Hetrombopag is a novel thrombopoietin receptor agonist that has shown an additive effect in stimulating platelet production when combined with recombinant human thrombopoietin (rhTPO). However, it remains unclear whether this combination can promote hematopoietic reconstruction after autologous stem cell transplant (ASCT).

To compare the effect of rhTPO plus thrombopoietin receptor agonists (TPO-RA) versus rhTPO alone on hematopoietic recovery, adverse events, postoperative complications, and cost-effectiveness in patients with newly diagnosed multiple myeloma (NDMM) undergoing ASCT.

A total of 67 consecutive NDMM patients who underwent ASCT at our hospital from January 2021 to May 2024 were included. Of these patients, 35 received a combination of rhTPO and the TPO-RA hetrombopag after stem cell reinfusion (observation group), whereas 32 patients received rhTPO alone (control group). Hematopoietic reconstitution between the two groups was compared.

Baseline clinical characteristics were similar between both groups. In the observation group, the median time to platelet recovery was 9 days after stem cell reinfusion, which was significantly shorter than that in the control group (P = .003). The mean number of platelet transfusions in the observation group was significantly lower than that in the control group (1.0 vs. 2.0 units, P = .034). All patients tolerated rhTPO and TPO-RA well, with no thrombotic events observed. Survival analysis showed no reduction in time to progression (TTP) and overall survival (OS) with the addition of TPO-RA. There were no statistical differences in the incidence of adverse events, drug expenses, and hospital stay between two groups (P  > 0.05).

Although sample size and study design limit the data from this study, our findings suggest that the combination of TPO-RA (hetrombopag) and rhTPO enhances platelet recovery in comparison with rhTPO alone, without increasing adverse effects.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting. We hypothesized that the routine use of G-CSF for outpatient-based ASCT might not result in the same benefit with respect to a reduced duration of hospitalization and thus should be reconsidered in this setting. We performed a retrospective cohort study of 633 consecutive patients with multiple myeloma (MM; n = 484) or non-Hodgkin lymphoma (NHL; n = 149) who underwent ASCT between September 2018 and February 2023. Outpatient ASCT comprised 258 (53%) of combined MM and NHL cases. Starting in September 2021, post-transplantation G-CSF was incorporated into the supportive care regimen for all ASCTs. A total of 410 patients (309 with MM, 101 with NHL) underwent ASCT during the pre-G-CSF policy period and 223 (175 with MM, 48 with NHL) did so in the post-G-CSF policy period. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion. As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced in the patients with MM (mean, -2.8 days; P < .0001) and patients with NHL (mean, -2.9 days; P < .0001). However, among the patients with MM, roughly one-half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (P = .40). Comparatively, the inpatient duration (mean, -1.8 days; P = .030) was reduced among patients with NHL, all of whom were electively admitted for ASCT. For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30.

Infectious disease (ID) pharmacists and antimicrobial stewardship (AMS) programs are integral to the infection management of hematopoietic cell transplant (HCT) recipients demonstrating effective implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN), allergy assessments, and use of rapid diagnostic testing. The HCT procedure is complex, dynamic, and a high risk for infectious complications. Therefore, there is an important role for an ID and AMS pharmacist to collaborate with the primary treating team, with ongoing care, involving the optimal individual patient prophylactic, pre-emptive and treatment management of infections in this high-risk population.

This review highlights key factors for consideration of ID/AMS Pharmacists in relation to HCT, including important aspects in the evaluation of infection risk prior to transplant, risk from donor sources, length of, and changes in immunosuppression, and potential drug-drug interactions from other essential supportive care therapies.

High-dose melphalan-based autologous stem cell transplant (ASCT) remains a standard of care for plasma cell disorders (PCDs). Currently, there is variability in the literature surrounding the timing of melphalan administration to avoid potential cytotoxic effects, although the administration has been safely proposed when given at least 8 hours prior to stem cell infusion. The objectives of this study were to assess differences in safety and efficacy outcomes between day -1 and day -2 single-dose melphalan administration in patients undergoing ASCT for PCDs. A retrospective chart review was performed at our institution comparing patients receiving melphalan on day -1 to an equal number of patients receiving melphalan on day -2. The primary endpoint was time to neutrophil engraftment from stem cell infusion. Univariate analyses were performed. Mean time to neutrophil engraftment from stem cell infusion was identical at 10.7 days for both cohorts (p = 0.88). Mean time to platelet engraftment from stem cell infusion was shorter with day -1 administration (17.4 vs. 18.6 days, p = 0.06). Mean time to neutrophil and platelet engraftment from melphalan infusion were significantly shorter with day -1 administration. Similar outcomes were observed for length of hospitalization, infection- and mucositis-related toxicities, hematologic response, transplant-related mortality, and overall survival. Our findings show no difference in time to neutrophil engraftment from stem cell infusion and a trend toward shorter time to platelet engraftment with day -1 administration. Based on our study, day -1 melphalan administration is an acceptable and safe practice.

