Day Of Apheresis Research Articles

YF-H-2015005, a CXCR4 Antagonist, for the Mobilization of Hematopoietic Stem Cells in Non-Hodgkin Lymphoma Patients: A Randomized, Controlled, Phase 3 Clinical Trial

Background: YF-H-2015005, a novel CXCR4 antagonist, has been proven to increase the quantities of circulating hematopoietic stem cells (HSCs), which results in an adequate collection of HSCs in non-Hodgkin lymphoma (NHL) patients.Methods: This was a multicenter, double-blind, randomized (1:1), placebo-controlled phase III clinical trial. All patients received granulocyte colony-stimulating factor (G-CSF) for up to 8 consecutive days. YF-H-2015005 or placebo was administrated on the evening of day 4 and continued daily for up to 4 days. Apheresis was conducted 9–10 h after each dose of YF-H-2015005 or placebo. The primary endpoint was the proportion of NHL patients procuring ≥5 × 106/kg CD34+ HSCs within ≤4 apheresis sessions.Results: In total, 101 patients with NHL were enrolled. The proportions of patients achieving primary endpoint were 57 and 12% in YF-H-2015005 and placebo groups, respectively (P < 0.001). Moreover, a higher proportion of YF-H-2015005-treated patients reached a minimum target collection of ≥2 × 106/kg CD34+ HSCs in ≤4 apheresis days compared to placebo-treated patients (86 vs. 38%, P < 0.001). Furthermore, the median time to collect ≥2 or 5 × 106/kg CD34+ HSCs were 1 and 3 days in YF-H-2015005-treated patients, but 4 days and not reached in placebo-treated patients, respectively. No severe treatment emergent adverse events were observed in both YF-H-2015005 treatment and placebo groups.Conclusions: YF-H-2015005 plus G-CSF regimen was a tolerable combination with high efficacy, which might be used to rapidly mobilize and collect HSCs in NHL patients.

Analysis of the efficacy and safety of plerixafor combined with G-CSF in plasma cell disease mobilization

目的分析普乐沙福联合G-CSF在浆细胞疾病自体造血干细胞中动员的效果及安全性。方法回顾性分析2018年1月至2019年12月在北京大学人民医院使用普乐沙福联合G-CSF进行自体造血干细胞动员的浆细胞疾病患者的基线临床资料、采集成功率及不良反应。结果共纳入49例浆细胞疾病患者，多发性骨髓瘤（MM）39例（79.6%），淀粉样变性8例（16.3%），肾脏意义的单克隆免疫球蛋白沉积病（MGRS）2例（4.1%），肾功能不全16例（32.7%）。其他动员方案既往采集失败患者7例（14.3%）。使用普乐沙福动员后，中位采集次数1（1～3）次，中位采集天数2（1～3）d，一次采集成功47例（95.9%），两次采集累积成功率为100%。在16例肾功能不全的患者中，5例（31.3%）患者第1天采集成功，8例（50%）需要第2天采集，3例（18.8%）需要第3天采集。主要不良反应依次为乏力、失眠、腹痛、腹泻、头晕、关节痛。共37例患者行auto-HSCT，白细胞中位植活时间11（8～13）d，血小板中位植活时间11（9～26）d。结论普乐沙福联合G-CSF用于浆细胞疾病患者自体造血干细胞动员成功率高，不良反应少，即使在肾功能不全的患者中也具有较高的动员成功率。

On-Demand Plerixafor with Cyclophosphamide and G-CSF for Hematopoietic Stem-Cell Mobilization in Multiple Myeloma Patients: Preliminary Results of a Prospective Observational Study (MOZOBL06877)

On-Demand Plerixafor with Cyclophosphamide and G-CSF for Hematopoietic Stem-Cell Mobilization in Multiple Myeloma Patients: Preliminary Results of a Prospective Observational Study (MOZOBL06877)

Timing of Daratumumab Administered Pre-Mobilization in Multiple Myeloma Impacts Pre-Harvest Peripheral Blood CD34+ Cell Counts and Plerixafor Use

