Parathyroid Hormone May Improve Autologous Stem Cell Mobilization Via the Stem Cell Niche.

Abstract Autologous stem cell transplantation is curative for many patients with hematologic malignancies. Approximately 20% of patients do not have an adequate stem cell mobilization. Recently, work from our laboratories has shown that parathyroid hormone (PTH) increases osteoblast number and expansion of the stem cell compartment in mice. In murine models, the addition of PTH caused an increase in the absolute number of stem cells. Daily PTH injection caused an increase in the absolute number of murine stem cells and improved survival in transplant recipients of limiting numbers of stem cells. (Nature425: 841, 2003). This observation suggested that PTH might be able to increase stem cell numbers in humans. PTH is an FDA approved drug used for treatment of osteoporosis. In this Phase I study, patients who have collected less than 2 million CD34+ cells/kg after 1 or 2 stem cell mobilization attempts received 14 days of sc PTH, in escalating dose cohorts of 40 mcg, 60 mcg, 80 mcg, and 100 mcg per day, with G-CSF 10mcg/kg/day for the last four days. Patients with >5 CD34+/uL on Day +14 proceeded to stem cell apheresis and autologous stem cell transplant. 14 patients have enrolled on this study, now enrolling at the highest dose cohort, and 12 patients have completed treatment for this analysis with 3 patients per dose cohort. The median age was 57 years (range 24–71 years), and 9 (75%) patients are female. In 10 patients (83%) one attempt at stem cell mobilization failed with either growth factor alone or growth factor plus chemotherapy; in the other 2 patients (17%) two attempts at mobilization failed to attain adequate cells. The diagnoses were as follows: non Hodgkin’s lymphoma (7 patients, 58%), Hodgkin’s disease (5 patients, 42%). There were no dose limiting toxicities defined as calcium > 11.5, ionized calcium > 1.5, phosphate <1.0, or systolic blood pressure less than 80mm Hg. 3 patients had a self-limited fever, one patient had an unexplained eosinophilia, and 1 patient required an admission with fever, rigors, and headache. 6 of 12 patients (50%) achieved the target peripheral CD34 level of 5/uL, of whom 4 underwent stem cell apheresis. The median CD34 cells/uL on Day +14 was 4.3 (range 0–18.8). 2 patients who achieved the target peripheral CD34 level of 5/uL did not complete collections, 1 due to access problems, and 1 due to physician preference. The 4 patients who continued with the study collected a median CD34+ dose/kg of 2.2 x 106 (range 0.9–2.7) from stem cell apheresis with a median of 2 collections (range 1–4). These 4 patients proceeded to autologous stem cell transplant, with median days to neutrophil and platelet engraftments of 11 (range 10–12) and 14 (range 12–19), respectively. In conclusion, 1) PTH is well tolerated in this population, even at a dose of 100 mcg; 2) PTH plus G-CSF may be effective in patients that fail primary or secondary stem cell mobilization attempts; 3) PTH plus G-CSF should be tested in a larger Phase II study to improve donor stem cell yield. Future directions may also include the use of parathyroid hormone to improve engraftment efficiency in settings of low stem cell dose such as adult cord blood transplantation.

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Efficacy of Administration of Plerixafor (Mozobil®) at 5:00 PM for Stem Cell Mobilization (SCM) in Patients Receiving Autologous Stem Cell Transplant.

Blood ◽

10.1182/blood.v114.22.3218.3218 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3218-3218

Author(s):