Objectives Granulocyte colony-stimulating factor (G-CSF) is commonly used to accelerate neutrophil recovery after allogeneic stem cell transplantation (ASCT) in most transplant centers. There was no consensus on the optimal use of G-CSF after ASCT. Although we use G-CSF to minimize morbidity and mortality, G-CSF can increase the risk of graft-versus-host disease (GVHD). In our study, we want to show the effect of prophylactic G-CSF on infection frequency, neutrophil and platelet engraftment, the duration of neutropenia, the development of GVHD, hospitalization time, and transplant-related mortality (TRM) after ASCT. Materials and methods One hundred (71 males and 29 females) patients who did not receive G-CSF and 100 (58 males and 42 females) patients who received prophylactic G-CSF were included in the study. Results Age, diagnosis, the time between diagnosis and transplantation, preparation regimen, donor type, and the number of infused cluster of differentiation (CD) 34+ cells were not different in both groups (p>0.05). The frequency of female patients was higher in the group receiving G-CSF. Febrile neutropenia was more frequent in patients who did not receive G-CSF. Neutrophil engraftment and platelet engraftment were detected longer in patients not receiving G-CSF. The frequency of veno-occlusive disease (VOD) and hyperacute, chronic, and acute GVHD was not different in both groups (p>0.05). One hundred-day TRM and five-year overall survival (OS) were similar in the two groups (p>0.05). Conclusions Our study supports that G-CSF usage does not cause an increase in the frequency of GVHD and has a positive effect on the process by accelerating myeloid engraftment. In light of the data in our study, we can say that the use of G-CSF should be investigated in a randomized controlled clinical trial.

Tigecycline has been used to treat patients with febrile neutropenia (FN). This study aims to analyse the effectiveness of tigecycline as salvage treatment of FN. Patients records from 09/2004 to 04/2019 were reviewed. Cases were eligible if fever persisted/recurred (p/r-FN) after 3 days of second-line treatment with a carbapenem, and were divided into three groups: switch to tigecycline (TGC group), switch to other antibiotics (OAB group), and no switch (W&W group). The primary endpoint was response rate (defervescence for ≥ 7 days or at least until discharge); the key secondary endpoint was 30-day mortality rate. Two hundred cases from 176 patients (median 59 years; 53.5% men) treated were included, mostly acute myeloid leukaemias (61.0%). 45.5% of cases were in the TGC group (in combination with an anti-pseudomonal antibiotic, mostly ceftazidime [95.6%]); 35.5% were in the OAB and 19.0% in the W&W group. There was no significant difference in response rates (TGC, 73.6%; OAB, 62.0%; W&W, 78.9%; p = 0.12) or 30-day mortality rates (TGC, 7.7%; OAB, 7.0%; W&W, 5.3%; p = 0.94). Tigecycline plus an anti-pseudomonal antibiotic does not improve response or 30-day mortality rate compared to other antibiotics in patients with p/r-FN. Also, in some cases, no switch in antibiotics may be necessary at all.

The mesenchymal Stem Cells (MSCs) is one of the leading contender in therapeutic management of cytokine storm implicated in the COVID-19 and other inflammatory conditions. This study was aimed to investigate the effect of Interferon gamma (IFN-γ) and Ascorbic Acid (AA) preconditioning on the secretome of the human Umbilical Cord Derived MSCs (UCMSCs) and their potential to ameliorate the lipopolysaccharide (LPS) induced cytokine storm in the human peripheral blood mononuclear cells (PBMCs). UCMSCs were preconditioned with IFN-γ, AA and secretome (UCMSCs-S, IFNγ-UCMSCs-S and AA-UCSMCs-S) was analysed for the levels of growth factors and cytokines by flow cytometry. The potential of secretome to ameliorate cytokine storm and augment angiogenesis was assessed in the LPS induced PBMCs and yolk sac membrane (YSM) assay respectively. The mRNA transcript and protein levels of IL-6, IL-1β and TNF-α was analysed by RT-PCR and flow cytometry respectively. IFNγ-UCMSCs-S and AA-UCSMCs-S ameliorated the LPS induced cytokine storm as revealed by the decreased mRNA and protein expression of IL-6, IL-1β and TNF-α as compared to the UCMSCs-S. IFNγ-UCMSCs-S and AA-UCSMCs-S augmented angiogenesis in YSM assay. Furthermore, IFNγ and AA preconditioning of UCMSCs exhibited distinct growth factors and cytokine profile in the secretome. Our results unequivocally show that IFNγ and AA preconditioning of MSCs could give better therapeutic outcomes in the cell mediated therapies for COVID-19 and other inflammatory conditions.

Multiple myeloma (MM) is the main indication for autologous stem cell transplantation (ASCT). Novel supportive therapies (e.g., granulocyte colony-stimulating factor) have significantly improved post-ASCT-related mortality; however, data on biosimilar pegfilgrastim-bmez (BIO/PEG) in this setting is lacking. This prospective cohort study compared Italian patients with MM who received BIO/PEG post-ASCT with data collected retrospectively from historical control groups from the same center who received either filgrastim-sndz (BIO/G-CSF) or pegfilgrastim (PEG; originator). The primary endpoint was time to neutrophil engraftment (three consecutive days with an absolute neutrophil count ≥ 0.5 × 109/L). Secondary endpoints included incidence and duration of febrile neutropenia (FN). Of the 231 patients included, 73 were treated with PEG, 102 with BIO/G-CSF, and 56 with BIO/PEG. Median age was 60 years and 57.1% were male. Neutrophil engraftment was reached after a median of 10 days in the BIO/PEG and PEG groups and 11 days in the BIO/G-CSF group. Among patients who achieved neutrophil engraftment earlier than this (i.e., day 9), 58% (29/50) were on PEG; of those who achieved it later (i.e., day 11), 80.8% (59/73) were on BIO/G-CSF. FN incidence was higher with BIO/G-CSF (61.4%) versus PEG (52.1%) or BIO/PEG (37.5%) (p = 0.02 among groups). Patients on BIO/PEG had less frequent grade 2-3 diarrhea (5.5%) compared with BIO/G-CSF (22.5%) or PEG (21.9%); grade 2-3 mucositis was most frequent in the BIO/G-CSF group. In conclusion, pegfilgrastim and its biosimilar displayed an advantageous efficacy and safety profile compared with biosimilar filgrastim in patients with MM post-ASCT.

