Stem Cells Collection and Mobilization in Adult Autologous/Allogeneic Transplantation: Critical Points and Future Challenges.

Achieving successful hematopoietic stem cell transplantation (HSCT) relies on two fundamental pillars: effective mobilization and efficient collection through apheresis to attain the optimal graft dose. These cornerstones pave the way for enhanced patient outcomes. The primary challenges encountered by the clinical unit and collection facility within a transplant program encompass augmenting mobilization efficiency to optimize the harvest of target cell populations, implementing robust monitoring and predictive strategies for mobilization, streamlining the apheresis procedure to minimize collection duration while ensuring adequate yield, prioritizing patient comfort by reducing the overall collection time, guaranteeing the quality and purity of stem cell products to optimize graft function and transplant success, and facilitating seamless coordination between diverse entities involved in the HSCT process. In this review, we aim to address key questions and provide insights into the critical aspects of mobilizing and collecting hematopoietic stem cells for transplantation purposes.

Autologous peripheral blood stem cell mobilization and apheresis in pediatric patients with cancer: A single-center report of 64 procedures.

BACKGROUND: The published experience concerning autologous peripheral blood stem cell collection in children is very limited. METHODS: The data of pediatric patients who underwent autologous stem cell mobilization and apheresis between January 2011 and April 2020 were analyzed retrospectively. RESULTS: We studied retrospectively 64 mobilization and apheresis procedures in 48 pediatric patients (34 males, 14 females), mean age of 7.31 ± 5.38 (range, 1.5-19.7) years, the underlying disease was mostly neuroblastoma (NBL). The body weight of 21 patients (43.75%) was 15 kg or less. The targeted autologous peripheral stem cell apheresis (APSCA) was successfully achieved in 98% of patients. Neuroblastoma patients were younger than the rest of the patients and underwent apheresis after receiving fewer chemotherapy cycles than others and all of them mobilized within the first session successfully. Plerixafor was added to mobilization in nine heavily pretreated patients (18.7%), median two doses (range, 1-4 doses). 11 patients (22.9%) underwent radiotherapy (RT) before mobilization with doses of median 24 Gy (range, 10.8-54.0 Gy). Patients with RT were older at the time of apheresis and had received more chemotherapy courses than patients without RT. As a result, patients with a history of RT had significantly lower peripheral CD34+ cells and CD34+ yields than those without RT. In 17 patients (35.4%), 22 different complications were noted. The most common complications were catheter-related infections (n:10, 20.8%), followed by catheter-related thrombosis in eight patients (16.7%). CONCLUSIONS: Patients who had far less therapy before apheresis were more likely to mobilize successfully. Our study provides a detailed practice approach including complications during APSCA aiming to increase the success rates of apheresis in transplantation centers.

G-CSF + plerixafor versus G-CSF alone mobilized hematopoietic stem cells in patients with multiple myeloma and lymphoma: a systematic review and meta-analysis.

AIM: The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile. METHODS: We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760). RESULTS: Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80). CONCLUSIONS: This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.

Hematopoietic stem cell collection for sickle cell disease gene therapy.

PURPOSE OF REVIEW: Gene therapy for sickle cell disease (SCD) is advancing rapidly, with two transformative products recently approved by the US Food and Drug Administration and numerous others under study. All current gene therapy protocols require ex vivo modification of autologous hematopoietic stem cells (HSCs). However, several SCD-related problems impair HSC collection, including a stressed and damaged bone marrow, potential cytotoxicity by the major therapeutic drug hydroxyurea, and inability to use granulocyte colony stimulating factor, which can precipitate severe vaso-occlusive events. RECENT FINDINGS: Peripheral blood mobilization of HSCs using the CXCR4 antagonist plerixafor followed by apheresis collection was recently shown to be safe and effective for most SCD patients and is the current strategy for mobilizing HSCs. However, exceptionally large numbers of HSCs are required to manufacture an adequate cellular product, responses to plerixafor are variable, and most patients require multiple mobilization cycles, increasing the risk for adverse events. For some, gene therapy is prohibited by the failure to obtain adequate numbers of HSCs. SUMMARY: Here we review the current knowledge on HSC collection from individuals with SCD and potential improvements that may enhance the safety, efficacy, and availability of gene therapy for this disorder.

Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation.