Jennifer Tornatta ◽

John J. Maciejewski ◽

Sunita Nathan ◽

Bruce C. McLeod ◽

Darilyn Rhoades ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplant ◽

Peak Level ◽

Autologous Stem Cell Transplant ◽

Stem Cell Mobilization ◽

Cell Transplant ◽

Dosing Schedule ◽

Pharmacodynamic Profile ◽

Cd34 Cells ◽

Cell Mobilization

Abstract Abstract 3218 Poster Board III-155 Introduction In the phase 3 clinical trials of plerixafor plus G-CSF for SCM, plerixafor was administered at 10:00 pm on days prior to apheresis. This dosing schedule is based on the peak level of CD34+ cells in the peripheral blood (PB) at 11-14 hours after administration; however PB CD34+ cell levels were elevated from 4-18 hours after plerixafor administration. Due to inconvenience in dosing plerixafor at 10:00pm, we took advantage of its pharmacodynamic profile and explored an alternative dosing schedule, giving plerixafor at 5:00 pm. Here, we report our initial experience with the efficacy of this schedule. Patients and Methods Between 01/09 & 08/09, 22 candidates for autologous stem cell transplant (13 female; mean age = 59, range 32-69; 9 MM, 11 NHL & 2 HD) received plerixafor plus G-CSF for SCM. Eight (4 female) were previous mobilization failures; 3 had failed G-CSF alone and 5 had failed chemotherapy + G-CSF; 2 had failed >1 mobilization. At the time of mobilization, 6 patients (27%) were in CR and 16 (73%) were in PR. Eight patients (36%) had disease in the bone marrow, 7 of these had MM and 1 had NHL. Of the 9 MM patients 3 (33%) had previous lenalidomide therapy. Nine patients (41%) had received >2 different chemotherapy regimens prior to mobilization; 2 of these had failed traditional mobilization with either G-CSF or chemo + G-CSF. Seven patients (32%) had, had previous radiation therapy, of whom 2 had failed traditional mobilization. Our mobilization protocol for autologous SCM consisted of G-CSF 10mcg/kg given at daily at 6:00 am beginning on day 1 and plerixafor 0.24mg/kg SQ x1 (0.16mg/kg if creatine clearance < 50ml/min) given daily at 5:00 pm in our Outpatient Clinic beginning on day 4. Apheresis began at 8:30 a.m. on the morning of day 5. The minimum collection goal was 2 × 106 CD34+cells/kg per transplant while the maximum goal was 4 × 106CD34+cells/kg per transplant. SCM and apheresis were stopped after 1 collection if the maximum goal was reached or after the minimum goal was reached on any subsequent day. Results Administration of G-CSF plus 5:00 pm plerixafor resulted in a median PB CD34+ cell count in the morning of apheresis of 32.1 CD34+ cells/ml (range, 1.2-135.7). The median total apheresis yield was 4.83 × 106 CD34 cells/kg (range, 0.06-10.98 × 106) in a median of 2 days of apheresis (range, 1-4). Of the patients with multiple myeloma, 3/9 (33%) collected >6 × 106 CD34 cells/kg with a median time of 1.3 days, although per our protocol patients were stopped after 2 apheresis sessions if >4 × 106 CD34+ cells/kg had been collected. 2/22 patients (9%) failed a plerixafor mobilization. One of these had MM and had failed 2 previous traditional mobilization attempts; this patient reached the minimum collection goal after a second plerixafor mobilization attempt following a 3-week break. The other had received 4 previous chemotherapy regimens for NHL prior to mobilization. Nineteen patients (86%) had proceeded to transplant as of August 12th 2009, including the patient with a second plerixafor mobilization. The median days to neutrophils and platelet engraftment were 16 (range, 14-26) and 9 (range, 10-14) respectively. The side effect profile was similar to that described previously. Conclusion An alternative dosing SCM regimen giving at 5:00 pm allowed >90% of the patients to collect the minimum CD34+cell dose necessary to proceed to transplantation. This dosing schedule is more convenient and ensures 100% compliance with plerixafor dosing. Disclosures Tornatta: Genzyme: Consultancy, Speakers Bureau. Off Label Use: Plerxiafor is a chemokine recpeptor antagonist approved for use in pts with MM and NHL for mobilization of stem cells for autologous transplant. Our information includes patients with HD who were mobilized using plerxafor for stem cell mobilization and ultimately autologous stem cell transplantation. Fung:Genzyme: Consultancy, Speakers Bureau.

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Utility of Stem Cell Collection in Anticipation of Future Need for Autologous Stem Cell Transplant in Follicular Lymphoma Patients

Blood ◽

10.1182/blood.v118.21.1926.1926 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1926-1926

Author(s):

Robin R. Klebig ◽

Stephen M. Ansell ◽

Joseph P. Colgan ◽

Dennis A. Gastineau ◽

Thomas M. Habermann ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Autologous Stem Cell Transplant ◽

