximately 11 hours prior to apheresis, which translates into dosing 10 :00 PM the night before apheresis, and 54% of MM patients collect ≥ 6 × 106 CD34+ cells/kg following a single apheresis procedure. The current regimen is inconvenient for patients and requires additional health care resources. Based on PK and PD, we hypothesized that plerixafor given at 3 :00 PM (17 hr prior to apheresis) would yield equivalent CD34+ HSC yield to 10 :00 PM dosing in MM patients. Methods: In a Simon's two-stage design, we enrolled MM patients undergoing cytokine-only HSC mobilization. All subjects received filgrastim 7.5 mcg/kg SC BID for 4 days followed by plerixafor (0.24 mg/kg SC daily) for up to 4 days beginning at 3 :00 PM the day prior to the first day of a 24-liter apheresis procedure at 8 :00 AM. Target CD34+ HSC collection for stem cell transplant (SCT) was ≥ 10 × 106 CD34+ cells/kg. Blood samples for CD34+ fluorescence-activated cell sorting analysis were collected prior to the first plerixafor dose and at 1, 3, and 17 ± 1 hr, then daily prior to apheresis as needed. Results: Thirty patients (17 female, median age 59 years [range 44–70]) were evaluable; 27 received 1 pre-mobilization regimen (RVD n=20, VTD n=2, VD n=2, V/PLD/D n=1, VT n=1, RD n=1) for a median of 4 (1–6) cycles. Three received 2 regimens [CMF × 6 (breast cancer), then VTD × 5; RD × 4, then RVD × 4; and V/PLD × 1 with maintenance R]. Six patients received prior radiation. Mean (± SD) CD34+ cell counts in peripheral blood pre-plerixafor and 1, 3, and 17 hr post-first dose increased through the dosing interval (Figure). Twenty-two (73%) patients collected target cell numbers in 1 day of apheresis, 7 (23%) in 2 days, and 1 (3%) in 3 days. Twenty-seven (90%) patients collected ≥ 6 × 106 CD34+ cells/kg in 1 day. Institutional data with filgrastim 7.5 mcg/kg SC BID for 4 days alone in MM in 22 subjects showed a day 1 collection of ≥ 10 × 106 CD34+ cells/kg in 18% of patients (Renfroe H, et al. Transfusion Feb 2011). Adverse events were generally mild and consistent with known side effects of the combination [gastrointestinal disorders (diarrhea, nausea) and injection site reactions]. To date, 16 (53%) patients have proceeded to autologous SCT with melphalan conditioning and all patients have engrafted, with median time to an ANC ≥ 500/mm3 of 13 (range 11–15) days and platelets ≥ 20, 000/mm3 of 16 (range 11–21) days. Conclusion: This is the first prospective trial demonstrating the safety and efficacy of plerixafor given 17 hr prior to apheresis. Pharmacodynamic data showed the peripheral blood CD34+ cell population increased throughout the dosing interval, with a 4.6-fold increase over pre-plerixafor counts at 17 hr. Comparison with historical institutional controls and published data suggests this regimen yields at least equivalent, if not superior, collection rates with one apheresis procedure. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding.

scholarly journals 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 ◽  
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.

Results of an Autologous Noncryopreserved, Unmanipulated Peripheral Blood Hematopoietic Stem Cell Transplant Program: A Single-Institution, 10-Year Experience

2003 ◽  
Vol 110 (4) ◽  
pp. 179-183 ◽  
Author(s):  
Guillermo J. Ruiz-Argüelles ◽  
David Gómez-Rangel ◽  
Guillermo J. Ruiz-Delgado ◽  
Alejandro Ruiz-Argüelles ◽  
Beatriz Pérez-Romano ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Single Institution ◽  
Hematopoietic Stem ◽  
Transplant Program

Outcome of High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplant In Myeloma Associated with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2400-2400
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan

Abstract Abstract 2400 Background: Approximately 10% of patients with multiple myeloma (MM) have clinically overt primary systemic light-chain (AL) amyloidosis, and about 30% have concurrent occult AL amyloidosis. The impact of concurrent AL amyloidosis on the prognosis of myeloma is not well known. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) has shown significant activity in both MM and AL amyloidosis. Methods: We performed a retrospective analysis of patients who had concurrent MM and AL amyloidosis and underwent auto HSCT with high dose Melphalan at MDACC between 01/1998 to 05/2010. We identified 41 patients with concurrent MM and AL amyloidosis. Patient characteristics are summarized in Table 1. Twenty -six patients had occult AL amyloid, while 15 had clinically overt disease. Results: Median age at auto HSCT was 56 years (39-77), 58.5% being male with median follow up of 58.7 months from the time of diagnosis and 42.5 months from auto HCT. The median time from diagnosis to auto HCT was 8.9 mos (2.7-102.4 mos). 39% had Salmon Durie Stage III disease and 36.6% had more than one involved site at the time of transplant.Cytogenetic abnormalities were detected in 24.4% of patients. Post transplant hematologic responses were as follows: ≥CR=10 (24%), ≥VGPR=16 (39%), >PR=33 (80.5%), ≥stable disease= 40 (97.6%). Among the patients with overt organ involvement, one had early death. Of the 15 evaluable patients, organ responses were scored using the published consensus guidelines for amyloidosis and were as follows: PR=5 (33.3%), ≥SD=7 (46.7%). No correlation was seen between organ response and hematologic response. The 100-day treatment related mortality (TRM) was 0 and 1-year TRM of 2.4% which is comparable to patients transplanted for MM alone at our center. The median progression-free (PFS) and overall survival (OS) from auto HCT were 33.8 and 58.3 months, respectively.The median PFS and OS from diagnosis were 49.8 and 96 mos, respectively. In multivariate analysis, creatinine ≥ 2mg/dl was associated with a shorter PFS (p=0.043) and hemoglobin <10g/dl showed a trend towards a shorter PFS (p=0.093). None of these variables (Hb <10g/dl, Age>60yrs, Creatinine≥2mg/dl, B2M >3.5mg/l, BM plasma cells>30%) emerged as significant predictors of OS. There was no significant difference in outcome between patients with occult or symptomatic AL amyloidosis for OS (p=0.24) or PFS (P=0.9) Conclusion: In this analysis the outcome of patients with concurrent MM and AL amyloidosis was comparable to patients with MM alone. We believe these patients are acceptable candidates for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

scholarly journals Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Russell Emmons ◽  
Grace M. Niemiro ◽  
Michael De Lisio
Keyword(s):  
Stem Cell ◽  
Adjuvant Therapy ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Cell Transplant ◽  
Pharmacological Agents ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Mobilization ◽  
Cell Mobilization ◽  
Exercise Induced

Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers.

Bortezomib Given in Sequence with Anthracycline and Thalidomide-Containing Regimens Does Not Adversely Affect Stem Cell Mobilization and Engraftment in Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 541-541
Author(s):  
Geoffrey L. Uy ◽  
Nicholas M. Fisher ◽  
Steven M. Devine ◽  
Hanna J. Khoury ◽  
Douglas R. Adkins ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Stem Cell Mobilization ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Cell Mobilization ◽  
High Dose Melphalan

Abstract Bortezomib (VELCADE®) is a selective inhibitor of the 26S proteasome proven to be safe and effective in the treatment of relapsed or refractory multiple myeloma (MM). While high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) remains the standard of care, there is considerable interest in incorporating bortezomib into the initial treatment of MM. However, the role of bortezomib in frontline therapy for MM will depend in part on its effects on subsequent stem cell mobilization and engraftment. We conducted a pilot study of bortezomib administered pretransplant followed by high-dose melphalan with AHSCT. Two cycles of bortezomib 1.3 mg/m2 were administered on days 1, 4, 8, and 11 of a 21-day treatment cycle. One week after the last dose of bortezomib, stem cell mobilization was initiated by administering filgrastim 10 mcg/kg/day subcutaneously on consecutive days until stem cell harvest was completed. Stem cell collection began on day 5 of filgrastim via large volume apheresis (20 L/day) performed daily until a minimum of 2.5 x 106 CD34+ cells/kg were collected. Patients were subsequently admitted to the hospital for high-dose melphalan 100 mg/m2/day x 2 days followed by reinfusion of peripheral blood stem cells 48 hours later. Sargramostim 250 mcg/m2/day subcutaneously was administered starting day +1 post-transplant and continued until the absolute neutrophil count (ANC) ≥ 1,500/mm3 for 2 consecutive days. To date, 23 of a planned 40 patients have been enrolled in this study with 19 patients having completed their initial therapy with bortezomib followed by AHSCT. Patient population consists of 16 male and 7 female patients with the median age at diagnosis of 58 years (range 38–68). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (16), IgA (7) with stage II (9) or stage III (14) disease. Prior to receiving bortezomib, 11 patients were treated with VAD (vincristine, Adriamycin and dexamethasone) or DVd (Doxil, vincristine and dexamethasone), 5 patients with thalidomide and 5 patients with both. Two patients did not receive any prior chemotherapy. All patients successfully achieved the target of 2.5 x 106 CD34+ cells/kg in either one (15/19 patients) or two (4/19 patients) collections with the first apheresis product containing a mean of 5.79 x 106 CD34+ cells/kg. Analysis of peripheral blood by flow cytometry demonstrated no significant differences in lymphocyte subsets before and after treatment with bortezomib. Following AHSCT, all patients successfully engrafted with a median time to neutrophil engraftment (ANC ≥ 500/mm3) of 11 days (range 9–14 days). Platelet engraftment (time to platelet count ≥ 20,000/mm3 sustained for 7 days without transfusion) occurred at a median of 12 days (range 9–30 days). Eleven patients were evaluable for response at 100 days post-transplant. Compared to pre-bortezomib paraprotein levels, 3 patients achieved a CR or near CR, 7 maintained a PR while 1 patient developed PD. We conclude that pretransplant treatment with 2 cycles of bortezomib does not adversely affect stem cell yield or time to engraftment in patients with MM undergoing AHSCT. Updated results and detailed analysis will be available at the time of presentation.