A consensus threshold of pre-cryopreservation CD34-positive cells (CD34s) has been used as the minimum dose to initiate autologous stem cell transplantation (ASCT). Advances in cryopreservation posed a debate whether post-thaw CD34s might be a superior surrogate instead. We addressed the debate in this retrospective study of 217 adult ASCTs in five different haematological malignancies treated at a single centre. We showed that post-thaw CD34s was highly correlated with pre-cryopreservation CD34s (r = 0.97) and explained ∼2.2% (p = 0.003) of the variation of the post-thaw total nucleated cell viability that however had no power to predict engraftment outcomes. After stratifying the ASCT cases into four dose groups based on post-thaw CD34s reinfused, stepwise multivariate regression analyses detected significant effects in dose group and interactions with diseases for neutrophil and platelet recovery respectively. The significant dose effects and interactions were triggered by two technical outliers in the low dose group, and disappeared in the repeated regressions after exclusion of the outliers where disease and age were the significant predictors remained. Our data clearly support the validity of the consensus threshold in ASCT applications but also highlight neglected conditions where monitoring post-thaw CD34s and clinical attributes are valuable.

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.

The immunosuppression and inhibition of hematopoiesis are considered to be reasons for the development of complications after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation. Chondroitin sulfate (CS), isolated from the fish Salmo salar, and fucosylated chondroitin sulfate (FCS), isolated from the sea cucumber Apostichopus japonicus, were studied for their roles as stimulators of hematopoiesis in a model of cyclophosphamide-induced immunosuppression in mice. The recombinant protein r G-CSF was applied as a reference. The studied polysaccharides were shown to stimulate the release of white and red blood cells, as well as platelets from bone marrow in immunosuppressed mice, while r G-CSF was only responsible for the significant increase in the level of leucocytes. The analysis of different populations of leucocytes in blood indicated that r G-CSF mainly stimulated the production of neutrophils, whereas in the cases of the studied saccharides, increases in the levels of monocytes, lymphocytes and neutrophils were observed. The normalization of the level of the pro-inflammatory cytokine IL-6 in the serum and the recovery of cell populations in the spleen were observed in immunosuppressed mice following treatment with the polysaccharides. An increase in the proliferative activity of hematopoietic cells CD34(+)CD45(+) was observed following ex vivo polysaccharide exposure. Further study on related oligosaccharides regarding their potential as promising drugs in the complex prophylaxis and therapy of hematopoiesis inhibition after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation seems to be warranted.

We compare, in this manuscript, antibiotic prophylaxis versus granulocyte-colony stimulating factor (G-CSF) support as anti-infective strategies, in patients with multiple myeloma (MM), undergoing high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). At our institution, antibiotic prophylaxis after HDT/ASCT in MM was stopped in January 2017 and replaced by G-CSF support in March 2017. Consecutive MM patients who received HDT/ASCT between March 2016 and July 2018 were included in this single-center retrospective analysis. In total, 298 patients and 353 individual cases of HDT/ASCT were evaluated. In multivariate analyses, G-CSF support was associated with a significantly shortened duration of severe leukopenia < 1/nL (p < 0.001, hazard ratio (HR) = 16.22), and hospitalization (estimate = -0.19, p < 0.001) compared to antibiotic prophylaxis. Rates of febrile neutropenia, need of antimicrobial therapy, transfer to intensive care unit, and death, were similar between the two groups. Furthermore, antibiotic prophylaxis was associated with a significantly increased risk for the development of multidrug resistant bacteria especially vancomycin-resistant Enterococcus faecium compared to G-CSF support (odds ratio (OR) = 17.38, p = 0.01). Stop of antibiotic prophylaxis as an anti-infective strategy was associated with a reduction in overall resistance rates of bacterial isolates. These results indicate that G-CSF support should be the preferred option in MM patients undergoing HDT/ASCT.