Stem Cell Mobilization ◽

Cell Transplant ◽

Collection Cost ◽

Cell Mobilization ◽

The Cost ◽

And Storage ◽

Stem Cell Collection

Abstract Abstract 1926 Background: Follicular lymphoma (FL) is the second most common non Hodgkin lymphoma in the United States, comprising up to 30% of all non Hodgkin lymphomas. Typically an indolent disease, relapses are common. High dose therapy followed by autologous stem cell transplant is an option that has shown to produce prolonged progression-free and relapse-free survival in patients who relapse. Adequate bone marrow reserve for peripheral stem cell mobilization has been shown to be adversely effected by prior regimens such as fludarabine and radioimmunotherapy. Concerns regarding stem cell mobilization at the point of relapse have led some to collect stem cells early in the course of disease to allow for potential subsequent transplant after relapse. Recent advances in stem cell mobilization have resulted in a 3% collection failure rate for lymphoma patients at the point of planned transplant at our institution versus a historical rate of up to 30%. We studied the utilization of stem cells collected for potential future use in FL patients in remission or prior to therapy at the point of relapse or progression in order to determine the utility of this approach. Methods: Record review of patients diagnosed with FL through the Mayo Clinic Tumor Registry and the Mayo Clinic Lymphoma Data Base who had cryopreserved stem cells for potential future transplant at relapse. Cost of stem cell storage at our institution was reviewed as was the subsequent use of the collected cells. Results: 73 patients with FL had stem cells collected and stored. 37 (51%) were collected prior to a double dose yttrium-90 (90Y) ibritumomab tiuxetan trial for relapsed lymphoma as required by the study. The median age at collection of this group was 56 years (range 28–70). Stem cells remain in storage for a median of 44 months (range 8–119). The median cost of cryopreservation and storage is $4,094 based on the median storage time of 44 months (range $3,628 to 5,065) with a collection cost of $3,524.20 and an annual storage fee of $155.39. This does not include the cost of filgrastim for mobilization, nor line placement. At 5 years, 60% of the cells were not utilized, and at 10 years, 56% of the cells were not utilized. 36 (49%) of the total number of patients were not part of the double dose 90Y ibritumomab tiuxetan trial, but were collected in remission for possible future use or in the setting of relapsed, progressed or transformed disease for potential future transplant. Five of these patients required the use of plerixafor for adequate mobilization. The median age at collection of this group was 47 years (range 24–76). Stem cells remain in storage for a median of 39 months (range 2–128). The median cost of cryopreservation and storage is $4,029 based on the median storage time of 39 months (range $3,550 to 5,182) with a collection cost of $3,524.20 and an annual storage fee of $155.39. This does not include the cost of filgrastim or plerixafor for mobilization, nor line placement. At 5 years, 89% of these cells were not used, and at 10 years, 71% of cells were not used. Conclusion: The utilization of stem cells collected early in the course of FL patients is low, with the majority of cells not being utilized at 10 years. Given improved mobilization techniques resulting in 97% efficacy of stem cell collection at relapse, routine collection and storage of stem cells early in the course FL is not recommended. Disclosures: Micallef: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Efficacy of Plerixafor Administered At 5:00PM for Stem Cell Mobilization in Lymphoma and Myeloma Patients Undergoing Autologous Stem Cell Transplant,

Blood ◽

10.1182/blood.v118.21.4061.4061 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4061-4061

Author(s):

Jennifer Tornatta ◽

John J. Maciejewski ◽

Sunita Nathan ◽

Bruce Mcleod ◽

Sridevi Palaparthy ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Peripheral Blood ◽

Stem Cell Mobilization ◽

Cell Yield ◽

Cell Transplant ◽

Dosing Schedule ◽

Pharmacodynamic Profile ◽

Cd34 Cells ◽

Cell Mobilization

Abstract Abstract 4061 Background: High-dose chemotherapy and/or radiotherapy are effective treatment strategies for patients with life-threatening hematologic malignancies. A critical step to the success of transplantation is achieving adequate mobilization of CD34+ stem cells from the bone marrow into the peripheral blood to provide sufficient cell yield after apheresis for the transplant. Plerixafor combined with granulocyte colony-stimulating factor (G-CSF) has proven efficacious in mobilizing CD34+ stem cells in patients with lymphoma and myeloma prior to autologous stem cell transplantation. In the phase 3 clinical trials of plerixafor plus G-CSF for SCM, plerixafor was administered at 10:00 pm on days prior to apheresis. This dosing schedule is based on the peak level of CD34+ cells in the peripheral blood (PB) at 11–14 hours after administration; however PB CD34+ cell levels were elevated from 4–18 hours after plerixafor administration. Due to inconvenience in dosing plerixafor at 10:00pm, we took advantage of its pharmacodynamic profile and explored an alternative dosing schedule, giving plerixafor at 5:00 pm. Here, we report our updated experience with the efficacy of this schedule. Method: We performed a retrospective study using our Stem Cell Harvest database. A total of 58 patients (31 lymphoma, 27 myeloma) underwent mobilization with G-CSF + plerixafor, either as front-line (n=51) or as salvage (n=7) mobilization strategies between February 2009 through May 2010. Mobilization consisted of G-CSF 10 μg/kg SC administered daily at 6:00 am day 1 through 4 plus plerixafor 0.24 mg/kg SC given once daily at 5:00 pm in an outpatient clinic beginning on day 4. For patients with renal impairment (ie, creatinine clearance ≤50 mL/min), the dose of plerixafor was lowered by a third to 0.16 mg/kg. Daily apheresis began at 8:30 am on the morning of day 5 and continued for up to 4 days, with a minimum collection goal defined as ≥ 2 × 106 CD34+ cells/kg for lymphoma patients and ≥ 4 × 106 CD34+ cells/kg for myeloma patients. Mobilization with G-CSF plus plerixafor and apheresis were halted once the minimum goal was reached between day 2 and 4 of apheresis, or after a single collection achieved the optimal goal which was defined as ≥ 4 × 106 (lymphoma) or ≥ 8 × 106 (myeloma) CD34+ cells/kg. The mobilization strategy was considered a failure if patients did not reach the minimum CD34+ cell collection goal within the 4 days of apheresis. Results: G-CSF + plerixafor mobilization yielded a median 5.13 × 106 CD34+ cells/kg (range, 0.06–25.8) in a median of 2 apheresis days. Forty-five of 58 (78%) patients achieved the minimum CD34+ cells/kg required for transplantation, including 30 (52%) patients who achieved this goal on the first day of apheresis. Overall, 52 (90%) patients proceeded to transplantation, with median neutrophil and platelet engraftment times of 11 and 18 days, respectively. Conclusion: In summary, the alternative 5:00 pm dosing of plerixafor for stem cell mobilization provided a more convenient dosing schedule while ensuring that a majority of lymphoma and myeloma patients achieved the minimum CD34+ cell yield required to proceed to transplantation. Disclosures: Tornatta: Genzyme: Consultancy, Honoraria, Speakers Bureau. Fung:Genzyme: Consultancy, Honoraria, Speakers Bureau.