Background: Daratumumab (DARA) is a monoclonal antibody which targets CD38 on plasma cells and B cell progenitors. DARA has been effectively combined with other therapies in newly diagnosed and relapsed/refractory multiple myeloma (RRMM), while DARA-based induction regimens in transplant-eligible patients (pts) are increasingly being used in clinical practice. Given that hematopoietic stem cells also express CD38, DARA may potentially affect stem cell mobilization and hematopoietic reconstitution following autologous stem cell transplant (ASCT). Although no clinically significant impact of DARA on stem cell mobilization or hematopoietic recovery was described in large phase 3 trials of triplet induction regimens +/- DARA in newly diagnosed MM, stem cell yields were lower and plerixafor more commonly used in the DARA-containing arms [Moreau et al, Lancet 2019; Voorhees et al, Blood 2020]. Significantly longer time to neutrophil (PMN) engraftment was also reported in pts receiving DARA-based induction who underwent upfront ASCT [Al Saleh et al, Am J Hematol 2020]. In this study, we examine the impact of timing of DARA administration pre-mobilization on day 4 pre-harvest peripheral blood CD34 cell count, stem cell apheresis yield, and post-ASCT engraftment. Methods: Between 1/1/2016 and 12/31/2019, newly diagnosed and RRMM pts receiving DARA-based induction regimens with ≥1 dose of DARA administered within 1 month prior to stem cell mobilization were identified retrospectively and compared to matched controls receiving similar induction regimens without DARA. Granulocyte colony-stimulating factor (G-CSF) was administered per institutional standards and plerixafor added based on day 4 pre-harvest peripheral blood CD34 counts. PMN and platelet engraftment post-ASCT was defined as the first of 3 consecutive days with sustained PMN count &amp;gt;500 x 106/L and independence from platelet transfusion in the preceding 7 days with a count &amp;gt;20 x 109/L, respectively. Pre-harvest peripheral blood CD34 counts and stem cell apheresis yields were obtained from the Cellular Therapy Laboratory at NewYork-Presbyterian Hospital. The study was approved by the Weill Cornell Medicine IRB. Results: We identified 16 pts who received DARA-based induction with ≥1 dose of DARA administered within 1 month of apheresis (DARA group) and 16 non-DARA-containing regimen-matched controls (non-DARA group). Demographics of the DARA and non-DARA groups were well matched (Table 1). DARA pts received their last dose of DARA a mean of 17.3 days prior to the first day of apheresis, with 8 pts receiving their last dose within 2 weeks and the remaining 8 pts between 2 weeks and 1 month prior. Overall, mobilization outcomes were inferior in the DARA group (Table 2). DARA pts had significantly lower day 4 pre-harvest peripheral blood CD34 counts compared to non-DARA pts (17.2 vs 35.4 cells/µL; P=0.0146). Institutional algorithm required plerixafor to be given for day 4 CD34 count ≤40 cells/µL. Fifteen of the 16 DARA pts received plerixafor vs. 11 non-DARA pts (P=0.07). Additionally, DARA pts required significantly more apheresis days (2.4 vs 1.6 days; P=0.0279). Differences in stem cell yield were not significant (8 vs 10 x106cells/kg; P=0.1391). Hematopoietic recovery post-ASCT was not affected by DARA administered in the month preceding mobilization. Conclusions: In summary, we report lower day 4 pre-harvest peripheral blood CD34 count, increased requirement for plerixafor, and longer apheresis duration in newly diagnosed and RRMM pts receiving DARA within 1 month ofstem cell mobilization. These limitations are largely overcome by plerixafor usage which, combined with G-CSF, resulted in successful stem cell collection in all patients. Limitations in our study include small sample sizes, retrospective control selection, and fewer pts in the DARA group achieving ≥VGPR prior to mobilization. Nevertheless, our findings are consistent with inferior mobilization outcomes reported in the DARA-containing arms of phase 3 trials of triplet induction +/- DARA and highlight the nearly universal requirement for plerixafor usage when DARA is administered within a month prior to apheresis. Prospective study of day 4 pre-harvest peripheral blood CD34 counts and other predictors of stem cell yield should be incorporated into future clinical trials of CD38 monoclonal antibody-based induction regimens for transplant-eligible MM pts. Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Niesvizky:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Rosenbaum:Amgen: Research Funding; GlaxoSmithKline: Research Funding; Akcea: Honoraria; Celgene: Honoraria; Janssen: Research Funding.