Human granulocyte colony-stimulating factor (hG-CSF) is a cytokine that regulates the proliferation, maturation, and differentiation of precursor cells to neutrophils. In the present study, we report the feasibility of inducing recombinant hG-CSF expression (rhG-CSF) in a pET vector system by combinatorial induction using low-concentration ethanol, IPTG, and lactose and auto-induction media (AIM). The coding sequence of hG-CSF transcript variant 2 was expressed in pET14 vector, and the effect of combinatorial induction was analyzed on inclusion body (IB) formation, biomass, protein purification, and bioactivity. Results showed that there was an inverse relationship between the temperature and soluble expression of rhG-CSF. Three-step washing with Triton-X, 2 M, and 5 M urea resulted in the maximum recovery of IBs. Combinatorial single-spike induction with IPTG, ethanol, and lactose in a batch culture led to a 3-fold increase in the expression of rhG-CSF. It was also observed that low concentration of ethanol (1-3% v/v) could be used in lieu of IPTG for inducing the rhG-CSF protein expression without adversely affecting biomass production. A 2.4-fold increase in productivity was obtained in LB-AIM media with combinatorial ethanol induction, and the overall yield of 2.8 g/L rhG-CSF was found. The purified rhG-CSF was bioactive and increased the cellular proliferation of umbilical cord blood-derived mesenchymal stem cells (U-MSC) by 29%. In conclusion, our study shows that combined ethanol induction can enhance the expression of rhG-CSF with three-step washing for recovery of the proteins from IBs and a single-step purification of rhG-CSF by affinity chromatography. KEY POINTS: • Low concentration of ethanol (1-3%) could be used in lieu of IPTG for inducing rhG-CSF expression. • Combinatorial single-spike induction with IPTG, ethanol, and lactose improved rhG-CSF expression. • Purified rhG-CSF was bioactive and increased the proliferation of U-MSC.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Peripheral blood hematopoietic stem cell mobilization is widely performed in a variety of clinical facilities and is believed to be a safe outpatient procedure. In this report, we describe a child with neuroblastoma who developed an extremely severe acute lung injury after granulocyte colony-stimulating factor was used for peripheral hematopoietic stem cell mobilization. A 3-year-old boy with a medical history of patent foramen ovale and secundum atrial septal defect was diagnosed with an MYCN-amplified neuroblastoma and treated with chemotherapy. During stem cell mobilization with filgrastim, the boy was in very good clinical condition, with a peripheral white blood cell (WBC) count of 57.17 K/μL, but he suddenly deteriorated, and nausea, seizures, and nystagmus were observed. The patient developed dyspnea with hemoptysis, and lung computed tomography showed bilateral asymmetrical pulmonary opacification demonstrating an anteroposterior density gradient. Because of rapidly progressing circulatory and respiratory failure, the child was hospitalized in the intensive care unit. Corticosteroid therapy, broad-spectrum antibiotic therapy, and cardiovascular support with mechanical ventilation were immediately instituted, and the child recovered without sequelae. The presented case emphasizes that life-threatening complications can occur during granulocyte colony-stimulating factor administration, and patient surveillance is warranted, especially if high leukocyte counts are observed or the patient exhibits cardiopulmonary signs.

Bone marrow failure is the primary cause of death after nuclear accidents or intentional exposure to high or low doses of ionizing radiation. Hematopoietic stem cell transplantation is the most potent treatment procedure for patients suffering from several hematopoietic malignancies arising after radiation injuries. Successful hematopoietic recovery after transplantation depends on efficient homing and subsequent engraftment of hematopoietic stem cells in specific niches within the bone marrow. It is a rapid and coordinated process in which circulating cells actively enter the bone marrow through the process known as transvascular migration, which involves the tightly regulated relay of events that finally leads to homing of cells in the bone marrow. Various adhesion molecules, chemokines, glycoproteins, integrins, present both on the surface of stem cells and sinusoidal endothelium plays a critical role in transvascular migration. But despite having an in-depth knowledge of homing and engraftment and the key events that regulate it, we are still not completely able to avoid graft failures and post-transplant mortalities. This deems it necessary to design a flawless plan for successful transplantation. Here, in this review, we will discuss the current clinical methods used to overcome graft failures and their flaws. We will also discuss, what are the new approaches developed in the past 10-12 years to selectively deliver the hematopoietic stem cells in the bone marrow by adopting proper targeting strategies that can help revolutionize the field of regenerative and translational medicine.

To evaluate a single institution's experience with granulocyte colony-stimulating factor after autologous hematopoietic stem cell transplant in myeloma patients to identify populations that benefit most from granulocyte colony-stimulating factor administration.

Retrospective chart reviews were conducted on patients 18+ years with multiple myeloma that underwent autologous hematopoietic stem cell transplant at UW Health from January 2012 to May 2016. Data collection included demographics, length of stay, time to engraftment, Eastern Cooperative Oncology Group performance status score, and hematopoietic cell transplantation-comorbidity index. The primary outcome was days from transplant to engraftment, defined as absolute neutrophil count  > 500/mm³ for two consecutive days or absolute neutrophil count > 1000/mm³ once. A subset analysis was performed on patients whose date of engraftment was known.

In total, 216 individual patients were included in the full cohort and 122 patients included in the subset analysis. Median time to engraftment between patients administered granulocyte colony-stimulating factor and the nongranulocyte colony-stimulating factor group was 12 versus 19 days (P < 0.001) in the full cohort and 12 versus 14 days (P < 0.001) in the subset analysis. The average length of stay posthematopoietic stem cell transplant in the granulocyte colony-stimulating factor group was 15 days versus 17 days in the nongranulocyte colony-stimulating factor group (P = 0.026) in the subset analysis. Additionally, no difference in time to engraftment was seen when stratified by age, Eastern Cooperative Oncology Group performance status score, or hematopoietic cell transplantation-comorbidity index.

Our study supports use of granulocyte colony-stimulating factor posthematopoietic stem cell transplant in myeloma patients to decrease time to engraftment and length of stay. Consideration should be given to utilization in all patients in this population posthematopoietic stem cell transplant. Further research is needed to identify the populations that benefit most from granulocyte colony-stimulating factor administration.