ABSTRACT: Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs). We showed that bone marrow (BM)-residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit antimyeloma immunity during SCM. Thus, we performed ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells, which dramatically enhanced myeloma control after ASCT. Thus, we explored clinically tractable translational approaches to mimic this scenario. Antibody-based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic interleukin-2 (IL-2)/IL-15 mimetic that stimulates the IL-2 receptor on CD8 T cells without binding to the high-affinity IL-2Ra used by Tregs efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirmed that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represent a clinically testable strategy to improve responses after ASCT.

Safety and efficacy of peripheral blood stem cells collection in healthy children and pediatric patients with thalassemia major weighing 20 kg or less.

BACKGROUND: Peripheral blood stem cell (PBSC) collection in children poses challenges due to their small size, low body weight (BW), and unique pediatric physiology, especially among children weighing 20 kg (kg) or less. METHODS: PBSC collection data of both healthy children and patients with thalassemia major (TM) weighing 20 kg or less between January 2013 and December 2020 were reviewed. Moreover, PBSCs characteristics along with various aspects of efficiency and safety between healthy donors and patients with TM were compared. RESULTS: A total of 262 PBSC procedures were performed on 255 children. Of these, 91 procedures were carried out on 85 allogeneic healthy donors, and 171 auto-backup collections were performed on 170 patients with TM to ensure PBSC availability and prevent transplantation failure. A minimum pre-apheresis hemoglobin (HGB) level of 60 g/L was discovered to be safe and feasible in patients with TM. The median CD34+ cell dose in the PBSC product during the initial apheresis procedure was higher in healthy donors compared to patients with TM (7.29 ± 5.28 × 106 cells/kg vs5.88 ± 4.23 × 106 cells/kg, P = .043). The total CD34+ cells/kg recipient weight exhibited a positive correlation with pre-apheresis monocyte counts, but a negative correlation with donor weight. Apheresis significantly reduced hematocrit and platelet counts in the allogeneic group compared to the autologous group. Patients with TM experienced a higher occurrence of bone pain related to granulocyte colony-stimulating factor treatment. Notably, no serious complications related to PBSCs mobilization, central venous catheter placement, or the apheresis procedure were observed in either group. CONCLUSIONS: PBSCs collection was both safe and effective in healthy children and pediatric patients with TM weighing 20 kg or less.

Efficacy of prophylactic antibiotics for the prevention of neutropenic fever in patients with multiple myeloma receiving high-dose cyclophosphamide for stem cell mobilization.

High-dose cyclophosphamide (HD-Cy) (3 g/m2) plus granulocyte colony-stimulating factor (G-CSF) is a very effective regimen for peripheral blood stem cell (PBSC) mobilization. Unfortunately, it is associated with an increased risk of neutropenic fever (NF). We analyzed the effect of NF on PBSC apheresis results and the efficacy of prophylactic antibiotics for the prevention of NF associated with HD-Cy plus G-CSF for PBSC mobilization in patients with newly diagnosed multiple myeloma (MM). First, patients were divided into NF ( +) and NF ( -) groups according to whether they suffered from NF during mobilization. Second, we divided patients into an antibiotic prophylaxis group and a nonantibiotic prophylaxis group according to whether antibiotic prophylaxis was used during the mobilization period. Our study showed that NF( +) patients (n = 44) had lower CD34 + cell dose collection (median 2.60 versus 5.34 × 106/kg, P < 0.001) and slower neutrophil engraftment and platelet engraftment (median 11 versus 10 days, P = 0.002, and median 13 versus 11 days, P = 0.043, respectively) than NF( -) patients (n = 234). Of note, the nonantibiotic prophylaxis group patients (n = 30) had a 26.7% incidence of NF. In the patients receiving antibiotic prophylaxis (n = 227), the incidence was reduced to 9.3% (P = 0.01). The antibiotic prophylaxis patients had higher CD34 + cell collection (median 5.41 versus 2.27 × 106/kg, P < 0.001) and lower hospitalization cost of mobilization ($ median 3108.02 versus 3702.39, p = 0.012). Thus, our results demonstrate that NF is associated with lower CD34 + cell collection and that antibiotic prophylaxis can reduce the incidence of NF and improve stem cell mobilization and collection outcomes, which reduces the hospitalization cost of mobilization.

Effect of voxelotor on murine bone marrow and peripheral blood with hematopoietic progenitor cell mobilization for gene therapy of sickle cell disease.

