Multiple Myeloma: Risk Adapted Use of Plerixafor for Stem Cell Mobilization Prior to Autologous Stem Cell Transplantation is Effective and Cost Efficient

BackgroundWe used plerixafor in ‘a risk adapted approach’ for stem cell mobilization for multiple myeloma (MM) patients prior to autologous stem cell transplantation (ASCT).Patients and MethodsBetween January, 2017 and December, 2019 105 consecutive patients of MM were recruited (Study Cohort). Patients received inj G-CSF 10 µg/kg in 2 divided doses for 5 days. Day 4 peripheral blood (PB) CD34+ count was used as a guide; if count was < 20 cells/µl, patients received plerixafor. For those with ≥ 20 cells/µl apheresis was commenced on day 5. We compared their outcome with 156 MM patients transplanted between 2012 and 2016 with G-CSF mobilized PB stem cells (Control Cohort). Primary end point was to collect ≥2.0  ×  10⁶ CD34+ cells/kg (minimal harvest). Secondary end points were: no of apheresis sessions, percentage of patients with optimal stem cell harvest (≥4.0  ×  10⁶ CD34+ cells/kg) and cost analysis. An intent to treat analysis was done.Result96.2% of patients achieved ≥ 2.0  ×  10⁶ CD34+ cells/kg in the study cohort vs. 87.2% in the control cohort, P < .01. Mean apheresis sessions were 1.5 vs. 1.7 respectively, P < .014 . Optimal stem cell harvest was 29.5% vs. 16%,P = .23. Days for neutrophil engraftment (P < 0.025) and for IV antibiotics (P < .0017) were favorable for the study cohort. Incremental cost effectiveness ratio was $ 15.80/- and $ 10.56/- per 1% increase to achieve a minimal and optimal harvest.ConclusionPlerixafor in this risk adapted strategy resulted in successful mobilization, decreased time to engraftment and was cost effective.     

Mobilization of peripheral blood stem cells using regimen combining docetaxel with granulocyte colony-stimulating factor in breast cancer patients

Objective:To evaluate the effectiveness and safety of the mobilization of peripheral blood hematopoietic stem cells by combining docetaxel with granulocyte colony-stimulating factor(G-CSF) in breast cancer patients.Methods:A total of 57 breast cancer patients were treated with docetaxel 120 mg/m2.When the white blood cell(WBC) count decreased to 1.0×109/L,patients were given G-CSF 5-g/kg daily by subcutaneous injection until the end of apheresis.Peripheral blood mononuclear cells(MNC) were isolated by Cobe Spectra Apheresis System.The percentage of CD34+ cell was assayed by flow cytometry.Results:At a median 6 of days(range 3-8) after the administration of docetaxel,the median WBC count decreased to 1.08×109/L(range 0.20-2.31).The median duration of G-CSF mobilization was 3 days(range 2-7).The MNC collection was conducted 8-12 days(median 10 days) after docetaxel treatment.The median MNC was 5.35×108/kg(range 0.59-14.07),the median CD34+ cell count was 2.43×106/kg(range 0.16-16.69).The CD34+ cell count was higher than 1.00×106/kg in 47 of 57 cases(82.46%) and higher than 2.00×106/kg in 36 cases(63.16%).The CD34+ cell count was higher than 2.00×106/kg in 27 collections(23.68%).The MNC count and the CD34+ cell count were correlated with the bottom of WBC after docetaxel chemotherapy(r=0.364,0.502,P=0.005,0.000).The CD34+ cell count was correlated with the MNC count(r=0.597,P=0.000).The mobilization and apheresis were well tolerated in all patients.Mild perioral numbness and numbness of hand or feet were observed in 3 cases.No serious adverse events were reported.Conclusion:Mobilization of peripheral blood hematopoietic stem cell by combining docetaxel with G-CSF was effective and safety in breast cancer patients.     