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Plerixafor and G-CSF For Autologous Stem Cell Mobilization In AL Amyloidosis: A Single Center Experience

Blood ◽

10.1182/blood.v122.21.4516.4516 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4516-4516

Author(s):

Esha Kaul ◽

Gunjan L Shah ◽

Chakra P Chaulagain ◽

Raymond L. Comenzo

Keyword(s):

Stem Cell ◽

Research Funding ◽

Median Number ◽

Initial Therapy ◽

Stem Cell Mobilization ◽

High Dose ◽

Al Amyloidosis ◽

Cell Transplant ◽

Cd34 Cells ◽

Cell Mobilization

Background Risk-adapted melphalan and stem cell transplant (SCT) is standard initial therapy for a minority of patients with systemic AL amyloidosis (Blood 2013;121: 5124; Blood 2011;118: 4298). Stem cell mobilization is often accomplished with high dose G-CSF (16μg/kg/d) (Blood 2011;118:4346). In the current era with effective new agents such as bortezomib, many AL patients are receiving initial therapy and achieving profound rapid cytoreduction with organ improvement (Blood 2012;119:4391; Blood 2011;118:86). But not all patients respond and in some cases the duration of response is limited. In addition, the use of SCT for consolidation after an initial response, although reasonable, has not been systematically evaluated. Whether SCT is employed as consolidation or as a second- or third-line option, the efficacy and tolerance of mobilization become important issues. Because AL patients have organ involvement limiting chemotherapy-based mobilization options, we decided to explore the option of Plerixafor and G-CSF for stem cell mobilization, based on the phase III experience in MM (Blood 2009;113:5720). We now report the first experience with this mobilization approach in AL. Patients and Methods Patients were evaluated and diagnosed by standard criteria including, in all cases, tissue biopsies showing amyloidosis. They were mobilized and collected between 4/16/12 and 6/19/13 with G-CSF 10μg/kg/d subcutaneously (SC) for 5 days (continued through collection process) and Plerixafor adjusted for renal function starting on day 4 and continuing until collection was completed. Results We report on 10 patients whose median age at mobilization was 58 years (range 46-72), 60% of whom were men. Median number of organs involved was 2 (range 1-3). Heart and kidneys were the most frequently involved organs (7 patients in each group). Median time from diagnosis to mobilization was 9 months (range 2-123). Eight patients had received prior bortezomib-based therapy. The median number of cycles was 3 (range 0-6). One had received a prior MEL 140 transplant 10 years prior and had relapsed, and 2 were treatment naïve, one of whom was 1 year status post orthotopic heart transplant. At the time of mobilization, 3 patients had non-responsive hematologic disease, 3 had achieved PR, 1 VGPR and 1 had achieved CR. Five patients had a creatinine ≥ 1.5 mg/dL including 2 patients on hemodialysis. The target cell dose was 10x106CD34/kg for all but one patient (with previous history of transplantation). The median number of collections was 2 (range 2-3). On day one, the median number of CD34+ cells collected per kg was 3.6 x106 (0.4-6x106) and on day two 6.4 x106 (2.7-19x106). The median total CD34+ cells collected per kg was 12.5x106 (5-18x106). Two patients had grade 1 bleeding from the catheter site during apheresis and one patient had dyspnea with suspected fluid overload which responded to a single dose of intravenous furosemide. There were no significant toxicities observed with Plerixafor in mobilization. All patients went on to receive high dose chemotherapy with melphalan followed by autologous stem cell transplant. The median length of hospital stay was 25 days (18-32). The median stem cell dose infused was 7.6x106CD34/kg and median days to ANC > 500 was 11 (10-22), to platelets > 20K untransfused 22 (15-44) and to lymphocytes > 500/μl 14.5 (11-25). One patient who had VOD and persistent thrombocytopenia was given the remainder of his stem cells on day +31 with full recovery and normalization of the blood counts by day +65. Conclusions In the era of more effective initial therapies, an era in which AL patients are living longer, many with moderate organ damage, mobilization with Plerixafor and G-CSF was well tolerated and made it possible to collect ample numbers of CD34+ cells with limited leukaphereses in previously treated patients and in those with advanced renal failure. This approach not only allowed the collection of sufficient CD34+ cells for optimal immediate stem cell dosing but also permitted the cryopreservation of aliquots for post-SCT boost and potentially for future cell-based therapies. Disclosures: Comenzo: Millenium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Teva: Research Funding.