A retrospective, observational study was performed of 112 patients who underwent autologous haematopoietic stem cell transplantation (ASCT) to determine the relationship between CD34+ stem cell dose and neutrophil engraftment. Importantly, a novel approach to more accurately calculate time to neutrophil engraftment was employed. The results demonstrated that a higher CD34+ stem cell dose was associated with faster neutrophil recovery (P < 0.05). CD34+ stem cell dose using actual and ideal patient body weight were both equally predictive of neutrophil engraftment as were absolute and viable CD34+ measurements. The clinical implications for this relationship are limited with an increase in CD34+ stem cell dose by 1 × 10⁶/kg reducing the neutrophil engraftment time by only 3 h and 50 min. The median time to neutrophil recovery was 217 h (9 days and 1 h) and this relatively early engraftment time may be related to an early initiation of granulocyte colony-stimulating factor (G-CSF) on day +1 post-transplant. Female patients engrafted 17 h faster than their male counterparts on multi-variate analysis (P < 0.05). Conditioning chemotherapy, bacteraemia, G-CSF dose/kg body weight and increasing age had no impact on time to neutrophil recovery.

Autologous stem cell transplantation (PBSCT) is standard for young patients in MM and its TRM has decreased after the 2000s. Bortezomib and immunomodulatory agents (IMiDs) in MM have improved the outcome. However, they seem to boost pro-inflammatory stage increasing the incidence of engraftment syndrome (ES). Favorable factors in PBSCT such as G-CSF could increase inflammatory stage during transplant. Corticosteroids have shown an excellent response of ES and some authors propose them as prophylaxis for ES. The aim was to analyze the impact of G-CSF avoidance and corticosteroids' prophylaxis in 170 patients diagnosed of MM treated with bortezomib/IMiDs that underwent PBSCT. We established three groups: Group-I [(G-CSF_administration), 60 patients (35%)], group-II [(nonG-CSF), 60 patients (35%)] and group-III [(nonG-CSF plus corticosteroid's prophylaxis), 50 patients (30%)]. A decreased ES incidence among groups was observed: 62, 42, and 22% (P < 0.0001). The incidence of symptoms mimicking a capillary leak syndrome associated with ES dropped: 43, 32, and 0% (P = 0.03). The G-CSF avoidance and corticosteroids had impact over admission 24, 21, and 20 days (P = 0.001). The most important variables related to ES were HCT-CI >2 (p < 0.0001; HR 8.5) and risk groups (p < 0.0001; HR 7.2). Hence, G-CSF avoidance and corticosteroid's prophylaxis decrease morbidity in patients undergoing PBSCT with MM treated with bortezomib/IMiDs.

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 10⁹/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physician's discretion, 6% (n = 3) started after day +12 at the physician's discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival.

The science of multiple myeloma (MM) and related plasma cell disorders is rapidly evolving with increased understanding of the disease biology and recent approval of the newer drugs widening the therapeutic armamentarium. Despite multiple international guidelines regarding the management of this disease, the practice of managing MM is not uniform amongst Indian physicians. There are challenges in management which are unique to the Indian patients. This review discusses these challenges and the consensus of the nation-wide experts in dealing with the same. We also briefly highlighted the perspective of international experts as discussed in the Myeloma State of the Art conference held in September 2016 at PGI, Chandigarh. An Indian Myeloma Academic Groupe (IMAGe) group was formed to strengthen the research, create awareness about myeloma and related disorders and form consensus guidelines/ recommendations that can be adapted to the Indian Scenario.

Granulocyte transfusion (GTX) is a potential approach to correcting neutropenia and relieving the increased risk of infection in patients who are refractory to antibiotics. To mobilize enough granulocytes for transfusion, healthy donors are premedicated with granulocyte-colony-stimulating factor (G-CSF) and dexamethasone. Granulocytes have a short circulatory half-life. Consequently, patients need to receive GTX every other day to keep circulating granulocyte counts at an acceptable level. We investigated whether plasma from premedicated donors was capable of prolonging neutrophil survival and, if so, which factor could be held responsible.

The effects of plasma from G-CSF/dexamethasone-treated donors on neutrophil survival were assessed by annexin-V, CD16. and CXCR4 staining and nuclear morphology. We isolated an albumin-bound protein using α-chymotrypsin and albumin-depletion and further characterized it using protein analysis. The effects of dexamethasone and G-CSF were assessed using mifepristone and G-CSF-neutralizing antibody. G-CSF plasma concentrations were determined by Western blot and Luminex analyses.

G-CSF/dexamethasone plasma contained a survival-promoting factor for at least 2 days. This factor was recognized as an albumin-associated protein and was identified as G-CSF itself, which was surprising considering its reported half-life of only 4.5 hours. Compared with coadministration of dexamethasone, administration of G-CSF alone to the same GTX donors led to a faster decline in circulating G-CSF levels, whereas dexamethasone itself did not induce any G-CSF, demonstrating a role for dexamethasone in increasing G-CSF half-life.

Dexamethasone increases granulocyte yield upon coadministration with G-CSF by extending G-CSF half-life. This observation might also be exploited in the coadministration of dexamethasone with other recombinant proteins to modulate their half-life.