Hematopoietic progenitor cell collection and neoplastic cell contamination in breast cancer patients receiving chemotherapy plus granulocyte-colony stimulating factor (G-CSF) or G-CSF alone for mobilization

Background: We compared hematopoietic progenitor cell (HPC) collection and neoplastic cell contamination in breast cancer patients given cyclophosphamide (CTX) plus granulocyte-colony stimulating factor (G-CSF) or G-CSF alone for mobilization.Patients and methods: In 57 stage II–III breast cancer patients, CD34+ cells, colony-forming units-granulocyte macrophage (CFU-GM), early HPC and breast cancer cells were counted in HPC collections obtained after CTX plus G-CSF (n = 27) or G-CSF-alone mobilization (n = 30).Results: The CD34+ cell collection was about two-fold greater after CTX plus G-CSF mobilization (11.0 ± 7.9 vs. 5.8 ± 3.5 × 10⁶/kg, P < 0.001). Similarly, the total number of CFU-GM, CD34+CD38– cells and of week-5 cobblestone area forming cells (CAFC) collected was significantly higher in patients mobilized with CTX plus G-CSF. Breast cancer cells were found in the apheresis products of 22% of patients mobilized with CTX plus G-CSF and in 10% of patients mobilized with G-CSF alone (P = 0.36). Of seven patients who failed G-CSF-alone mobilization and eventually underwent chemotherapy plus G-CSF mobilization, none had cytokeratin-positive cells after G-CSF mobilization, whereas four out of seven had cytokeratin-positive cells after chemotherapy plus G-CSF (P = 0.07 by ² test).Conclusion: The CTX plus G-CSF mobilization protocol was associated with a significantly higher HPC collection. However, this benefit was not accompanied by a reduction in the incidence of tumor-contaminated HPC graft.     

Late afternoon dosing of plerixafor for stem cell mobilization: a practical solution

BackgroundPlerixafor was recently approved for stem cell mobilization in patients who have non-Hodgkin lymphoma or multiple myeloma. However, the use of late evening (10 PM) injections is inconvenient for patients and requires an after-hours infrastructure that may not be readily available.Patients and MethodsBased on an earlier study showing prolonged mobilization of stem cells in patients given plerixafor plus granulocyte colony-stimulating factor (G-CSF), we administered plerixafor at 5 PM and performed apheresis approximately 15 hours later. Plerixafor was administered primarily to patients who either had failed previous mobilization or were at risk for poor mobilization because of previous therapy, especially lenalidomide in patients who had multiple myeloma.ResultsOf 48 patients, including 24 with myeloma and 24 with lymphoma, 47 had enough stem cells collected (> 2 × 10E6 CD34+ cells/kg) to proceed to transplant, including all 13 patients who had failed previous chemotherapy plus G-CSF mobilization and 18 patients treated with four cycles or more of lenalidomide. The day +1 post-plerixafor increment in circulating CD34+ cells was greatest in patients who had the highest preplerixafor CD34 count; however, in patients with preplerixafor CD34+ cell counts < 10/μL (and who typically mobilize poorly), 83% of patients had enough stem cells collected to proceed to transplant.ConclusionThis study suggests that plerixafor is effective when given 15 hours before apheresis, even in a population at high risk for mobilization failure. A proposed cost-effective use of plerixafor is to administer it to patients who are inadequately mobilized with G-CSF alone or for salvage in patients who fail previous mobilization with chemotherapy plus G-CSF.     

外周血造血祖细胞检测对外周血干细胞动员采集的预测意义

 目的　通过血细胞分析仪检测外周血造血祖细胞（HPC）含量,探寻一种快速预测采集物干细胞含量、判断外周血造血干细胞采集时机的手段,并评价其应用意义。方法　对27例化疗联合粒细胞集落刺激因子（G-CSF）进行外周血造血干细胞动员采集者及17例单用G-CSF动员的采集者,利用血细胞分析仪检测外周血HPC计数,血液治疗和移植工程国际组织（ISHAGE）法检测外周血及采集物CD+34 细胞计数,并进行相关回归分析。对外周血HPC计数预测采集物CD+34 含量进行受试者工作曲线（ROC）分析。结果　无论化疗组或非化疗组,外周血HPC计数与CD+34 计数均具有线性相关性（r＝0.711,P＝0.000及r＝0.656,P＝0.004）。化疗组外周血CD+34 计数＝-0.829+0.648×外周血HPC计数;非化疗组外周血CD+34 细胞计数＝45.033+0.460×外周血HPC计数。化疗组患者外周血HPC计数与采集物CD+34 细胞量呈线性相关（r＝0.602,P＝0.001）,采集物CD+34 计数＝1.106+0.046×外周血HPC计数。以HPC≥85／μl预测采集物CD+34 计数≥5×106／kg的灵敏度为78 %,特异度为82 %。结论　在自体干细胞移植动员患者中,外周血HPC计数可部分替代外周血CD+34 计数预测采集效果,HPC≥85／μl为较好的预测阈值。     

