Intermediate-dose cyclophosphamide and bortezomib for PBSC mobilization in multiple myeloma.

Although the incorporation of bortezomib into induction regimens has improved response rates in patients with multiple myeloma (MM), the role of bortezomib in the peripheral blood stem cell (PBSC) mobilization remains unclear. We assessed the PBSC mobilization efficacy, safety, and disease response of intermediate-dose cyclophosphamide and bortezomib in the PBSC mobilization. Twenty-one patients with newly diagnosed MM were enrolled in a phase II, non-randomized study that used bortezomib (1.3 mg/m2/day on days 1, 4, 8, and 11) and intermediate-dose cyclophosphamide (2 g/m2/day on days 2, 3) (Bor-ID-CY). The data from 15 patients who received intermediate-dose cyclophosphamide (ID-CY) were used as a historical control group. The total CD34 + cell yield of Bor-ID-CY and ID-CY groups were not significantly different (median 6.3 ×106/kg vs. 6.5 ×106/kg, p = 0.26). All three patients with mobilization failure of two groups had t(11;14). Six patients in Bor-ID-CY group were upgraded from a status that was less than a very good partial response (VGPR) at the time of PBSC mobilization to a VGPR or better after PBSC mobilization (p = 0.014). Four patients in Bor-ID-CY group developed sepsis. The time to engraftment was similar in the two groups. The addition of bortezomib to ID-CY did not impact the stem cell yield or quality.

The efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma patients.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) plus plerixafor has been shown to improve the efficacy of peripheral blood stem cell (PBSC) mobilization, however, due to its high price, the use of plerixafor is limited in China. The purpose of this study was to assess the efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma (MM) patients. MATERIALS AND METHODS: In this single-center retrospective study, 69 MM patients received G-CSF + plerixafor to mobilize PBSCs, which were collected from 28 patients only for one day and 41 patients for two days. Some of the patients received residual plerixafor, and PBSCs were collected on the second day. The data on the characteristics, different doses of plerixafor and efficacy of PBSC mobilization were collected and analyzed. RESULTS: After 1 or 2 apheresis procedures, 85.5% of patients collected more than 2 × 106 cells/kg PBSCs. There was no statistically significant difference in the success rate of CD34 + PBSC mobilization with the different doses of plerixafor on the first day, but the higher residual plerixafor dose resulted in better success rates on the second day (P＜0.001). Among the patients who collected PBSCs for two days, the level of the CD34 + cell yield of 24 patients (58.5%) changed better, which was significantly correlated with the dose of residual plerixafor on the second day (P = 0.001). DISCUSSION: These results suggested that the administration of residual plerixafor to mobilize stem cells on the second day is an economical, efficient and clinically feasible method.

A nonparametric method for classification trees using grouped covariates.

A group of variables are commonly seen in diagnostic medicine when multiple prognostic factors are aggregated into a composite score to represent the risk profile. A model selection method considers these covariates as all-in or all-out types. Model selection procedures for grouped covariates and their applications have thrived in recent years, in part because of the development of genetic research in which gene-gene or gene-environment interactions and regulatory network pathways are considered groups of individual variables. However, little has been discussed on how to utilize grouped covariates to grow a classification tree. In this paper, we propose a nonparametric method to address the selection of split variables for grouped covariates and their following selection of split points. Comprehensive simulations were implemented to show the superiority of our procedures compared to a commonly used recursive partition algorithm. The practical use of our method is demonstrated through a real data analysis that uses a group of prognostic factors to classify the successful mobilization of peripheral blood stem cells.

Plerixafor-based mobilization in pediatric healthy donors with unfavorable donor/recipient body weight ratio resulted in a better CD34+ collection yield: A retrospective analysis.