Infections are the most common and significant cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The presence of neutropenia and mucosal damage are the leading risk factors in the early pre-engraftment phase. In the early post-engraftment phase, graft versus host disease (GvHD) induced infection risk is increased in addition to catheter related infections. In the late phase, in which reconstitution of cellular and humoral immunity continues, as well as the pathogens seen during the early post-engraftment phase, varicella-zoster virus and encapsulated bacterial infections due to impaired opsonization are observed. An appropriate vaccination schedule following the cessation of immunosuppressive treatment after transplantation, intravenous immunoglobulin administration, and antimicrobial prophylaxis with penicillin or macrolide antibiotics during immunosuppressive treatment for GvHD might decrease the risk of bacterial infections. Older age, severe mucositis due to toxicity of chemotherapy, gastrointestinal tract colonization, prolonged neutropenia, unrelated donor and cord blood originated transplantations, acute and chronic GvHD are among the most indicative clinical risk factors for invasive fungal infections. Mold-active anti-fungal prophylaxis is suggested regardless of the period of transplantation among high risk patients. The novel serological methods, including Aspergillus galactomannan antigen and beta-D-glucan detection and computed tomography are useful in surveillance. Infections due to adenovirus, influenza and respiratory syncytial virus are encountered in all phases after allo-HSCT, including pre-engraftment, early post-engraftment and late phases. Infections due to herpes simplex virus-1 and -2 are mostly seen during the pre-engraftment phase, whereas, infections due to cytomegalovirus and human herpes virus-6 are seen in the early post-engraftment phase and Epstein-Barr virus and varicella-zoster virus infections often after +100th day. In order to prevent mortality and morbidity of infections after allo-HSCT, the recipients should be carefully followed-up with appropriate prophylactic measures in the post-transplant period.

G-CSF post-allogeneic HSCT accelerates neutrophil engraftment, but evidence that it impacts on cost-related outcomes is lacking. We performed a retrospective child and adolescent single-center cohort study examining G-CSF administration from Day +6 of allogeneic HSCT vs. ad hoc G-CSF use where clinically indicated. Forty consecutive children and adolescents undergoing allogeneic HSCT were included. End-points were as follows: time to engraftment; incidence of acute and chronic GvHD; number of patients alive at Day +100; 180-day TRM; post-transplant days in hospital; and cost of antimicrobials, TPN, and G-CSF usage. Neutrophil engraftment occurred earlier in the group that received G-CSF from Day +6. There was no difference between groups in any of the other end-points with the following exception: the cost of GCSF was significantly higher in the D + 6 G-CSF group. However, median G-CSF cost in this group amounted to only €280. There was a trend towards reduced cost of antimicrobials in the D + 6 G-CSF group, although this did not reach significance (p = 0.13). The median cost per patient of antimicrobial agents between groups differed by €1116. This study demonstrated the administration of G-CSF on Day +6 in pediatric HSCT to be safe. A further study using a larger cohort of patients is warranted to ascertain its true clinico-economic value.

Eighty adult patients with acute myeloid leukemia (AML) received peripheral blood T cell-replete HLA haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Disease status at transplantation was either first or second complete remission (CR, n = 69) or relapse/refractory (n = 11). Identical transplant-related procedures with conditioning regimen consisting of fractionated 800 cGy total body irradiation (TBI), fludarabine (30 mg/m(2)/day for 5 days), busulfan (3.2 mg/kg/day for 2 days), and antithymocyte globulin (1.25 mg/kg/day on days -4 to -1) and graft-versus-host disease (GVHD) prophylaxis with tacrolimus and methotrexate were used in all patients. Recovery of neutrophil (median, 11 days) and platelet (median, 10 days) counts was achieved in all patients with full donor chimerism (≥ 99%), and no delayed engraftment failure was observed. The cumulative incidence of grades III to IV acute GVHD and moderate to severe chronic GVHD was 11.2% and 26.3%, respectively. A donor CD8(+) and CD4(+) T cell dose above the median value was significantly associated with the incidences of grades II to IV acute GHVD and moderate to severe chronic GVHD, respectively. After a median follow-up of 28 months for survivors, the 2-year cumulative incidences of relapse (n = 20) and nonrelapse mortality (n = 10) were 26.6% and 12.2%, respectively. Although all but 1 patient in relapse/refractory status died, the 2-year overall and progression-free survival of patients in first CR was 82.5% and 75.1%, respectively. We suggest the strategy of fractionated 800 cGy TBI-based conditioning with unmanipulated peripheral blood stem cell grafts seems feasible with favorable outcomes for adult patients with AML undergoing haplo-HSCT in CR.

To report the development of a spontaneous subcapsular splenic hematoma following filgrastim administration in a patient undergoing an allogeneic hematopoietic stem cell transplant.

A 60-year-old female with myelodysplastic syndrome was admitted for a reduced-intensity allogeneic hematopoietic stem cell transplant from an unrelated donor. She received filgrastim 5 μg/kg starting on day 1 to accelerate neutrophil recovery. On day 5, she began reporting severe left chest-wall pain. Contrast-enhanced computed tomography of the abdomen/pelvis revealed a spontaneous subcapsular splenic hematoma. Upon discontinuation of filgrastim, the pain fully resolved. The patient was subsequently rechallenged with filgrastim, which led to recurrence of the left-sided chest-wall pain. Filgrastim was discontinued and the patient reported resolution of the pain.