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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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CD34+ Subclasses of Blood Stem Cell Grafts Collected After Plerixafor Injection in Non-Hodgkin Lymphoma (NHL) Patients Mobilizing Poorly with Chemotherapy Plus G-CSF

Blood ◽

10.1182/blood.v118.21.2990.2990 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2990-2990

Author(s):

Esa Jantunen ◽

Ville Varmavuo ◽

Piia Valonen ◽

Taru Kuittinen ◽

Tapio Nousiainen ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Mobilization ◽

High Dose ◽

In Vitro Growth ◽

Control Groups ◽

Cd34 Cells ◽

Cell Mobilization

Abstract Abstract 2990 Background: Mobilization of blood stem cells is difficult in a subgroup of patients with standard methods. Plerixafor, a CXCR4 antagonist, has been used for stem cell mobilization in combination with G-CSF for some years. Mobilization method used may affect not only efficacy of stem cell mobilization and collection but also graft content which on the other hand may have effect on post-transplant outcomes. No data is available on CD34+ subclasses in grafts collected after plerixafor administration in patients who mobilize poorly with chemotherapy plus G-CSF. Patients and Methods: Altogether blood stem cell grafts collected from 26 NHL patients were studies. Thirteen patients (8 M, 5 F, median age 51 yrs) were mobilized with a combination of chemotherapy and G-CSF ad received plerixafor due to poor mobilization followed by stem cell apheressis. Thirteen patients (10 M, 3 F, median age 56 yrs) were mobilized with chemotherapy plus G-CSF without plerixafor and served as controls. Samples from the first collection after plerixafor and from the first apheresis of control patients were studied by flow cytometry using the following antibodies: CD34, CD38, CD 117, CD133, CD19 and CD45. Viability of CD34+ cells after freezing was assessed with 7-aminoactinomycin D staining. Also in vitro growth of granulocyte/macrophage progenitors (GM-CFU) were assessed from all grafts. Patients were followed after high-dose chemotherapy in regard to hematopoietic reconstitution. Results: The number of viable cells in the grafts was comparable between the plerixafor and the control groups (Table 1). The number of the most primitive stem cells (CD34+CD38−CD133+) was higher in plerixafor mobilized grafts (Table 1). Most of the CD34+ cells were myeloid progenitors, as defined by their CD117 antigen co-expression. No differences in GM-CFU were observed between the groups. All except one patient had received high-dose therapy. The median number of CD34+ cells collected from the patients was comparable (3.1 vs. 3.3 × 106/kg). The median time to reach neutrophils > 10 × 109/L was 10 days from the stem cell infusion in both groups and time to unsupported platelets was also comparable (16 d vs. 13 d). Platelet counts at 1 month, 3 months and 6 months were comparable between the groups. Absolute lymphocyte counts were higher in plerixafor group but the differences were not statistically significant. One early toxic death occurred in the plerixafor mobilized group and one death due to disease recurrence in both groups with a median follow-up of 301 and 348 days from stem cell infusion in prelixafor and control groups, respectively. Conclusions: Plerixafor added to chemomobilization in NHL patients resulted in higher number of the most primitive CD34+ cells in the graft with comparable in vitro growth and engraftment potential after BEAM chemotherapy when compared to patients mobilized without plerixafor. Longer follow-up of higher patient numbers are needed to evaluate whether differences in graft content have an effect on patient outcomes. Disclosures: Jantunen: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Pilot Study of Eltrombopag Plus G-CSF for Human CD34+ Cell Mobilization in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant

Blood ◽

10.1182/blood.v128.22.5815.5815 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5815-5815

Author(s):

Jacob P. Laubach ◽

Revital Freedman ◽

Robert A Redd ◽

Mason Tippy ◽

Kristen Cummings ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Pilot Study ◽

Adverse Events ◽

Median Number ◽

Clinical Development ◽

Stem Cell Mobilization ◽

Cd34 Cells ◽

Cell Mobilization

Abstract Background: Administration of recombinant human thrombopoietin (rhTPO) with G-CSF for stem cell mobilization is associated with high CD34+ stem cell yield, rapid neutrophil recovery following autologus transplantation (ASCT), and decreased red blood cell (rbc) and platelet (plt) transfusions (Solomo, G. et al. Blood 1999). However, clinical development of rhTPO was complicated by the formation of neutralizing anti-TPO antibodies (Li, J. et al. Blood 2001), prompting discontinuation of further clinical development of recombinant TPO. Eltrombopag (Elt) is an orally bioavailable small molecule thrombopoietin receptor (TPO-R) agonist approved by the FDA for treatment of chronic immune thrombocytopenic purpura (ITP). In vitro studies have demonstrated that Elt promotes megakaryocyte proliferation and differentiation of CD34+ bone marrow progenitor cells (Erickson-Miller CL Stem Cells 2009), suggesting that Elt might be a surrogate for rhTPO for stem cell mobilization. In this pilot trial, we evaluated the combination of Elt plus standard G-CSF and cyclophosphamide (C) for stem cell mobilization in patients (pts) with multiple myeloma (MM), a disease for which ASCT remains a standard of care (Blade et al. Blood 2010). Methods: Primary objectives included determination of the median number of CD34+ cells/kg mobilized and the maximum tolerated dose (MTD) of Elt. Pts had MM that was stable or responsive to at least two cycles of chemotherapy with plans for stem cell mobilization and ASCT. Four pts were to be enrolled in each of four dose escalation arms in which they received 0 (Arm D), 50 (Arm A), 100 (Arm B), or 150 mg (Arm C) of eltrombopag in combination with standard C + G-CSF. Adverse events (AEs) were graded by NCI-CTCAE v4. Results: 17 pts have been screened and enrolled to date. Two patients withdrew consent prior to receiving Elt and were excluded from statistical analysis. 15 patients have completed participation in the study to date and two patients remain to be enrolled in Arm C. The first subject in Arm A experienced delayed engraftment that was determined to be unrelated to ELT; rather, the event was attributed to administration of a one-time high dose of corticosteroid for management of a severe hypersensitivity reaction to DMSO that occurred during stem cell infusion. A second subject in Arm A had undergone mobilization with Elt prior to the previously described delayed engraftment event, and to ensure safety underwent a second mobilization with G-CSF and plerixafor. During ASCT, this patient received cells from the second mobilization procedure. While neither event met criteria for a dose-limiting toxicity, the protocol was amended such that three additional patients enrolled in Arm A underwent two rounds of mobilization - the first with Elt plus C and G-CSF and a second with G-CSF plus plerixafor - and received as part of ASCT cells mobilized with Elt. Each of these patients engrafted successfully. The median number of CD34+ cells/kg collected during the first collection day of apheresis in Arms D, A, B, and C was 8.0, 11.0, 15.3, and 26.4. The median total number of CD34+ stem cells collected following mobilization with Elt plus C and G-CSF in Arms D, A, B, and C was 13.2, 12.7, 15.4, and 26.4. The percentage of patients in Arms D, A, B, and C who achieved a target collection of 8 x 10^6 CD34+ stem cells in one collection day was 50, 60, 75, and 100%. There have been no severe adverse events related to Elt . Conclusions: Administration of Elt in combination with C plus G-CSF for stem cell mobilization in pts with MM undergoing ASCT was safe and well tolerated, with no DLTs or severe AEs attributable to Elt. The small size of this pilot study precludes formal statistical comparison of outcomes across treatment Arms, but there appears to be a trend toward increase in yield of CD34+ cells and decrease in apheresis procedures required with increasing doses of Elt. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Allogeneic Stem Cell Transplantation with Peripheral Blood Stem Cells Mobilized by Pegylated-G-CSF.