Outcomes of GCSF and Pre-Emptive Plerixafor Based Peripheral Blood Stem Cell Mobilization Among Patients with Multiple Myeloma-Experience from Newly Established Transplant Unit in Eastern Mediterranean Area

Introduction Granulocyte Colony Stimulating Factor (GCSF) with cyclophosphamide based peripheral blood stem cell (PBSC) mobilization is a widely used strategy among patients with multiple myeloma (MM), however, it is associated with toxicity and morbidity including severe infectious complications needing hospitalization. Plerixafor with GCSF has been widely used for mobilization as a preemptive strategy or during second attempt at collection with encouraging results. Methods We describe our experience from a newly established transplant unit in the Eastern Mediterranean region. A retrospective chart review was done and all consecutive patients of MM who underwent PBSC mobilization by GCSF and plerixafor between 2017 to 2020 were included in the study. Patients received GCSF (filgrastim, 10 µg/kg/day) and if peripheral blood CD34 count was less than 20/µl on day 4, patients received the first dose of plerixafor (240 µg/kg/day) on the evening of Day 4. Daily apheresis started on Day 5 for a maximum of 4 days, or until enough stem cells collected for one or two transplants at physician's discretion. Results A total of seventeen PBSC collections were carried out among patients with myeloma (n=17). There were 10 males and 7 females. The median age was 53 years (range 38-71), and 8/17 were less than 50 years of age. 14/ 17 were of IgG myeloma subtype, 2/17 were light chain myeloma, 1/17 was IgA myeloma type. 6/17 patients had R-ISS stage 3 disease while rest (11/17) had R-ISS stage 2 disease. 15/17 patients were in first remission. Only 1/17 patients had high-risk cytogenetics. 12/17 patients had bortezomib based therapy while 5/17 had lenalidomide based therapy. 13/17 patients had GCSF alone mobilization while 4/17 had GCSF plus pre-emptive plerixafor. 9/17 had a single collection while 8/17 had 2 collections. All patients on plerixafor needed two collections. Median CD34 stem cell dose was 8.6 x10^6 cells/kg (range 3.4-20 x 10^6 cells/kg). No grade 2-4 adverse events were recorded with this strategy post-collection and none required hospitalization for any adverse events. All patients underwent melphalan based conditioning and autologous stem cell transplant, although only 12/17 received a full dose of 200 mg/m2. 13/17 patients had fresh stem cells infused while the rest had cryopreserved stem cells. Median time to neutrophil recovery was 11 days (range 9-27) while median time to platelet recovery was 12 days (range 10-37). Day 100 mortality was zero percent. Conclusions Our study demonstrates successful collection with high stem cell yield enough for two stem cell transplants with GCSF and preemptive plerixafor strategy, in patients with MM, thus saving patients toxic effects of cyclophosphamide including cytopenias, infections which at times are severe causing morbidity and mortality. Over two-thirds of patients collected with GCSF alone. No major adverse events post stem cell collection were noted and all our patients engrafted early thus reducing hospital stay. Although the use of plerixafor increases cost but failure of mobilization, second mobilization, and infections (at times severe), delayed engraftment have their own costs and implications. Our study at our new transplant unit confirms that this pre-emptive strategy is safe, effective and reasonable chemo free first line option with no major adverse events as demonstrated by other studies. Disclosures No relevant conflicts of interest to declare.

Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial

We conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 106 CD34 + cells/kg recipient body-weight (CD34+/kg RBW) after 1st apheresis. A single dose of 240 µg/kg P was injected subcutaneously at 10 p.m. on the day of the 1st apheresis. Thirty-seven allogeneic PBSC donors underwent study treatment. The median CD34+ count in peripheral blood was 15/µl on Day 1 after G-CSF alone, versus 44/µl on Day 2 after G-CSF plus P (p < 0.001). The median yield of CD34+ cells was 1.1 × 108 on Day 1 and 2.8 × 108 on Day 2. In contrast to a median yield of only 1.31 × 106 CD CD34+/kg RBW on Day 1, triggering study inclusion, a median of 3.74 × 106 CD CD34+/kg RBW were collected with G-CSF plus P on Day 2. Of 37 donors, 21 reached the target cell count of >4.5 × 106 CD34+/kg RBW (57%, 95%CI 40–73%). No donor experienced a severe adverse event requiring treatment. In conclusion, P might be considered on a case-by-case basis for healthy allogeneic donors with very poor stem cell mobilization success after G-CSF.

Efficacy of a conversion from filgrastim to filgrastim-sndz in stem cell transplant patients undergoing mobilization.