A Phase I Study of the Safety and Feasibility of Bortezomib in Combination With G-CSF for Stem Cell Mobilization in Patients With Multiple Myeloma

BackgroundWe previously reported that administration of bortezomib (BTZ) after 4 days of granulocyte colony-stimulating factor (G-CSF) significantly augments mobilization in mice. We hypothesized that administration of BTZ at peak G-CSF mobilization in patients with multiple myeloma (MM) would be safe, augment mobilization, and have an in vivo purging effect on circulating myeloma cells.Patients and MethodsThis was a phase I study using 3 dose levels of BTZ. G-CSF was administered for 5 days. On the evening of the fourth day, a single dose of BTZ was administered. Peripheral blood was drawn 1 to 2 hours before and 15 to 18 hours after BTZ administration (before day 5 G-CSF administration) to analyze the mobilization effect of BTZ. Standard apheresis was then performed starting on day 5. After mobilization, patients underwent autologous stem cell transplantation (ASCT) per institutional guidelines.ResultsTen patients were enrolled. There were no dose-limiting toxicities. Median peripheral blood CD34⁺ cells at day 4 before BTZ administration was 16 per microliter and 15 hours later was 32 per microliter suggesting that administration of BTZ at peak G-CSF mobilization augments the mobilization effect of G-CSF. The effect of BTZ on circulating MM cells was unclear. All patients had successful engraftment after ASCT.ConclusionAdministration of 1 dose of BTZ at peak G-CSF mobilization was safe and well tolerated, enhanced stem cell mobilization, and did not affect graft viability. The mobilization effect of BTZ at peak G-CSF mobilization shown in this phase I study needs to be confirmed in a larger randomized trial.     

ESHAP and G-CSF is a superior blood stem cell mobilizing regimen compared to cyclophosphamide 1.5 g m(-2) and G-CSF for pre-treated lymphoma patients: a matched pairs analysis of 78 patients

Cyclophosphamide 1.5 g m(-2) followed by granulocyte colony-stimulating factor (G-CSF) is an effective peripheral blood stem cell (PBSC) mobilizing regimen, but has limited anti-lymphoma activity. We therefore assessed the mobilizing potential of ESHAP (etoposide, ara-C, methylprednisolone and cisplatin), a potent second-line lymphoma regimen followed by G-CSF. The results were compared in 78 patients with relapsed or resistant lymphomas with the use of cyclophosphamide 1.5 g m(-2) followed by G-CSF in a matched pairs analysis, matching the ESHAP recipients (for predetermined prognostic factors) from a cohort of 178 lymphoma patients mobilized with cyclophosphamide and G-CSF. The total numbers of mononuclear cells collected at apheresis was similar with both regimens but ESHAP plus G-CSF resulted in a significantly higher percentage of CD34+ cells, absolute number of CD34+ cells and GM-CFC (all with P-values < 0.001). The number of patients requiring only one apheresis harvest to achieve a CD34+ cell yield of > 2.0 x 10(6) kg(-1) was greatly increased in the ESHAP recipients (56/78 vs 17/78, P < 0.001). The total number of progenitor cells collected was not significantly different with the two mobilization regimens because of this higher number of apheresis in the cyclophosphamide group. The proportion of patients who failed to achieve a minimum CD34+ cell target of 1 x 10(6) kg(-1) with the pooled harvests was less in the ESHAP arm (four patients vs nine patients) despite an increased number of aphereses in the cyclophosphamide recipients. ESHAP plus G-CSF is well tolerated and is an excellent mobilization regimen in patients with pre treated lymphoma.     

Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony-stimulating factor in pediatric donors.

The advantages/disadvantages of the use of peripheral blood stem cells (PBSCs) for allogeneic transplantation still need to be clarified, particularly in children. We compared the kinetics, efficacy, and safety of PBSC mobilization by granulocyte colony-stimulating factor (G-CSF) and collection by apheresis between healthy pediatric and adult donors. A total of 19 pediatric (median age, 6 years) and 25 adult healthy donors (median age, 37 years) were given 10 micro/kg/day of G-CSF for 5 consecutive days for PBSC mobilization, which were harvested by apheresis on days 5 and/or 6. All of the donors tolerated the whole procedures. Serum trough levels of G-CSF determined by ELISA were significantly lower in the 16 pediatric donors evaluated than in adults (n = 16) on days 3 and 4 (P < 0.05). Although the WBC counts on days 4 and 5 were significantly higher in adults than in children (P = 0.006 and 0.004, respectively), the numbers of circulating CD34+ cells/unit of blood were identical. The number of blood CD34+ cells collected per unit of blood processed was identical in both donor populations. We propose that PBSCs could be effectively mobilized and collected in small children so that they could be donors for adult patients.     