Blood ◽

10.1182/blood.v106.11.1970.1970 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1970-1970

Author(s):

Geoff Hill ◽

Edward S. Morris ◽

Maddona Fuery ◽

Cheryl Hutchins ◽

Jason Butler ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Peripheral Blood ◽

Cell Function ◽

Ideal Body Weight ◽

Stem Cell Mobilization ◽

Peripheral Blood Stem Cells ◽

Cd34 Cells ◽

Cell Mobilization ◽

12Mg Dose

Abstract The mobilization of stem cells with pegylated-G-CSF (peg-G-CSF) modulates regulatory T cell and NKT cell function, separating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects in animal models. We have initiated a phase I/II study to analyse the feasibility of mobilizing stem cells from sibling donors with peg-G-CSF and their ability to restore hematopoiesis in HLA matched transplant recipients who have received myeloablative conditioning. Results were compared to a cohort of donors mobilized with standard G-CSF at 10ug/kg/day (n=19). The administration of 6mg of peg-G-CSF (n=6) resulted in suboptimal stem cell mobilization with a peak peripheral blood CD34+ count of 29 ± 4/uL. Apheresis 4 days after peg-G-CSF administration yielded 2.7 ± 0.3 x106 CD34+ cells/kg recipient ideal body weight and all patients required a second collection on day 5 to yield a total of 4.0 ± 0.5 x106 CD34+ cells/kg recipient weight. Following escalation of the dose to 12mg (n=9), the peak CD34+ count was 109 ± 13/uL and all donors collected sufficient stem cells for transplantation in a single apheresis (9.8 ± 1.7 x106 CD34+ cells/kg recipient weight). The 6mg dose of peg-G-CSF was significantly inferior to standard G-CSF for stem cell mobilization (P<0.01) while the 12mg dose was at least equivalent (P=0.07). Bone pain was similar between the 6mg and 12mg cohorts and to that seen with standard G-CSF. However, in addition to the expected rises in serum ALP and LDH, transient rises in hepatic transaminases were noted 5 to 12 days after peg-G-CSF administration in 7 of 9 donors receiving the 12mg dose. One donor developed NCI grade 3 hepatic toxicity and splenomegaly. After allogeneic transplantation of peg-G-CSF mobilized grafts (Cy/TBI conditioning in 13 of 14 recipients), median neutrophil and platelet engraftment occurred on days 18 and 14 respectively and was identical to that seen with grafts mobilized by standard G-CSF. With a median follow up of 165 days (range 55–532), the incidence of grade II-IV and grade III/IV acute GVHD is 50% and 21% respectively. No patients have relapsed to date and overall survival is 86%. The mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12mg appears the optimal dose. Further data are required to more closely analyse the effect of peg-G-CSF on donor liver function and the ability of stem cell grafts to separate GVHD and GVL effects. Figure Figure

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Plerixafor and G-CSF Versus Cyclophosphamide and G-CSF for Stem Cell Mobilization in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2146.2146 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2146-2146 ◽

Cited By ~ 2

Author(s):

Aziz Nazha ◽

Rachel Cook ◽

Dan T. Vogl ◽

Patricia A. Mangan ◽

Kimberly Hummel ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Incomplete Data ◽

Median Number ◽

Stem Cell Mobilization ◽

Cell Transplant ◽

Long Term Outcome ◽

Cell Mobilization ◽

Stem Cell Collection

Abstract Abstract 2146 Poster Board II-123 Introduction: High dose melphalan and autologus stem cell transplant remains an effective treatment for patients with either early or refractory multiple myeloma (MM). Collection of sufficient numbers of stem cells for more than one transplant is optimal. G-CSF with chemotherapy, particularly cyclophosphamide (CY/G-CSF), has been a widely used and effective regimen for stem cell collection in MM. Plerixafor, a CXCR4 antagonist, when combined with G-CSF has been shown in a large randomized clinical trial to be superior to G-CSF alone. A comparison of plerixifor/G-CSF to CY/G-CSF is presented here. Materials and Methods: We performed a single institution retrospective analysis of 365 patients with MM who underwent stem cell mobilization and harvest at the University of Pennsylvania Abramson Cancer Center from January 2002 to December 2007. All patients were harvested early in the course of their disease. 76 patients were excluded from this analysis (23 had incomplete data on induction regimen, 19 had incomplete data on stem cell collection, 16 had incomplete data on mobilization regimen, 10 underwent allogeneic transplants, 2 had bone marrow rather than peripheral blood harvests, 2 had stem cells collected at an outside institution, 2 had chemotherapy mobilization other than CY and 2 had medical complications prior to harvest and after mobilization). Therefore, 289 patients were included in the analysis; 16 received plerixafor/G-CSF, 198 received CY/G-CSF, and 75 received G-CSF alone. Results: The median number of collected stem cells was 7.95 × 106 CD34+/kg in plerixafor/G-CSF group, 7.7 × 106 CD34+/kg in Cy/G-CSF group and 4.5 × 106 CD34+/kg in G-CSF alone group. The median number of apheresis days was 2 days, 2 days and 4 days respectively. The percentage of the patients who collected ≥ 6 × 106 CD34+/kg in < 3 apheresis was 63% (10/16), 62% (123/198) and 19% (14/75) respectively. The percentage of the patients who collected ≥ 6 × 106CD34+/kg <5 apheresis was 81% (13/16), 69% (136/198) and 23% (17/75) respectively. The mean CD34+/kg collected erither after CY/G-CSF or plerixafor/G-CSF was higher than G-CSF alone (p<0.0001 for each analysis). Conclusion: This analysis suggests that plerixafor/G-CSF and CY/G-CSF mobilization result in similar and adequate stem cell harvest numbers for autologous stem cell transplantation for MM. Both approaches are superior to G-CSF alone. The choice of plerixafor/G-CSF vs CY/G-CSF for stem cell mobilization will therefore depend on further analysis of the relative costs, toxicities and long term outcome of these regimens. Disclosures: Stadtmauer: genzyme: Consultancy.