During autologous stem cell transplant, granulocyte colony-stimulating factors (G-CSF) serve the integral role of mobilizing hematopoietic cells into the peripheral blood for subsequent collection by leukapheresis. Filgrastim (Neupogen®) is a G-CSF and affects hematopoietic cells by stimulating growth and differentiation of neutrophils. Filgrastim-sndz (Zarxio®), a biosimilar of filgrastim, received landmark approval as the first biosimilar product approved by the FDA in the United States. As a result of the recent FDA approval, our medical center made the conversion in August 2016 from using filgrastim to filgrastim-sndz to provide patients the same benefits of the filgrastim injection at a reduced cost. This retrospective, observational cohort study evaluated the comparative efficacy of the filgrastim-sndz biosimilar in 147 patients who underwent mobilization prior to stem cell transplant with filgrastim between 1 August 2015 and 31 July 2016 or filgrastim-sndz between 1 September 2016 and 30 November 2017. The mean number of CD34 cells collected during apheresis was 7.38 × 106 in the filgrastim group and 8.86 × 106 in the filgrastim-sndz group. Filgrastim-sndz was significantly non-inferior, as the difference between filgrastim and filgrastim-sndz was -1.48 × 106 with an upper 95% confidence bound equal to -0.24 × 106 that did not include the non-inferiority margin of 1 × 106 (p = 0.0006). The median number of days of apheresis was 2 in both groups (p= 0.3273). In conclusion, the biosimilar product was non-inferior for mobilization and the conversion from filgrastim to filgrastim-sndz afforded patients similar efficacy for mobilization in stem cell transplant at a reduced cost.

Characteristics of autologous peripheral blood stem cells collection over a one-year period.

Aim To present characteristics of collecting autologous peripheral blood stem cells over a one-year period with an emphasis on efficiency and safety. Methods A retrograde analysis of 24 leukapheresis in 20 adult patients with malignant haematological diseases in the Blood Transfusion Institute of the Federation of Bosnia and Herzegovina in Sarajevo, was done. Cell separators Amicus and Spectra Optia were used for collection procedures. Results The patient's age ranged from 27 to 65 years. Target cells were collected in one procedure in sixteen patients, while in four patients they were collected in two procedures. The mean CD34+ collection efficiency was 57.7%. The median number of CD34+ cells and percentage of CD34+ cells in the products were 5.52x10e6/kg (range 3.28-9.00) and 1.57% (range 0.96-2.91). A strong positive correlation was found between the number of CD34+ cells in peripheral blood on the apheresis day and the amount of CD34+ cells collected in the products (rs =0.73). A total of 95% of patients collected the amount of ≥3x10e6/kg and 55% of ≥5x10e6/kg CD34+ cells for a single transplant. A decrease in platelet count, haemoglobin and haematocrit values after the procedure was not significant. Potassium decrease showed statistical significance (p<0.000). Adverse events occurred during one procedure (4.2%). Conclusion A low number of adverse events and good collection efficiency with adequate patient monitoring, indicate that leukapheresis is a safe procedure that is successfully used in the autologous transplantation process in the treatment of malignant haematological diseases.

Stem Cell Mobilization and Autograft Minimal Residual Disease Negativity with Novel Induction Regimens in Multiple Myeloma.

Autologous stem cell transplantation (ASCT) remains the standard of care for transplantation-eligible patients with multiple myeloma (MM). Bortezomib with lenalidomide and dexamethasone (VRD) is the most common triplet regimen for newly diagnosed MM in the United States. Carfilzomib with lenalidomide and dexamethasone (KRD) has shown promising efficacy and may supplant VRD. We compared stem cell yields and autograft minimal residual disease (MRD)-negativity after VRD and KRD induction. Deeper responses (ie, very good partial response or better) were more common with KRD. Precollection bone marrow (BM) cellularity, interval from the end of induction therapy to start of stem cell collection, and method of stem cell mobilization were similar for the 2 cohorts. Days to complete collection was greater with KRD (2.2 days, versus 1.81 days with VRD), which more often required ≥3 days of apheresis. Precollection viable CD34+ cell content was greater with VRD, as was collection yield (11.11×106, versus 9.19×106 with KRD). Collection failure (defined as <2×106 CD34+ cells/kg) was more frequent with KRD (5.4% versus .7% with VRD). The difference in stem cell yield between VRD and KRD is associated with the degree of lenalidomide exposure. Age ≥70 years predicted poorer collection for both cohorts. Stem cell autograft purity/MRD-negativity was higher with KRD (81.4%, versus 57.1% with VRD). For both cohorts, MRD-negativity was attained in a larger fraction of autografts than in precollection BM. For patients proceeding to ASCT, the time to neutrophil/platelet engraftment was comparable in the 2 study arms. In summary, our data demonstrate that KRD induces deeper clinical responses and greater autograft purity than VRD without compromising stem cell yield or post-transplantation engraftment kinetics.