Filgrastim has been associated with splenic hematoma and splenic rupture, predominantly in healthy donors undergoing mobilization of peripheral blood stem cells. Although splenic rupture attributed to filgrastim in a patient undergoing allogeneic hematopoietic stem cell transplantation has been reported, to our knowledge, this is the first case report to establish causality. Using the Naranjo probability scale, an objective causality assessment revealed that the adverse drug event was highly probable.

Although filgrastim-induced splenomegaly, splenic hematomas, and splenic rupture are rare, clinicians working in the bone marrow transplant setting should be cognizant of the potential of growth factors to cause these adverse events.

To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN) in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT).

The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes.

Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57) and 10.44 days (SD 2.44) in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days), fever of unknown origin (79% vs. 78%), proven infection (34% vs. 28%), mucositis (76% vs. 59%). After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3), 20 deaths were observed due to disease progression.

We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT. EU CLINICAL TRIAL REGISTER NUMBER: 2007-001430-14.

Hematopoietic growth factors are often given for prevention of febrile neutropenia (FN), infections, and other complications by hastening neutrophil recovery in the treatment of malignancies after high dose chemotherapy (HDCT). Although several meta-analyses have already demonstrated beneficial effects of prophylactic granulocyte colony-stimulating factors (G-CSF) administration, the effects of G-CSF have not been confirmed in cancer patients receiving stem cell transplantation (SCT) after HDCT. Therefore, we performed a statistical combination of controlled clinical trials to investigate the efficacy of prophylactic use of G-CSF in preventing the neutropenic complications associated with SCT following HDCT in cancer patients. We searched PubMed to identify potentially relevant references and finally selected seven randomized controlled trials that met all of the eligibility criteria. Our meta-analysis demonstrated that prophylactic G-CSF reduced the risk of documented infections and time to hematologic recovery manifested by days to absolute neutrophil count (ANC) ≥ 0.5 × 10(9)/L, days to ANC ≥ 1.0 × 10(9)/L, and days to platelets ≥ 20 × 10(9)/L in SCT patients with cancer following HDCT. The G-CSF treated group also showed a decrease in the length of hospital stay. However, there was no difference between G-CSF treatment group and placebo group in regard to all-cause mortality, infection-related mortality, grade 2∼4 acute graft-versus-host-disease, and episode of fever.

The routine use of recombinant human granulocyte-colony stimulating factor (rhG-CSF) after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is associated with increased costs. We prospectively explored a strategy that used prophylactic delayed filgrastim only in patients with risk factors.

This sequential cohort analysis compared the outcomes of consecutive patients, treated on the risk-adapted protocol (RAP) (risk factors: prior febrile neutropenia; age >60 years; and CD34+ cell infused dose of <2 × 10(6/)/kg), who received filgrastim from day +6 after auto-SCT with a historical cohort (historical day-1 cohort [HD1]), who received filgrastim from day +1.

Eighty-two patients were treated in the RAP cohort and compared with 115 patients in the HD1 cohort. There were no differences in median age (55 years) or median CD34+ cell dose (5.21 × 10(6)/kg [range, 2-62.2 × 10(6)/kg] vs. 5.24 × 10(6)/kg [range, 2.4-29.8 × 10(6)/kg]). Filgrastim was used for 6 fewer days in the RAP cohort (median 5 days [range, 0-11 days] vs. 11 days [range, 9-47 days]). There was a small absolute but significant difference in median time to neutrophil recovery in the HD1 cohort for the whole group, 10 days (range, 8-46 days) vs. 11 days (range, 9-22 days) (P = .03) and in patients with myeloma; 10 days (range, 9-14 days) vs. 11 days (range, 9-18 days) (P < .0001) as compared to the RAP cohort. There was no difference in median inpatient duration, 13 days (range, 10-26 days) vs. 12 days (range, 1-38 days) (P = .22) and 3-year survival (79% vs. 83% [P = .43]) between HD1 and RAP cohorts respectively.

The use of a RAP to identify patients likely to benefit from prophylactic filgrastim is safe and results in cost savings. Patients with myeloma benefit from earlier introduction of filgrastim in terms of neutrophil recovery; this disease-specific observation is an important consideration for future studies.

Successful utilization of SCT modalities often requires utilization of both red cell and platelet transfusions. In this retrospective evaluation of clinical factors affecting transplant engraftment and transfusion utilization at a single transplant center in 505 patients from 2005 through 2009, we found that graft type, donor type and the conditioning regimen intensity significantly affected both the neutrophil engraftment time (P<0.001) and the platelet engraftment time (P<0.001). SCT patients required an average of 6.2 red cell units, and 7.9 platelet transfusions in the first 100 days with a wide s.d. Among auto-SCT patients, 5% required neither RBC nor platelet transfusions. Some reduced-intensity transplants were also associated with no transfusion need, and in allogeneic transplants, conditioning regimen intensity was positively correlated with platelet transfusion events as assessed by multivariate analysis. Other patient characteristics such as gender, graft type, donor type, underlying disease and use of TBI were all independently associated with transfusion needs in SCT patients. Further studies are required to understand the means to minimize transfusions and potential related complications in SCT patients.