In preparation for hematopoietic stem cell mobilization and collection, current ex vivo gene therapy protocols for sickle cell disease require patients to undergo several months of chronic red cell transfusion. For health care equity, alternatives to red cell transfusion should be available. We examined whether treatment with GBT1118, the murine analog of voxelotor, could be a safe and feasible alternative to red cell transfusion. We found that 3 weeks of treatment with GBT1118 increased the percentage of bone marrow hematopoietic stem cells and upon plerixafor mobilization, the percentage of peripheral blood hematopoietic stem cells. Our data suggest that voxelotor should be further explored for its potential safety and utility as preparation for hematopoietic stem cell mobilization and collection.

Crude collection efficiency of CD34+ hematopoietic stem cell apheresis.

Understanding the apheresis principles for harvesting hematopoietic stem cells (HSCs) is critical for performing efficient procedures. However, despite significant advances in estimating the collection efficiency (CE) of aphereses, many confounding factors still need to be addressed in the classical calculations. The CE values are unrestricted, and many procedures exhibit CEs of a given cell population greater than 100%. This report introduces a simple equation that estimates the "crude" CE, which ranges from 0% to 100% and intrinsically considers the contribution of donor-related variables such as the pre-procedure mobilization and intra-apheresis recruitment of CD34+ cells (as a convenient marker for HSCs), as well as the performance of the apheresis system itself.

Hematopoietic Progenitor Cell Counts of the Leukapheresis Product Determined Using Sysmex XN Analyzers Predict a Sufficient Number of CD34+ Stem Cells in a Peripheral Blood Stem Cell Harvest for Autologous Transplantation.

Objective Several institutions outsource CD34+ cell counting of leukapheresis products, limiting rapid measurements, as results are obtained the next day. This problem is compounded with plerixafor use, a stem cell-mobilizing drug that increases leukapheresis efficiency but requires administration the day before leukapheresis. Use of this drug for a second leukapheresis procedure before the first-day leukapheresis CD34+ count results are confirmed causes unnecessary leukapheresis and expensive plerixafor administration. We investigated whether or not measuring hematopoietic progenitor cells in leukapheresis products (AP-HPCs) using a Sysmex XN-series analyzer could resolve this problem. Methods We retrospectively compared the absolute AP-HPC value per body weight with the CD34+ (AP-CD34+) count in 96 first-day leukapheresis product samples obtained between September 2013 and January 2021. Comparisons were also conducted according to regimen: granulocyte colony-stimulating factor (G-CSF) monotherapy, chemotherapy plus G-CSF, or plerixafor mobilization. Results AP-CD34+ and AP-HPC counts correlated strongly (rs=0.846) overall and, in particular, under chemotherapy plus G-CSF (rs=0.92) but correlated mildly under G-CSF monotherapy (rs=0.655). AP-HPCs could not completely be dichotomized based on an AP-CD34+ threshold of 2×106/kg for any stimulation procedure. In most cases with AP-HPCs >6×106/kg, the AP-CD34+ count exceeded 2.0×106/kg, but in 5.7% of these cases, the AP-CD34+ count was <2.0×106/kg. A cut-off of AP-HPCs >4.843×106/kg yielded a sensitivity of 71% and specificity of 96% for predicting AP-CD34+≥2×106/kg. Conclusion AP-HPCs can identify cases in which sufficient stem cells have been collected.

G-CSF-induced hematopoietic stem cell mobilization from the embryonic hematopoietic niche does not require neutrophils and macrophages.

Hematopoietic stem cell transplantation requires the collection of hematopoietic cells from patients or stem cell donors. Granulocyte colony-stimulating factor (G-CSF) is widely used in the clinic to mobilize hematopoietic stem and progenitor cells (HSPCs) from the adult bone marrow niche into circulation, allowing a collection of HSPCs from the blood. The mechanism by which G-CSF acts to mobilize HSPCs is unclear, with some studies showing a direct stimulation of stem cells and others suggesting that myeloid cells are required. In this study, we developed a heat-inducible G-CSF transgenic zebrafish line to study HSPC mobilization in vivo. Live imaging of HSPCs after G-CSF induction revealed an increase in circulating HSPCs, demonstrating a successful HSPC mobilization. These mobilized HSPCs went on to prematurely colonize the kidney marrow, the adult zebrafish hematopoietic niche. We eliminated neutrophils or macrophages using a nitroreductase-based cell ablation system and found that G-CSF still mobilizes HSPCs from the niche. Our findings indicate that neutrophils and macrophages are not required for G-CSF-induced HSPC mobilization from the embryonic hematopoietic niche.