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Autologous Stem Cell Transplant in Patients with Multiple Myeloma Previously Treated with Lenalidomide: A Single-Institution Experience Using An Intermediate-Dose Cyclophosphamide-Based Regimen

Blood ◽

10.1182/blood.v118.21.4391.4391 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4391-4391

Author(s):

Asif Alavi ◽

Rada Grubovic ◽

Gary J. Schiller

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Treated Group ◽

Median Number ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Cd34 Cells ◽

Peripheral Stem Cells

Abstract Abstract 4391 Background: High dose chemotherapy followed by autologous transplantation of peripheral blood stem cells plays an important role in the management of intermediate- and advanced-stage multiple myeloma. In order for successful engraftment to occur, adequate numbers of high quality peripheral stem cells must be harvested prior to transplantation. Mobilization of PBSC in patients treated with lenalidomide has been associated with poor apheresis collections after G-CSF mobilization. The purpose of this study is to present our institution’s experience utilizing an intermediate-dose cyclophosphamide-based mobilization regimen. Methods: We retrospectively analyzed data for patients with multiple myeloma who underwent autologous stem cell transplant at UCLA between 2006 and 2010. Data were obtained from the database of the UCLA Heme Malignancy/Stem Cell Transplant Unit, the electronic health record system and stem cell processing laboratory. All patients underwent mobilization with a regimen of cyclophosphamide 2.5g/m2 IVPB, G-CSF 10 mcg/kg/day for 4 days SQ, and prednisone 2mg/kg/day for 4 days po. The number of CD 34+ cells was used as a marker for the number of peripheral stem cells collected. Minimum dose collected to ensure adequate engraftment was 2×106/kg CD34+ cells. Patients were conditioned with melphalan 100mg/m2/d x2 (unless there was evidence of renal failure, in which case the dose was reduced to 100mg/m2) with subsequent infusion of stem cells. Neutrophil engraftment was defined as the first day of absolute neutrophil count greater than 500×106/L ≥ 7 days after transplant. Results: Autologous stem cell transplant was performed in 103 patients with multiple myeloma at UCLA between 2006 and 2010. Median number of apheresis procedures was 1 (1–12) with a median of 4.4×106/kg (1.4–33.5) CD34+ cells collected. Median time to engraftment was 10 (8–18) days. Thirty-five patients received lenalidomide at some point in their pretransplant treatment. Median number of apheresis procedures was 1 in both lenalidomide and non lenalidomide treated groups. In the lenalidomide treated group 54% required only one collection versus 75% in the non lenalidomide treated group (p=0.033). In the lenalidomide treated group 31% required 3 more or more collections versus 10% in non lenalidomide treated group (p=0.0075). Three patients in the lenalidomide group had subsequent mobilization with plerixafor with one of these requiring bone marrow harvesting. Median CD34+ cells collected was 3.5×106/kg and 4.9×106/kg (p=0.246) in the lenalidomide and non-lenalidomide groups respectively. Both groups had a median time to neutrophil engraftment of 10 days with a similar range. Conclusion: Pre-transplant use of lenalidomide adversely affected the number of stem cell apheresis procedures required to procure adequate stem cell dose as evidenced by a greater percentage requiring 3 or more collections. However, despite prior lenalidomide exposure, the use of our mobilization regimen permitted adequate collection, with the majority of patients requiring only one apheresis procedure, and led to an equivalent time to neutrophil recovery. Disclosures: Off Label Use: Cyclophosphamide and G-CSF for mobilization of stem cells.

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