Selective in vivo mobilization with granulocyte macrophage colony-stimulating factor (GM-CSF)/granulocyte-CSF as compared to G-CSF alone of dendritic cell progenitors from peripheral blood progenitor cells in patients with advanced breast cancer undergoing autologous transplantation.

Dendritic cells (DCs) are potent antigen-presenting cells that are essential for the initiation of T cell-mediated immunity. DCs develop from myeloid progenitor populations under the influence of granulocyte macrophage colony-stimulating factor (GM-CSF) and pass through an intermediate stage of maturation that is characterized by CD14 expression. Interest has focused on generating human-derived DCs for antigen-specific tumor vaccines to be used as adjuvant immunotherapy in minimal disease settings, such as after autologous transplantation. In the present study, mobilized peripheral blood progenitor cells (PBPCs) were obtained from 18 patients with locally advanced or metastatic breast cancer preparing to undergo autologous stem cell transplantation. PBPCs mobilized in 10 patients with GM-CSF for 1 week, followed by the combination of GM-CSF and G-CSF, were compared with those obtained from patients receiving G-CSF alone with respect to the presence of DC progenitors and the capacity to generate functionally active mature DCs. PBPCs mobilized with GM-CSF/G-CSF were markedly enriched for CD14+ DC progenitor cells as compared with those mobilized with G-CSF alone. Consistent with an immature progenitor population, the CD14+ cells express Ki-67 antigen but not nonspecific esterase. CD14+ cells purified by fluorescence-activated cell sorting from PBPCs mobilized with either regimen and cultured for 1 week in GM-CSF and interleukin-4 generated nearly pure populations of cells with characteristic DC phenotype and function. The addition of GM-CSF to the mobilization regimen resulted in greater yields of functionally active DCs for potential use in posttransplant immunotherapy.     

Prolonged Lenalidomide Induction Does Not Significantly Impair Stem Cell Collection in Multiple Myeloma Patients Mobilized With Cyclophosphamide or Plerixafor: A Report From The Covid Era

IntroductionInduction therapy for multiple myeloma is traditionally capped at 6 cycles of lenalidomide due to concerns that longer treatment compromises the ability to collect sufficient stem cells for autologous stem cell transplantation (ASCT). However, during the COVID-19 pandemic, many of our patients received prolonged lenalidomide induction due to concerns about proceeding to ASCT. We investigated whether prolonged induction with lenalidomide affects the efficacy of stem cell collection among patients mobilized with cyclophosphamide and/or plerixafor.Patients and methodsThis single center, retrospective study included patients who were treated with lenalidomide induction regimens, received mobilization with cyclophosphamide or plerixafor, and underwent apheresis in preparation for ASCT. 94 patients were included, 40 of whom received prolonged induction with >6 cycles of lenalidomide containing regimen.ResultsPatients who received prolonged induction were more likely to require >1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (R² = 0.06423, P = .0148). However, there was no significant difference between patients who received prolonged induction and those who did not with respect to CD34⁺ stem cell yields at completion of apheresis (9.99 vs. 10.46 cells/Kg, P = .5513) or on the first day of collection (8.29 vs. 9.59 cells/Kg, P = .1788).ConclusionAmong patients treated with >6 cycles of lenalidomide, mobilization augmented with cyclophosphamide and/or plerixafor will likely facilitate sufficient stem cell harvest to permit ASCT.     

Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H.