Stem cell collection after lenalidomide, bortezomib and dexamethasone plus elotuzumab or isatuximab in newly diagnosed multiple myeloma patients: a single centre experience from the GMMG-HD6 and -HD7 trials.

BACKGROUND: While quadruplet induction therapies deepen responses in newly diagnosed multiple myeloma patients, their impact on peripheral blood stem cell (PBSC) collection remains incompletely understood. This analysis aims to evaluate the effects of prolonged lenalidomide induction and isatuximab- or elotuzumab-containing quadruplet induction therapies on PBSC mobilization and collection. METHODS: A total of 179 transplant-eligible patients with newly diagnosed MM treated at a single academic center were included. The patients were evaluated based on PBSC mobilization and collection parameters, including overall collection results, CD34+ cell levels in peripheral blood, leukapheresis (LP) delays, overall number of LP sessions, and the rate of rescue mobilization with plerixafor. The patients underwent four different induction regimens: Lenalidomide, bortezomib, and dexamethasone (RVd, six 21-day cycles, n = 44), isatuximab-RVd (six 21-day cycles, n = 35), RVd (four 21-day cycles, n = 51), or elotuzumab-RVd (four 21-day cycles, n = 49). RESULTS: The patients' characteristics were well balanced across the different groups. Collection failures, defined as the inability to collect three sufficient PBSC transplants, were rare (n = 3, 2%), with no occurrences in the isatuximab-RVd and elotuzumab-RVd groups. Intensified induction with six 21-day cycles of RVd did not negatively impact the overall number of collected PBSCs (9.7 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.331) compared to four 21-day cycles of RVd. Plerixafor usage was more common after six cycles of RVd compared to four cycles (16% versus 8%). Addition of elotuzumab to RVd did not adversely affect overall PBSC collection (10.9 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.915). Patients treated with isatuximab-RVd (six cycles) had lower numbers of collected stem cells compared to those receiving RVd (six cycles) induction (8.8 × 106/kg bw versus 9.7 × 106/kg bw, p = 0.801), without experiencing significant delays in LP or increased numbers of LP sessions in a multivariable logistic regression analysis. Plerixafor usage was more common after isatuximab plus RVd compared to RVd alone (34% versus 16%). CONCLUSIONS: This study demonstrates that stem cell collection is feasible after prolonged induction with isatuximab-RVd without collection failures and might be further explored as induction therapy. TRIAL REGISTRATION: Patients were treated within the randomized phase III clinical trials GMMG-HD6 (NCT02495922, 24/06/2015) and GMMG-HD7 (NCT03617731, 24/07/2018). However, during stem cell mobilization and -collection, no study-specific therapeutic intervention was performed.

The impact of diabetes mellitus on hematopoietic stem cell mobilization, a-single center cohort study.

BACKGROUND: Factors such as age, underlying hematological disease, chemotherapy and radiotherapy used, and bone marrow infiltration may cause mobilization failure. Several preclinical observed that diabetes mellitus (DM) leads to profound remodeling of the hematopoietic stem cell (HSC) niche, resulting in the impaired release of HSCs. We aim to examine the effect of DM on HSC mobilization and to investigate whether there is a relationship between complications developing in the DM process and drugs used to treat DM and mobilization failure. METHODS: In Erciyes University Bone Marrow Transplantation Unit, 218 patients who underwent apheresis for stem cell mobilization between 2011 and 2021 were evaluated retrospectively. One hundred and nine patients had a diagnosis of DM, and 109 did not. RESULTS: Mobilization failure developed in 17 (15.6 %) of the patients in the DM group, while it developed in 7 (6.4 %) patients in the non-DM group (p = 0.03). CD34+ stem cell count was 8.05 (1.3-30.2) × 106/kg in the DM group, while it was 8.2 (1.7-37.3) × 106/kg in the other group (p = 0.55). There was no statistically significant relationship between glucose and hemoglobin A1c levels and the amount of CD34+ cells (p = 0.83 and p = 0.14, respectively). Using sulfonylurea was the only independent predictor of mobilization failure (OR 5.75, 95 % CI: 1.38-24.05, p = 0.02). CONCLUSION: DM should be considered a risk factor for mobilization failure. Further research is needed fully to understand the mechanisms underlying the mobilization failure effects of sulfonylureas and to develop strategies to improve stem cell mobilization in diabetic patients.