Case Report: Haploidentical Stem Cell Transplantation In a 78 Year-Old Patient

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5468-5468
Author(s):  
Thiago Xavier Carneiro ◽  
André Domingues Pereira ◽  
Theodora Karnakis ◽  
Celso Arrais Rodrigues
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract An older chronologic age has been a consistent predictor of poor outcomes in hematopoietic stem cell transplantation (HSCT), mainly due to non-relapse mortality (NRM). Therefore, non-curative treatment strategies are commonly adopted for these patients. However, mortality and treatment toxicity has decreased as a result of improved supportive measures, such as reduced intensity conditioning regimens and optimized infection management. T-cell replete haploidentical HSCT emerged as a feasible alternative for leukemia patients without substantial differences in outcomes when compared to fully matched related donor. We report an old adult woman treated with haploidentical HSCT. A 78 year-old female patient presented with anemia, leukocytosis, thrombocytopenia and blasts in the peripheral blood. Diagnosis of acute myelogenous leukemia was established. Conventional cytogenetic demonstrated chromosome eight trisomy, and FISH was negative for other common MDS/AML cytogenetic abnormalities. FLT3-ITD and NPM1 mutations were negative. Her medical history was negative except for heavy smoking. Considering the patients advanced age, the first attending physician chose not to administer intensive treatment and started on decitabine 20 mg/m2 for 5 days. She was refractory to the first-line treatment with persistent cytopenias and blasts in the peripheral blood four weeks after treatment was started. Comprehensive geriatric assessment was performed. She was considered independent for Basic Activities of Daily Living (ADL score 6) and Instrumental Activities of Daily Living (IADL score 27), without cognitive impairment in mini-mental state examination (MMSE score 30), at risk of malnutrition in mini nutritional assessment (MNA 9). As she was considered fit, we decided to perform high-dose chemotherapy with idarubicin and cytarabine, but, once more, the disease was refractory. A rescue regimen was attempted with high-dose cytarabine and mitoxantrone, again, with no response. After discussing pros and cons with the patient and the family, we decided to start Another regimen consisting of topotecan and high dose cytarabine immediately followed by allogeneic hematopoietic stem cell transplantation (HSCT). At day 14, she had 3% blasts in the BM aspirate a T-cell replete haploidentical HSCT using her 52 year-old son as donor and mobilized peripheral blood as stem cell source was performed. Conditioning regimen consisted of fludarabine, cyclophosphamide, TBI 2Gy and post-transplant cyclophosphamide. Graft versus host disease (GVHD) prophylaxis consisted of mycophenolate mofetil and cyclosporine. She had neutrophil engraftment with complete donor chimerism at day+15 and platelet engraftment at day+17. At day+48, she had mild (stage II) skin acute GVHD resolved with topical steroids. Cyclosporine was withdrawn at day+ 93. Due to high relapse risk, the patient was started on monthly post-transplant azacitidine 36 mg/m2. At day+100 the patient remained in complete remission, complete donor chimerism in peripheral blood and bone marrow. Functionality was preserved (ADL score 6 and IADL score 24), presented discrete cognitive impairment (MMSE 28) and malnoutrition (MNA 5). She is now at day+182, doing well and performing again all usual daily activities. To the best of our knowledge, this is the oldest patient treated with haploidentical HSCT. Post transplant cyclophosphamide as T cell depletion strategy in haploidentical HSCT is well tolerated and widely available, being therefore an excellent alternative for patients without conventional donors who require immediate transplant. Older adults with hematologic malignancies are a heterogeneous group and decisions based on chronological age alone are clearly inappropriate. Recently, geriatric assessment proved to be an important prognostic tool in acute leukemia and may be useful in HSCT. In experienced centers, haploidentical HSCT in older adults may be a safe procedure and more accurate pre-transplantation risk stratification tools should be developed. Figure 1 Timeline of main events during hematopoietic stem cell transplant. Figure 1. Timeline of main events during hematopoietic stem cell transplant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

2020 ◽  
Author(s):  
Ka-Won Kang ◽  
Seung-Jin Lee ◽  
Ji Hye Kim ◽  
Byung-Hyun Lee ◽  
Seok Jin Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Cd34 Cells