Chronic lymphocytic leukemia (CLL) cells could be undetectable by flow cytometry or polymerase chain reaction after sequential treatment with fludarabine and Campath-1H. Concern has been raised regarding the ability to mobilize sufficient peripheral blood progenitor cells (PBPCs) for autografting after purine analogues, and there are few data about PBPC collection after Campath-1H. In all, 16 CLL patients responding to sequential chemo-immunotherapy entered the study. In 10, mobilization regimen consisted of granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/die. Patients failing mobilization or not achieving the target of 2.5 x 10(6) CD34+ cells/kg underwent a second attempt using intermediate-dose (ID) Ara-C, 800 mg/m(2) every 12 h for six doses+G-CSF. PBPC collection after G-CSF alone was successful in two out of 10 patients. An adequate number of CD34+ cells were collected after ID Ara-C+G-CSF in eight patients failing the mobilization with G-CSF alone and in five out of six who did not receive G-CSF before. Greater yields of PBPCs were collected with Ara-C+G-CSF compared with G-CSF alone (13.8 vs 3.3). The extrahematologic toxicity was manageable. In conclusion, PBPC collection is feasible in CLL patients treated with sequential therapy including fludarabine and Campath-1H. Excellent yields were obtained in 92.8% of patients primed with ID Ara-C+G-CSF.     

Randomized cross-over trial of progenitor-cell mobilization: high-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF.

PURPOSE: Patient response to hematopoietic progenitor-cell mobilizing regimens seems to vary considerably, making comparison between regimens difficult. To eliminate this inter-patient variability, we designed a cross-over trial and prospectively compared the number of progenitors mobilized into blood after granulocyte-macrophage colony-stimulating factor (GM-CSF) days 1 to 12 plus granulocyte colony-stimulating factor (G-CSF) days 7 to 12 (regimen G) with the number of progenitors after cyclophosphamide plus G-CSF days 3 to 14 (regimen C) in the same patient. PATIENTS AND METHODS: Twenty-nine patients were randomized to receive either regimen G or C first (G1 and C1, respectively) and underwent two leukaphereses. After a washout period, patients were then crossed over to the alternate regimen (C2 and G2, respectively) and underwent two additional leukaphereses. The hematopoietic progenitor-cell content of each collection was determined. In addition, toxicity and charges were tracked. RESULTS: Regimen C (n = 50) resulted in mobilization of more CD34(+) cells (2.7-fold/kg/apheresis), erythroid burst-forming units (1.8-fold/kg/apheresis), and colony-forming units-granulocyte-macrophage (2.2-fold/kg/apheresis) compared with regimen G given to the same patients (n = 46; paired t test, P<.01 for all comparisons). Compared with regimen G, regimen C resulted in better mobilization, whether it was given first (P =.025) or second (P =.02). The ability to achieve a target collection of > or =2x10(6) CD34(+) cells/kg using two leukaphereses was 50% after G1 and 90% after C1. Three of the seven patients in whom mobilization was poor after G1 had > or =2x10(6) CD34(+) cells/kg with two leukaphereses after C2. In contrast, when regimen G was given second (G2), seven out of 10 patients failed to achieve the target CD34(+) cell dose despite adequate collections after C1. Thirty percent of the patients (nine of 29) given regimen C were admitted to the hospital because of neutropenic fever for a median duration of 4 days (range, 2 to 10 days). The higher cost of regimen C was balanced by higher CD34(+) cell yield, resulting in equivalent charges based on cost per CD34(+) cell collected. CONCLUSION: We report the first clinical trial that used a cross-over design showing that high-dose cyclophosphamide plus G-CSF results in mobilization of more progenitors then GM-CSF plus G-CSF when tested in the same patient regardless of sequence of administration, although the regimen is associated with greater morbidity. Patients who fail to achieve adequate mobilization after regimen G can be treated with regimen C as an effective salvage regimen, whereas patients who fail regimen C are unlikely to benefit from subsequent treatment with regimen G. The cross-over design allowed detection of significant differences between regimens in a small cohort of patients and should be considered in design of future comparisons of mobilization regimens.     

Predictors of CD34+ Cell Mobilization and Collection in Adult Men With Germ Cell Tumors: Implications for the Salvage Treatment Strategy