Assessment of factors affecting mobilization and collection in autologous and allogeneic hematopoietic stem cell donors

Background & Aim Background Peripheral blood hematopoietic stem cells (PBSC) are preferred source of stem cells in the majority of autologous and allogeneic transplantations. Sufficient number of mobilized and collected hematopoietic stem cells (HSC) is needed for successful transplantation. The aim of our study was to analyze possible predictive factors that could influence hematopoietic stem cell yield. Methods, Results & Conclusion Methods This study was performed in the Institute for Transfusion Medicine of RM and the University Hematology Hospital. There were 30 allogeneic and 90 autologous donors that underwent mobilization and collection of PBSC. The association between the number of collected PBSC and possible predictive factors was analyzed using Spearman Rank Order Correlation. Results There were 226 apheresis, 182 in autologous donors (mean 2, range 1-3) and 44 apheresis in 30 allogeneic donors (mean 1.5, range 1-2). The mean number of collected MNC in autologous donors was 3.09 × 108/kg and 2.85 × 106/kg CD34+ cells, and 3.23 × 108/kg MNC and 3.20 × 106/kg CD34+ cells in allogeneic donors. Significantly larger number of MNC and CD34+ cells was collected with the WBC set. There was a statistically significant correlation between the total number of collected MNC in autologous donors and platelet count before mobilization, the number of cycles in one apheresis procedure, quantity of collected graft and the number of collected MNC and CD34+ cells on the first day of apheresis. There was a statistically significant correlation between the total number of collected MNC in allogeneic donors and platelet count before mobilization, the number of cycles in one apheresis procedure, quantity of collected graft and number of MNC on the first day of apheresis. There was a strong correlation between the number of collected MNC and CD34+ cells on the first harvest and the total number of collected MNC and CD34+ cells in poor mobilizers, and inverse correlation with the number of apheresis procedures. Donors who donated MNC ≤ 0.7 × 108/kg and/or ≤ 0.7 × 106/kg CD34+ cells on the first harvest (84.6%) were strong predictors of poor mobilizers. Conclusion Determining the proper level of laboratory parameters for initiating mobilization and apheresis procedure which is safe for donors and efficient in collection of PBSC is needed for optimization of these procedures, as well as for early intervention in poor mobilizers.

EMA Recommendation for the Pediatric Indications of Plerixafor (Mozobil) to Enhance Mobilization of Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Children with Lymphoma or Malignant Solid Tumors.

On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony-stimulating factor (G-CSF) to pediatric patients (aged 1 year to <18 years) to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. This treatment is indicated either preemptively, when circulating stem cell count on the predicted day of collection after adequate mobilization with G-CSF (with or without chemotherapy) is expected to be insufficient with regard to desired hematopoietic stem cells yield, or in children who previously failed to collect sufficient hematopoietic stem cells. The efficacy and safety of plerixafor were evaluated in an open label, multicenter, phase I/II, dose-ranging, and randomized controlled study (DFI12860) in pediatric patients with solid tumors, including neuroblastoma, sarcoma, Ewing sarcoma, or lymphoma, who were eligible for autologous hematopoietic stem cell transplantation. Forty-five patients (aged 1 year to <18 years) were randomized, 2:1, using 0.24 mg/kg of plerixafor plus standard mobilization (G-CSF with or without chemotherapy) versus control (standard mobilization alone). The primary analysis showed that 80% of patients in the plerixafor arm experienced at least a doubling of the peripheral blood (PB) CD34+ count, observed from the morning of the day preceding the first planned apheresis to the morning prior to apheresis, versus 28.6% of patients in the control arm (p = .0019). The median increase in PB CD34+ cell counts from baseline to the day of apheresis was 3.2-fold in the plerixafor arm versus by 1.4-fold in the control arm. The observed safety profile in the pediatric population was consistent with that in adults, with adverse events mainly related to injection site reactions, hypokalemia, and increased blood bicarbonate. Importantly, plerixafor exposure did not seem to negatively affect transplant efficiency. This article summarizes the scientific review of the application leading to regulatory approval in the European Union. IMPLICATIONS FOR PRACTICE: This review of the marketing authorization of plerixafor will raise awareness of pediatric indication granted for this medicinal product.