Abstract Background This study assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF) and determined how it differed from that using cyclophosphamide with G-CSF or G-CSF alone.Methods The study analyzed data from 173 non-Hodgkin’s lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), in vitro experiments using HSCs and bone marrow stromal cells (BMSCs), and in vivo mouse model studies.Results The etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. Etoposide triggered interleukin (IL)-8 secretion from BMSCs and caused long-term BMSC toxicity, which were not observed with cyclophosphamide treatment. The expansion of CD34+ cells cultured in BMSC-conditioned medium containing IL-8 was more remarkable than that without IL-8. The expression of CXCR2, mTOR, and cMYC in HSCs was gradually enhanced at 1, 6, and 24 h after IL-8 stimulation. In animal studies, the etoposide with G-CSF mobilization group presented stronger expression of IL-8-related cytokines and MMP9 and scantier expression of SDF-1 in the bone marrow, compared to the other groups not treated with etoposide.Conclusion Collectively, the unique mechanism of etoposide with G-CSF-mediated mobilization is associated with the secretion of IL-8 from BMSCs, causing the enhanced proliferation and mobilization of HSCs in the bone marrow, which was not observed in the mobilization using cyclophosphamide with G-CSF or G-CSF alone. Moreover, the long-term toxicity of etoposide to BMSC emphasizes the need for further studies to develop more efficient and safe chemo-mobilization strategies.

scholarly journals Outcomes of HMA and Venetoclax in Relapsed AML Post-Allogenic Hematopoietic Stem Cell Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Osama Diab ◽  
Haitham Abdelhakim ◽  
Joseph P. McGuirk ◽  
Tara Lin
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Complete Remission ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Pharmaceutical Research ◽  
Cell Transplant ◽  
Hematopoietic Stem

Background: There is no standard of care treatment for Acute Myeloid Leukemia (AML) in relapse post-allogeneic hematopoietic stem cell transplant (post-HSCT), with overall 5-year survival about 5-10%. Venetoclax (Ven) is a novel BCL2 inhibitor approved by the FDA for treatment of newly diagnosed AML in combination with hypomethylating agents (HMA) or low dose cytarabine for patients unfit for intensive induction. However, data in relapsed/refractory AML are limited, especially in the post-HSCT setting. In this retrospective study, we reviewed outcomes of patients with AML relapse post-HSCT who received Ven in combination with HMA in a single center. Methods: Charts of 17 patients who had AML relapse post-HSCT treated with combination of Ven and HMA between November 2018 - March 2020 at the University of Kansas Medical Center were reviewed. We utilized descriptive statistics for baseline characteristics and outcomes, and Kaplan-Meier log-rank test for calculating overall survival. Results Seventeen patients received Ven+HMA for AML relapse post-HSCT in our center. At the time of SCT, patients were in first complete remission (CR) (n=15); second CR (n=1) and primary failure induction (1). Median age was 62 at time of relapse (31-71) years, and 8 patients were female (47%). 9 patients (53%) had adverse risk AML (ELN 2017) 8 of them were in CR1 and 1 with primary induction failure. Common mutations included DNMT3a, ASLX-1, TET2 (3); TP53 (2); IDH1/2 (2); NPM1/FLT3 (1); NPM1/IDH2 (1); NPM1 (1 transplanted in CR2); FLT3 (1). 2/17 had received Ven+HMA prior to SCT; 4 patients received HMA alone prior to SCT. 11 patients (65%) were naïve to either Ven or HMA prior to relapse. Median time to relapse was 181 (44-851) days post-HSCT. 9 (53%) patients received Azacitidine+Ven and 8 (47%) received Decitabine+Ven. HMA+Ven was the first line of therapy post-HSCT relapse in 14 patients. 2 had donor lymphocyte infusion (DLI) after either MEC or dacogen but relapsed prior to Ven+HMA. 1 had IDH (2) inhibitor. Patients received median of 2 (1-10) cycles of HMA+Ven. Six (35%) patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi), and 2/6 patients had negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 361 days from relapse (Figure 1). 3/14 patients received subsequent DLI with Ven+HMA. Disease progression was the most common cause of death in 8/9 of patients who died during the follow up period. Most common side effects included neutropenic fever (n=8, 47%) and acute graft versus host disease (aGVHD) (n=5, 30%). 2/5 developed new aGVHD on HMA+Ven with no prior history of aGVHD. However, aGVHD was mainly grade I-II and responsive to therapy. Discussion HMA+Venetoclax demonstrates potential activity in patients with AML relapse post-HSCT with a CR/CRi rate of 35%, comparable to other salvage therapies. There were no unexpected side effect in this high-risk population. Larger studies are needed to confirm efficacy and toxicity in this setting. Disclosures McGuirk: Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Lin:Aptevo: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Astellas Pharma: Research Funding.

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