INTRODUCTION: In order to propose risk-adapted mobilization algorithms, several authors have tried to look for predictive factors of the CD34+ yield in healthy pediatric donors. Donor recipient body weight ratio (D/R ratio) was identified as one of the main variables related with the success to achieve the target cell dose for transplantation. According to this variable we modified the mobilization schedule. MATERIAL AND METHODS: We report the results of 46 mobilizations and apheresis procedures performed in our center with unfavorable D/R ratio. Mobilization was attempted by the standard regime of G-CSF (10 mcg/kg/24 hours) in 28 cases (60.9%), with high dose G-CSF (10 mcg/kg/12 hours) in 9 cases (19.6%), and with plerixafor and G-CSF single dose regime in 9 cases (19.6%). RESULTS: CD34+ cell quantification before apheresis is closely related to CD34+ yield, being the only factor related to collected CD34+ cells (beta .71; P < .0001). The mobilization efficiency was higher in plerixafor group compared to the other two schedules (P < .0001). By using plerixafor for mobilization, we achieved the target CD34+ cell dose of ≥2 × 106 /kg per recipient body weight in all cases with unfavorable D/R ratio. It was observed that 17.4% of cases that not reached the established target cell dose were located in the standard or high-dose mobilization regimes. This difference is even greater for optimal collections (≥5 × 106 /kg), since of the 54.3% cases that did not reach this goal none was mobilized by plerixafor. CONCLUSION: Tailoring the mobilization regime we can reach the target cell dose, even in those cases with the worst D/R ratio.

UK consensus statement on the use of plerixafor to facilitate autologous peripheral blood stem cell collection to support high-dose chemoradiotherapy for patients with malignancy.

Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte-colony stimulating factor [G-CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re-mobilization after a failed mobilization attempt with G-CSF, and rescue or pre-emptive mobilization in patients in whom mobilization with G-CSF is likely to fail. Pre-emptive use has the advantage that it avoids the need to re-schedule the transplant procedure, with its attendant inconvenience, quality-of-life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre-emptive plerixafor is associated with an incremental drug cost of less than £2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 µl-1 at the time of recovery after chemomobilization or after four days of G-CSF treatment, or an apheresis yield of <1 × 106 CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre-emptive plerixafor.

Platelet Count before Peripheral Blood Stem Cell Mobilization Is Associated with the Need for Plerixafor But Not with the Collection Result.

BACKGROUND: A low platelet count before mobilization has recurrently been identified as risk factor for poor mobilization. METHODS: To determine the relevance of this finding for peripheral blood stem cell (PBSC) mobilization, including pre-emptive or rescue plerixafor in the case of poor mobilization, we retrospectively analyzed all patients undergoing PBSC collection at our institution between January 2014 and December 2015 (n = 380). RESULTS: In total, 99% of the patients (377/380) successfully collected a minimum of 2 × 106 CD34+ cells/kg body weight sufficient for a single transplant. Rescue or pre-emptive plerixafor was administered to 11% of the patients (42/380). No correlations between the platelet count before mobilization and the number of peripheral blood CD34+ cells or the CD34+ cell collection result were detected in the entire population or the subgroups according to diagnosis (newly diagnosed multiple myeloma, relapsed multiple myeloma, lymphoma, amyloid light-chain amyloidosis, sarcoma, or germ cell tumor). However, patients requiring pre-emptive or rescue plerixafor had a significantly lower platelet count before mobilization (217/nl vs. 245/nl; p = 0.004). CONCLUSION: With the current state of the art PBSC mobilization strategies, the platelet count before mobilization was not associated with the CD34+ cell collection result but was associated with the need for pre-emptive or rescue application of plerixafor.

Engraftment and outcomes following autologous stem cell transplantation in Hodgkin lymphoma patients mobilized with plerixafor.

Plerixafor has been used to improve peripheral blood stem cell (PBSC) mobilization in multiple myeloma, non-Hodgkin lymphoma, and very recently in Hodgkin lymphoma (HL) patients. Because prior studies have suggested that mobilization with plerixafor affects the composition of mobilized cells, there are concerns that this may in turn adversely impact the immune reconstitution and longer term outcomes of transplanted patients. However, data on the engraftment characteristics and long-term post-transplant outcomes in patients transplanted with plerixafor-mobilized PBSCs are lacking. This retrospective study examined the post-transplant outcomes of 105 consecutive adult HL patients, and compared the post-transplant outcomes of 21 patients who received plerixafor in addition to G-CSF ± chemotherapy because of poor mobilization with those of 84 patients who mobilized well without plerixafor. Despite collecting significantly lower CD34+ cell doses (median of 3.41 vs. 6.05 × 106 /kg, p < 0.0001) than control patients and requiring more collection days, plerixafor-mobilized patients showed comparable early engraftment characteristics, except for slightly delayed neutrophil engraftment (median: 11 vs.10 days, p = 0.002) and lower median neutrophil counts (2.1 vs. 2.6 × 109 /L, p = 0.04) at one month after transplant. No significant differences were observed in longer term post-transplant outcomes, including cell counts at 3, 6, and 12 months, RBC and platelet transfusion support during the first 120 days, relapse incidence, overall and progression-free survival rates up to two years post transplant. The use of plerixafor not only enabled poorly mobilizing HL patients to collect enough PBSCs to proceed to ASCT, but also to have similar post-transplant outcomes compared to patients who mobilized well with conventional regimens. Copyright © 2016 John Wiley & Sons, Ltd.