BackgroundHigh-dose chemotherapy with tandem or triple carboplatin and etoposide course is currently the first curative choice for relapsing GCT. The collection of an adequate amount of hematopoietic (CD34⁺) stem cells is a priority.Patients and MethodsWe analyzed data of patients who underwent HDCT at 2 referral institutions. Chemotherapy followed by myeloid growth factors was applied in all cases. Uni- and multivariable models were used to evaluate the association between 2 prespecified variables and mobilization parameters. Analyses included only the first mobilizing course of chemotherapy and mobilization failures.ResultsA total of 116 consecutive patients underwent a mobilization attempt from December 1995 to November 2012. Mobilizing regimens included cyclophosphamide (CTX) 7 gr/m² (n = 39), cisplatin, etoposide, and ifosfamide (PEI) (n = 42), paclitaxel, cisplatin, and gemcitabine (TPG) (n = 11), and mixed regimens (n = 24). Thirty-seven percent were treated in first-line, 50% (n = 58) in second-line, 9.5% (n = 11) and 3.4% (n = 4) in third- and fourth-line settings, respectively. Six patients did not undergo HDCT because they were poor mobilizers, 2 in first- and second-line (1.9%), and 4 beyond the second-line (26.7%). In the multivariable model, third-line or later setting was associated with a lower CD34⁺ cell peak/μL (P = .028) and a lower total CD34⁺/kg collected (P = .008). The latter was also influenced by the type of mobilizing regimen (P < .001).ConclusionA decline in significant mobilization parameters was found, primarily depending on the pretreatment load. Results lend support to the role of CD34⁺ cell mobilization in the therapeutic algorithm of relapsing GCT, for whom multiple HDCT courses are still an option, and potentially a cure.     

Successful mobilization of peripheral blood stem cells with the DHAP regimen (dexamethasone, cytarabine, cisplatinum) plus granulocyte colony-stimulating factor in patients with relapsed Hodgkin's disease

High-dose chemotherapy followed by autologous stem cell transplantation can improve the outcome of relapsed and refractory Hodgkin's disease (HD) patients. The objective of the trial was to determine the mobilizing potential of the DHAP salvage regimen (dexamethasone, cytarabine, cisplatin) for the collection of peripheral blood stem cells (PBSC) in patients with relapsed HD. The target yield of harvesting CD34 + cells was ≥ 2 × 10⁶/kg in order to support the subsequent myeloablative chemotherapy. Most of the 105 patients included were intensively pre-treated with different combination chemotherapy regimens prior to mobilization. The use of DHAP followed by granulocyte colony-stimulating factor (G-CSF; 10 μg/kg) resulted in the successful collection of adequate numbers of PBSC in 97.1% of patients (102 of 105) with a median harvest of CD34 + cells of 13 × 10⁶/kg (range 2.6 - 85.1). More than 2.0 × 10⁶ CD34 + cells/kg were achieved in 65 of 103 (63%) patients after 1 apheresis, the maximum number of aphereses for all patients was 3. It was found that the optimal time of PBSC harvest was at days 13 - 16 after initiating the mobilization regimen.

These results demonstrate that the salvage chemotherapy regimen, such as DHAP combined with G-CSF, can be successfully used to mobilize PBSC in HD patients.     

Differences in kinetics of donor lymphoid cells in response to G-CSF administration may affect the incidence and severity of acute GvHD in respective HLA-identical sibling recipients

Granulocyte-colony stimulating factor (G-CSF), in addition to myeloid and stem cells, mobilizes a large number of lymphoid cells. We examined which lymphoid populations were mobilized in 21 consecutive donors of peripheral blood stem cells (PBSC) and whether the differences in mobilization could affect the incidence of acute and chronic GvHD in respective HLA-identical recipients. G-CSF administration induced significant increases of donor B (CD3⁻CD19⁺) lymphocytes and slight increases of T (CD3⁺) and cytotoxic (CD16⁺CD56⁺) NK cells. The number of extrathymic cells (CD3⁺ cells with NK markers, or CD7⁺) remained unchanged except for an increase of CD3⁺CD57⁺CD8⁺ cells. Donors of patients without subsequent grade II–IV acute GvHD compared to donors of patients who developed significant acute GvHD were found to have in peripheral blood stable numbers of CD3⁺CD4⁺ cells producing IL2, with a concomitant increased number of CD3⁺CD4^low+CD25⁺ T regulatory cells and decreased NK-mediated cytotoxicity, together with a higher number of suppressive extrathymic CD57⁺CD3⁺ cells in the blood and G-PBMC grafts. Increasing numbers of activated T and NK cells in the blood were associated with the development of chronic GvHD. We suggest that differences in steady-state levels and kinetics of G-CSF induced mobilization of donor lymphoid cells may in addition to other well-known factors affect the incidence of GvHD in HLA-identical recipients. However, owing to the small number of donor-recipient pairs studied, our results must be verified in a larger group of patients. Both authors contributed equally to this study.     