The synthetic triterpenoid CDDO-Me has been shown to directly inhibit the growth of myeloid leukemias and lends itself to a wide array of therapeutic indications, including inflammatory conditions, because of its inhibition of NF-κB. We have previously demonstrated protection from acute graft-versus-host disease after CDDO-Me administration in an allogeneic bone marrow transplantation model. In the current study, we observed that CDDO-Me promoted myelopoiesis in both naive and transplanted mice. This effect was dose dependent, as high doses of CDDO-Me inhibited myeloid growth in vitro. All lineages (granulocyte macrophage colony-forming unit, BFU-E) were promoted by CDDO-Me. We then compared the effects with granulocyte colony-stimulating factor, a known inducer of myeloid expansion and mobilization from the bone marrow. Whereas both drugs induced terminal myeloid expansion in the spleen, peripheral blood, and bone marrow, granulocyte colony-stimulating factor only induced granulocyte macrophage colony-forming unit precursors in the spleen, while CDDO-Me increased these precursors in the spleen and bone marrow. After sublethal total-body irradiation, mice pretreated with CDDO-Me further displayed an accelerated recovery of myeloid progenitors and total nucleated cells in the spleen. A similar expansion of myeloid and myeloid progenitors was noted with CDDO-Me treatment after syngeneic bone marrow transplantation. Combined, these data suggest that CDDO-Me may be of use posttransplantation to accelerate myeloid recovery in addition to the prevention of graft-versus-host disease.

Colony-stimulating factors (CSFs) are attractive adjunctive anti-infective therapies. Used to enhance innate host defenses against microbial pathogens, the myeloid CSFs increase absolute numbers of circulating innate immune effector cells by accelerating bone marrow production and maturation, or augment the function of those cells through diverse effects on chemotaxis, phagocytosis, and microbicidal functions. This article summarizes the evidence supporting the accepted clinical uses of the myeloid CSFs in patients with congenital or chemotherapy-induced neutropenia, and presents an overview of proposed and emerging uses of the CSFs for the prevention and treatment of infectious diseases in other immunosuppressed and immunocompetent patient populations.

In allogeneic hematopoietic stem cell transplantation (allo-SCT), most physicians in Japan utilize granulocyte colony-stimulating factor (G-CSF) at a high dose (HD) of 300 μg/m(2) per day for filgrastim to promote faster neutrophil engraftment. However, the necessity of the HD has not been validated under graft-versus-host disease (GVHD) prophylaxis by mycophenolate mofetil (MMF), which can also be expected to facilitate engraftment. In a total of 51 patients, we compared the clinical outcomes between a standard dose (SD) fixed at 300 μg per day and a HD of G-CSF. While time to neutrophil engraftment was not different in the HD and SD groups in patients receiving cord blood transplantation (CBT, 20 vs. 17.5 days, P = 0.243) or bone marrow transplantation (BMT, 11 vs. 10 days, P = 0.227), there seemed to be an increased risk of developing acute GVHD in the HD group with CBT (20 vs. 0%, P = 0.073) and BMT (57 vs. 24%, P = 0.165). Progression-free survival of patients in the HD group was likely to be worse compared with that of the SD group with CBT (P = 0.099). In this study, the clinical benefits of a HD of G-CSF could not be documented, and we find that the use of G-CSF at a SD after allo-SCT with MMF should be prospectively evaluated.

There are currently no recommendations indicating when stimulation should begin after autologous peripheral blood stem cell transplantation (PBSCT). We compared the outcome following between two treatment groups, in which daily granulocyte colony stimulating factor (G-CSF) administration began on either the fifth or the eighth day after PBSCT in lymphoma and myeloma patients. We studied eight clinical parameters: number of G-CSF injections, number of days of hospitalization, of red blood cell or platelet transfusions; days when body temperature exceeds 38°C; days of parenteral nutrition; weight loss and hospitalization costs. We studied also four biological parameters: number of CD34+ cells, days with leucocytes less than 1 × 10(9) /L, days with hemoglobin less than 90 g/L or with less than 50 × 10(9) /L of platelets. There were no statistical significant differences between the study arms. It seems that delayed stimulation by G-CSF after PBSCT is safety and does not seem to modify bone marrow recovery timing.

Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) are more frequently used as the cellular source in allogeneic hematopoietic stem cell transplantation (HSCT) than bone marrow stem cells (BMSCs) because they promote more rapid engraftment and immune reconstitution. However, the underlying mechanism for this is not fully understood. Here, we investigated the role of Toll-like receptor 2 (TLR2) on PBSCs in promoting rapid engraftment after allogeneic HSCT. We found that PBSCs highly expressed TLR2 in comparison to BMSCs, and TLR2 was directly induced by G-CSF signaling. Treatment with the TLR2 ligand, Pam(3)CSK(4) (PAM), more efficiently induced myeloid differentiation of PBSCs than BMSCs. Similarly, endogenous TLR2 ligands from the serum of recipients of allogeneic transplantation more rapidly stimulated myeloid differentiation of PBSCs compared with BMSCs. PAM treatment of TLR2(-/-) syngeneic recipient mice transplanted with PBSCs resulted in significantly elevated numbers of PBSC-derived myeloid cells and spleen colony formation compared with controls. Our results demonstrate that TLR2 signaling in PBSCs correlates with their ability to rapidly differentiate into myeloid cells, resulting in improved engraftment. Thus, TLR2 may be a novel target for increasing the efficiency of allogeneic HSCT by overcoming engraftment failure or delayed engraftment.