Acutely deteriorated extravascular volume overload during peripheral blood stem cell mobilization in POEMS syndrome: A case series with cytokine analysis.

We describe two cases of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome patients with deteriorated extravascular volume overload without increased levels of vascular endothelial growth factor after the administration of cyclophosphamide + granulocyte colony-stimulating factor for stem cell mobilization. We then measured the serum levels of 27 cytokines from these cases using a multiplex suspension array system. The analysis revealed the changes of cytokine profiles before cyclophosphamide + granulocyte colony-stimulating factor and after the development of capillary leak symptoms in both cases. This may improve our current level of understanding of the pathogenesis of POEMS syndrome not driven by vascular endothelial growth factor.

Efficacy of biosimilar granulocyte colony-stimulating factor versus originator granulocyte colony-stimulating factor in peripheral blood stem cell mobilization in de novo multiple myeloma patients.

BACKGROUND AIMS: Filgrastim and lenograstim are the standard granulocyte colony-stimulating factor (G-CSF) agents for peripheral blood stem cell mobilization (PBSC) in patients who undergo autologous stem cell transplantation. METHODS: To assess whether biosimilars are effective, we conducted a single-center, prospective study that included 40 consecutive de novo multiple myeloma patients who received cyclophosphamide 4 g/m(2) per day plus biosimilar filgrastim G-CSF to mobilize PBSC. These patients were compared with a group of 37 patients matched for age, diagnosis, previous chemotherapy and mobilization who had been treated with originator G-CSF. The mean number of CD34+ cells/µL in the peripheral blood was 199.6 ± 207.4 in the biosimilar and 192.8 ± 154.7 in the originator group (P = 0.87). The median number of CD34+ cells/kg recipient collected was 11.5 ± 5.8 and 12.3 ± 5.3 in the biosimilar and originator groups, respectively (P = 0.51). The mobilization failure rate was 2.5% and 2.7% in the biosimilar filgrastim and originator filgrastim cohorts (P = NS), respectively. RESULTS: Twenty-nine patients in the biosimilar group and 28 patients in the originator group underwent autologous transplantation. There were no statistically significant differences between the biosimilar and originator G-CSF cohorts in terms of hematopoietic recovery parameters and transplant-related toxicities. CONCLUSIONS: The efficacy of biosimilar G-CSF appears to be equivalent to the reference G-CSF.

PBSC mobilization in lymphoma patients: analysis of risk factors for collection failure and development of a predictive score based on the kinetics of circulating CD34+ cells and WBC after chemotherapy and G-CSF mobilization.

Autologous stem cell transplantation (ASCT) is a potentially curative treatment of lymphoma, but peripheral blood stem cell (PBSC) mobilization fails in some patients. PBSC mobilizing agents have recently been proved to improve the PBSC yield after a prior mobilization failure. Predictive parameters of mobilization failure allowing for a preemptive, more cost-effective use of such agents during the first mobilization attempt are still poorly defined, particularly during mobilization with chemotherapy + granulocyte colony-stimulating factor (G-CSF). We performed a retrospective analysis of a series of lymphoma patients who were candidates for ASCT, to identify factors influencing PBSC mobilization outcome. Premobilization parameters-age, histology, disease status, mobilizing protocol, and previous treatments-as well as white blood cell (WBC) and PBSC kinetics, markers potentially able to predict failure during the ongoing mobilization attempt, were analyzed in 415 consecutive mobilization procedures in 388 patients. We used chemotherapy + G-CSF in 411 (99%) of mobilization attempts and PBSC collection failed (<2 × 10(6) CD34+ PBSC/kg) in 13%. Multivariable analysis showed that only a low CD34+ PBSC count and CD34+ PBSC/WBC ratio, together with the use of nonplatinum-containing chemotherapy, independently predicted mobilization failure. Using these three parameters, we established a scoring system to predict risk of failure during mobilization ranging from 2 to 90%, thus allowing a selective use of a preemptive mobilization policy.