The stem cell mobilizing capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of the EORTC-GIMEMA AML-10 trial.

Variable numbers of CD34+ cells can be harvested from the blood of AML patients in CR after G-CSF supported mobilization following consolidation chemotherapy. We hypothesized that a decreased ability to mobilize stem cells reflects a chemotherapy-induced reduction in the number of normal and leukemic stem cells. We therefore analyzed whether the mobilizing capacity of these patients was of prognostic significance. 342 AML-patients in first CR received daily G-CSF from day 20 of the consolidation course and underwent 1-6 aphereses to obtain a minimum dose of 2 x 10(6) CD34+ cells/kg. Afterwards they were randomized for autologous bone marrow (BM) or blood SCT. As a surrogate marker for the mobilizing capacity, the highest yield of CD34+ cells of a single apheresis was adopted. Patients could be categorized into four groups: no harvest (n = 76), low yield (<1 x 10(6) CD34+/kg; n = 50), intermediate yield (1-6.9 x 10(6) CD34+ cells/kg; n = 128) and high yield (> or = 7 x 10(6) CD34+ cells/kg; n = 88). The median follow-up was 3.4 years; 163 relapses and 16 deaths in CR were reported. Autologous blood or BM SCT was performed in 36%, 64%, 81% and 88%, respectively, of the patients assigned to the no harvest, low, intermediate and high CD34+ yield group. The 3-year disease-free survival rate was 46.7%, 65.0%, 50.4% and 26.9% (P = 0.0002) and the relapse incidence was 47.5%, 30.1%, 43.1% and 71.9% (P < 0.0001). Multivariate Cox's proportional hazards model showed that the CD34+ yield was the most important independent prognostic variable (P = 0.005) after cytogenetics. Patients with the highest mobilizing capacity have a poor prognosis due to an increased relapse incidence.     

Plerixafor and G-CSF for PBSC mobilization in patients with lymphoma who failed previous attempts with G-CSF and chemotherapy: a REL (Rete Ematologica Lombarda) experience

Plerixafor has been previously reported to improve PBSC collection in pts undergoing PBSC mobilization. Aim of the study was to assess the efficacy of plerixafor and G-CSF in pts with lymphoma who failed previous attempts of PBSC mobilization with conventional schemes of chemotherapy + G-CSF. 35 heavily pre-treated lymphoma pts (29 NHL, 6 HL) classified as “poor mobilizers” were enrolled in a program of compassionate use of plerixafor in 7 Italian centres of REL (Rete Ematologica Lombarda). Median number of previous lines of therapy was 3 and median number of previous attempts of mobilizations was 2. The median number of circulating CD34+ cells/μL following plerixafor was 11/μL. It was ≥10/μL in 17 pts and ≥20/μL in 10 pts; 13 were able to collect ≥2 × 10⁶ CD34+ cells/kg with a median of 1 apheresis procedure; 4 pts collected ≥4 × 10⁶ CD34+ cells/kg. A total of 6 pts had proceeded to transplant at the time of analysis. The median dose of PBSCs infused was 4 × 10⁶/kg and hematopoietic recovery was regular. In conclusion, plerixafor combined with G-CSF allows a collection of adequate number of PBSC in approximately 40% of cases of poor mobilizer, heavily pre-treated pts with lymphoma, who need consolidation with ASCT.     

High-dose etoposide with granulocyte colony-stimulating factor for mobilization of peripheral blood progenitor cells: efficacy and toxicity at three dose levels.

High-dose etoposide (2.0-2.4 g m(-2)) with granulocyte colony-stimulating factor (G-CSF) is an effective strategy to mobilize peripheral blood progenitor cells (PBPCs), although in some patients this is associated with significant toxicity. Sixty-three patients with malignancy were enrolled into this non-randomized sequential study. The majority (55/63, 87%) had received at least two prior regimens of chemotherapy, and seven patients had previously failed to mobilize following high-dose cyclophosphamide with G-CSF. Consecutive patient groups received etoposide at three dose levels [2.0 g m(-2) (n = 22), 1.8 g m(-2) (n = 20) and 1.6 g m(-2) (n = 21)] followed by daily G-CSF. Subsequent leukaphereses were assayed for CD34+ cell content, with a target total collection of 2.0 x 10(6) CD34+ cells kg(-1). Toxicity was assessed by the development of significant mucositis, the requirement for parenteral antibiotics or blood component support and rehospitalization incidence. Ten patients (16%) had less than the minimum target yield collected. Median collections in the three groups were 4.7 (2 g m(-2)), 5.7 (1.8 g m(-2)) and 6.5 (1.6 g m(-2)) x 10(6) CD34+ cells kg(-1). Five of the seven patients who had previously failed cyclophosphamide mobilization achieved more than the target yield. Rehospitalization incidence was significantly lower in patients receiving 1.6 g m(-2) etoposide than in those receiving 2.0 g m(-2) (P = 0.03). These data suggest that high-dose etoposide with G-CSF is an efficient mobilization regimen in the majority of heavily pretreated patients, including those who have previously failed on high-dose cyclophosphamide with G-CSF. An etoposide dose of 1.6 g m(-2) appears to be as effective as higher doses but less toxic.     