Evaluating the efficiency and safety of large-volume leukapheresis using the Spectra Optia continuous mononuclear cell collection protocol for peripheral blood stem cell collection from healthy donors: A retrospective study.

BACKGROUND: Large-volume leukapheresis (LVL) refers to processing of more than three volumes of blood in a single session for peripheral blood stem cell collection. Recently, continuous mononuclear cell collection (cMNC) protocol has been developed using the Spectra Optia system, which is a widely used apheresis device. LVL using the novel protocol has been investigated in patients. However, the efficiency and safety of LVL in healthy donors using this protocol has not been characterized. Therefore, this study aimed to evaluate the efficiency and tolerability of CD34+ collection of LVL with the cMNC protocol in healthy donors. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (>3 total blood volume) and normal-volume leukapheresis (NVL) performed in healthy donors between October 2019 and December 2021. All procedures were performed using the cMNC protocol. RESULTS: Although pre-apheresis CD34+ cell count was lesser in LVL (23.5 vs. 58.0/µL, p < .001), CD34+ collection efficiency was comparable between LVL and NVL (61.2% vs. 61.4%, p = .966). Platelet loss was significantly higher in LVL compared to NVL (38.0% vs. 29.4%, p < .001), with no correlation between attrition of platelet and processing blood volume. Moreover, the incidence of citrate toxicity during procedures was comparable between the two groups (31.6% vs. 21.4%, p = .322). All LVL procedures could be completed without any adverse events. CONCLUSION: Allogeneic LVL procedure using Spectra Optia cMNC protocol was well tolerated by the donors and resulted in efficient collection of CD34+ cells, which was comparable to that of NVL.

Platelet-derived circulating soluble P-selectin is sufficient to induce hematopoietic stem cell mobilization.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF)-mediated mobilization of hematopoietic stem cells (HSCs) is a well-established method to prepare HSCs for transplantation nowadays. A sufficient number of HSCs is critical for successful HSC transplantation. However, approximately 2-6% of healthy stem cell donors are G-CSF-poor mobilizers for unknown reasons; thus increasing the uncertainties of HSC transplantation. The mechanism underlining G-CSF-mediated HSC mobilization remains elusive, so detailed mechanisms and an enhanced HSC mobilization strategy are urgently needed. Evidence suggests that P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) are one of the cell-cell adhesion ligand-receptor pairs for HSCs to keep contacting bone marrow (BM) stromal cells before being mobilized into circulation. This study hypothesized that blockage of PSGL-1 and P-selectin may disrupt HSC-stromal cell interaction and facilitate HSC mobilization. METHODS: The plasma levels of soluble P-selectin (sP-sel) before and after G-CSF administration in humans and male C57BL/6J mice were analyzed using enzyme-linked immunosorbent assay. Male mice with P-selectin deficiency (Selp-/-) were further employed to investigate whether P-selectin is essential for G-CSF-induced HSC mobilization and determine which cell lineage is sP-sel derived from. Finally, wild-type mice were injected with either G-CSF or recombinant sP-sel to investigate whether sP-sel alone is sufficient for inducing HSC mobilization and whether it accomplishes this by binding to HSCs and disrupting their interaction with stromal cells in the BM. RESULTS: A significant increase in plasma sP-sel levels was observed in humans and mice following G-CSF administration. Treatments of G-CSF induced a decrease in the level of HSC mobilization in Selp-/- mice compared with the wild-type (Selp+/+) controls. Additionally, the transfer of platelets derived from wild-type mice can ameliorate the defected HSC mobilization in the Selp-/- recipients. G-CSF induces the release of sP-sel from platelets, which is sufficient to mobilize BM HSCs into the circulation of mice by disrupting the PSGL-1 and P-selectin interaction between HSCs and stromal cells. These results collectively suggested that P-selectin is a critical factor for G-CSF-induced HSC mobilization. CONCLUSIONS: sP-sel was identified as a novel endogenous HSC-mobilizing agent. sP-sel injections achieved a relatively faster and more convenient regimen to mobilize HSCs in mice than G-CSF. These findings may serve as a reference for developing and optimizing human HSC mobilization in the future.

[Comparison of Plerixafor or Cyclophosphamide Combined with G-CSF in Mobilization of Peripheral Blood Stem Cells in Multiple Myeloma].