Plerixafor on-demand combined with chemotherapy and granulocyte colony-stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs.

To date, no prospective study on Plerixafor 'on-demand' in combination with chemotherapy and granulocyte colony-stimulating factor (G-CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on-demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G-CSF to mobilize peripheral blood stem cells (PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34(+) cells in peripheral blood was reduced by 'on-demand' strategy compared to conventional mobilization; from 13·0 to 3·0% (P = 0·004). Failure to harvest CD34(+) cells 2 × 10(6) /kg decreased from 20·9 to 4·0% (P = 0·0001). The on-demand Plerixafor strategy also resulted in a lower rate of mobilization failure (P = 0·03) and harvest failure (P = 0·0008) when compared to a 'bias-adjusted set of controls'. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G-CSF, the 'on-demand' use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost.

A case of acute lung injury in a peripheral blood stem cell donor mobilized with pegylated recombinant human granulocyte colony-stimulating factor.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been introduced for the mobilization of peripheral blood stem cells (PBSCs). However, no cases of acute lung injury (ALI) in healthy donors have been reported, and the underlying mechanisms remain poorly understood. We first reported a case of ALI caused by PEG-rhG-CSF in a healthy Chinese donor, characterized by hemoptysis, hypoxemia, and patchy shadows. Ultimately, hormone administration, planned PBSC collection, leukocyte debridement, and planned PBSC collection resulted in active control of the donor's ALI. The donor's symptoms improved without any adverse effects, and the PBSC collection proceeded without incident. Over time, the lung lesion was gradually absorbed and eventually returned to normal. PEG-rhG-CSF may contribute to ALI in healthy donors via mechanisms involving neutrophil aggregation, adhesion, and the release of inflammatory mediators in the lung. This case report examines the clinical manifestations, treatment, and mechanism of lung injury induced by PEG-rhG-CSF-mobilized PBSCs.

Peripheral blood stem cell mobilization; a look ahead.

THE PURPOSE OF REVIEW: Mobilized peripheral blood is the predominant source of stem and progenitor cells for hematologic transplantation. Successful transplant requires sufficient stem cells of high enough quality to recapitulate lifelong hematopoiesis, but in some patients and normal donors, reaching critical threshold stem cell numbers are difficult to achieve. Novel strategies, particularly those offering rapid mobilization and reduced costs, remains an area of interest.This review summarizes critical scientific underpinnings in understanding the process of stem cell mobilization, with a focus on new or improved strategies for their efficient collection and engraftment. RECENT FINDINGS: Studies are described that provide new insights into the complexity of stem cell mobilization. Agents that target new pathways such HSC egress, identify strategies to collect more potent competing HSC and new methods to optimize stem cell collection and engraftment are being evaluated. SUMMARY: Agents and more effective strategies that directly address the current shortcomings of hematopoietic stem cell mobilization and transplantation and offer the potential to facilitate collection and expand use of mobilized stem cells have been identified.

Altered expression of circadian clock genes during peripheral blood stem cell mobilization induced by granulocyte colony-stimulating factor.

Circulating hematopoietic stem cells exhibit robust circadian fluctuations, which influence the mobilized cell yield, even during enforced stem cell mobilization. However, alterations in the expression of circadian clock genes during granulocyte colony-stimulating factor (G-CSF)-induced peripheral blood stem cell (PBSC) mobilization are not fully elucidated. Therefore, we measured the expression of these genes in human peripheral blood leukocytes from 21 healthy donors. While CRY1 mRNA expression significantly increased by 3.9-fold (p < 0.01), the expression of PER3, CRY2 and BMAL1 mRNAs significantly decreased (by 0.2-fold, 0.2-fold, and 0.6-fold, respectively; p < 0.001) after G-CSF administration. Moreover, CRY1 mRNA expression was inversely correlated with the plasma level of noradrenaline (r = -0.36, p < 0.05), while PER3, CRY2, and BMAL1 mRNA expression directly correlated with the plasma level of noradrenaline (r = 0.55, r = 0.66, and r = 0.57, respectively; p < 0.001). Thus, significant correlations between the levels of circadian clock gene mRNAs and the plasma level of noradrenaline, a sympathetic nervous system neurotransmitter, were established. The modulation of sympathetic activation and of the circadian clock may be novel therapeutic targets for increasing stem cell yields in PBSC donors.