Pilot trial of interleukin-2 with granulocyte colony-stimulating factor for the mobilization of progenitor cells in advanced breast cancer patients undergoing high-dose chemotherapy: expansion of immune effectors within the stem-cell graft and post-stem-cell infusion.

PURPOSE: To evaluate whether administration of interleukin-2 (IL-2) with granulocyte colony-stimulating factor (G-CSF) improves mobilization of immune effector cells into the stem-cell graft of patients undergoing high-dose chemotherapy and autografting. PATIENTS AND METHODS: We performed a trial of stem-cell mobilization with IL-2 and G-CSF in advanced breast cancer patients receiving high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin and stem cells followed by IL-2. The trial defined immune, hematologic, and clinical effects of IL-2 in this setting. RESULTS: Of 32 patients enrolled, nine received G-CSF alone for mobilization. Twenty-one of 23 patients mobilized with IL-2 plus G-CSF had stem cells collected with more mononuclear cells than those receiving G-CSF (19.3 v 10.4 x 10(8)/kg; P =.006), but fewer CD34(+) progenitor cells (6.9 v 22.0 x 10(6)/kg; P =.049). The IL-2 plus G-CSF-mobilized patients had greater numbers of activated T (CD3(+)/CD25(+)) cells (P =.009), natural killer (NK; CD56(+)) cells (P =.007), and activated NK (CD56 bright(+)) cells (P: =.039) than those patients mobilized with G-CSF. NK (P =.042) and lymphokine-activated killer (LAK) (P =.016) activity was increased in those mobilized with IL-2 + G-CSF, whereas G-CSF-mobilized patients had a decline in cytolytic activity. In the third week posttransplantation, immune reconstitution was superior in those mobilized with IL-2 plus G-CSF based on greater numbers of activated T cells (P =.003), activated NK cells (P =.04), and greater LAK activity (P =.003). The 16 of 21 IL-2 + G-CSF-mobilized patients with adequate numbers of stem cells (> 1.5 x 10(6) CD34(+) cells/kg) collected engrafted rapidly posttransplantation. CONCLUSION: The results demonstrate that G-CSF + IL-2 can enhance the number and function of antitumor effector cells in a mobilized autograft without impairing the hematologic engraftment, provided that CD34 cell counts are more than 1.5 x 10(6) cells/kg. Mobilization of CD34(+) stem cells does seem to be adversely affected. In those mobilized with IL-2 and G-CSF, post-stem-cell immune reconstitution of antitumor immune effector cells was enhanced.     

New strategies for mobilization of hematopoietic stem cells

A significant number of tumor patients fail peripheral blood progenitor cell (PBPC) mobilization and thus cannot receive potentially curative high-dose chemotherapy with subsequently required PBPC transplantation. New insights into the physiology of mobilization have revealed the pivotal role of the CXCR4/stromal derived factor-1alpha receptor-ligand interaction for stem cell retention in the bone marrow. New CXCR4 antagonists such as AMD3100 are currently in clinical studies. They act synergistically with the established mobilizing agent granulocyte colony-stimulating factor (G-CSF); thus, patients can collect more PBPCs in fewer apheresis sessions, and others that previously failed can now successfully collect sufficient PBPCs for transplantation. Experimental and clinical data suggest that the quality of AMD3100-mobilized PBPC may even be superior to PBPCs mobilized following standard therapy. CXCR4 antagonists are the most exciting development in the field of PBPC mobilization for over a decade. Additionally, new analogs of G-CSF are being introduced with favorable pharmacologic features.