OBJECTIVE: To compare the efficacy of plerixafor (PXF) combined with granulocyte colony-stimulating factor (G-CSF) (PXF+G-CSF) and cyclophosphamide (Cy) combined with G-CSF (Cy+G-CSF) in the mobilization of peripheral blood stem cells (PBSCs) in patients with multiple myeloma (MM). METHODS: The clinical data of 41 MM patients who underwent PBSC mobilization using PXF+G-CSF (18 cases) or Cy+G-CSF (23 cases) in Shanxi Bethune Hospital from January 2019 to December 2021 were retrospectively analyzed, including the count of collected CD34+ cells, acquisition success rate, failure rate, and optimal rate. The correlation of sex, age, disease type, DS staging, ISS staging, number of chemotherapy cycle, disease status before mobilization, and mobilization regimen with the collection results was analyzed, and the adverse reactions, length of hospital stay, and hospitalization costs were compared between the two mobilization regimens. RESULTS: The 41 patients underwent 97 mobilization collections, and the median number of CD34+ cells collected was 6.09 (0-34.07)×106/kg. The acquisition success rate, optimal rate, and failure rate was 90.2%, 56.1%, and 9.8%, respectively. Univariate analysis showed that sex, age, disease type, and disease stage had no significant correlation with the number of CD34+ cells collected and acquisition success rate (P >0.05), but the patients with better disease remission than partial remission before mobilization were more likely to obtain higher CD34+ cell count (P <0.05). The PXF+G-CSF group had a larger number of CD34+ cells and higher acquisition success rate in the first collection than Cy+G-CSF group (both P <0.05), and had lower infection risk and shorter length of hospital stay during mobilization (both P <0.05), but the economic burden increased (P <0.05). CONCLUSION: PXF+G-CSF used for PBSC mobilization in MM patients has high first acquisition success rate, large number of CD34+ cells, less number of collection times, and short length of hospital stay, but the economic cost is heavy.

Overview on novel strategies and current guidelines for hematopoietic stem cell mobilisation and collection.

The success of the autologous stem cell transplantation is strictly related to an adequate hematopoietic stem cell mobilization and collection. The minimum threshold for a successful mobilization is currently defined as 2 × 106/kg CD34+ cells. However, the optimal stem cell mobilization strategy is still controversial. The availability of plerixafor, a selective and reversible CXCR4 inhibitor, has been associated with an higher use of chemo-free protocols by many centres. In the near future, it is conceivable that artificial intelligence may became more accurate and comprehensive, possibly guiding clinicians in choosing the optimal mobilisation treatment for the various patients undergoing hematopoietic stem cell transplantation. Machine learning-based scoring models may be the basis for the development of "intelligent" mobilisation algorithms.

Steady-state versus chemotherapy-based hematopoietic cell mobilization after anti-CD38-based induction therapy in newly diagnosed multiple myeloma.

BACKGROUND: The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. STUDY DESIGN AND METHODS: From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 µg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. RESULTS: Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/µL vs. 55.4/µL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. CONCLUSIONS: Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits ß-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (ß2AR). Co-treatment with CXCL12 and the ß2AR agonist epinephrine synergistically increases ß-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

A research on the influence of G-CSF mobilization on donor's peripheral blood MDSCs and its relationship with patient prognosis.

OBJECTIVE: To discuss the effects of mobilization of healthy donors with granulocyte colony-stimulating factor (G-CSF) on the absolute values and functions of myeloid-derived suppressor cells (MDSCs) and subpopulations of M-MDSCs and P-MDSCs in their peripheral blood. In addition, this study also aims to investigate the impacts of the adoptively transferred MDSCs from the grafts to the patients on their prognosis and immune reconstitution. METHODS: The selection of 72 donors and 72 patients were conducted for allogeneic hematopoietic stem cell transplantation (allo-HSCT) from August 2022 to December 2022 at Lu Daopei Hospital in Beijing, China. Statistical calculations were performed by Wilcoxon signed-rank test, Kruskal Wallis test, χ2 test, Kaplan Meier test, and log-rank test to analyze the data. RESULTS & CONCLUSION: G-CSF induced significant amplification of MDSCs in the peripheral blood of donors in percentage and absolute values. Whether the level of P-MDSCs in patients conducted for the adoptive transfer of P - MDSCs is higher than 3.7× 107/kg or lower than 1.4× 107/kg leads to a poor prognosis of the patients. Ensuring a balanced state of MDSCs is crucial for effective immunotherapy. Transferring a high level of MDSCs from the graft to the patient's body is advantageous for the development of MDSCs while simultaneously inhibiting the proliferation of lymphocyte subgroups.