Collection of Peripheral Blood Progenitor Cells in 1 Day Is Associated with Decreased Donor Toxicity Compared to 2 Days in Unrelated Donors.

Peripheral blood stem cells (PBSCs) have been increasingly used for allogeneic hematopoietic cell transplantation instead of bone marrow stem cells. Current National Marrow Donor Program policy recommends 5 days of daily filgrastim, followed by either 1 or 2 days of apheresis for unrelated donors, depending on collection center choice. To date, there are no published studies comparing the differences in donor experience between 1 day and 2 days of apheresis. We examined 22,348 adult unrelated donor collections in 184 centers between 2006 and 2016. Of these 22,348 donors, 20,004 (89.5%) had collection on 1 day, and the other 2344 (9.5%) had collection over 2 days. Information on why donors underwent apheresis in 1 day or 2 days was not available. Donors who underwent apheresis in 1 day were more likely to be male (67% versus 46%; P < .001), younger (age <30 years, 48% versus 36%; P < .001), and have a higher body weight (83.0 kg versus 75.9 kg; P< .001) and body mass index (BMI; >30, 30% versus 22%; P < .001). Successful collection of the requested CD34+ cell count was achieved on the first day in 82% of 1-day collections and in 16% of 2-day collections. Despite not administering filgrastim the evening after the first day of collection in patients who underwent 2 days of apheresis, the median concentration of CD34+ cells/L in the product was higher on the second day of apheresis compared with the first day (23.8×106 CD34+/L on day 1 versus 28.7×106 CD34+/L on day 2; P< .001). Donors who underwent collection in 1 day were less likely to experience citrate toxicity (36% versus 52%; P< .001), hospitalization (1% versus 6%; P< .001), and other side effects related to apheresis (Modified Toxicity Criteria incidence: 20% versus 26%; P < .001). Female sex, older age, collection via central lines, and higher BMI were factors associated with greater likelihood for the development of toxicity, whereas less toxicity was noted in those with higher CD34+ counts and more blood processed on the first day of collection. We conclude that although unrelated donors can be successfully collected in 1 day or 2 days, 1-day apheresis procedures were associated with less overall toxicity, and thus we recommend single-day collections, especially if the requested number of cells have been collected in 1 day.

The Effect of Skipped Collections on Stem Cell Product Yields in Difficult to Mobilize Multiple Myeloma Patients

Multiple Myeloma (MM) is incurable disease and autologous stem cell transplant (ASCT) remains an important modality of treatment. Current mobilization strategies result in mobilization failure rates as high as 5-10% among patients with MM1. According to our institutes policies, patients are prepared for stem cell collection with a Cytoxan based mobilization regimen plus GCSF/Mozobil (chemo-mobilization), or GCSF/Mozobil (growth factor) alone. Most often, patients undergoing chemo-mobilization and growth factor-based mobilization achieve adequate CD34 count in peripheral blood by day 14 and 5, respectively. Apheresis is performed after adequate CD34 is measured in the peripheral blood. We identified 18 MM patients, during 2016-2019, who did not achieve adequate CD34 count and were classified as difficult mobilizers. In this cohort, the median age was 57 years, 84% had diffuse marrow involvement and/or multiple lytic lesions, 39% had received an alkylating agent and 28% had received at least two previous lines of chemotherapy. 13 patients who were chemo-mobilized, did not achieve adequate CD34 yield, after 5 days of continuous apheresis. Similarly, 5 patients in GCSF/Mozobil arm did not achieve adequate CD34 yield after 5 days of continuous apheresis. Hence, we gave them planned 48 hours break from further GCSF or Mozobil exposure. After the break, we resumed GCSF/Mozobil for 1 day, and subsequently we noticed significant rise in peripheral blood CD34 count in some of the patients. We achieved a median collection of 3.98 CD34+ cell/kg in these difficult mobilizers. We compared collection to the easy mobilizers during the same time period and the median collection for easy mobilizers was 4.48 CD34+ cell/kg. The skipped day strategy led to adequate yields for ASCT in 100% of the difficult to mobilize patients. One possible explanation for the higher number of cells collected after the skipped day is that continuous exposure to GCSF leads to tachyphylaxis of GCSF receptors, and the break relieves this phenomenon, allowing better collection after the break. Further studies exploring this planned break strategy needs to be conducted in so called difficult mobilizer patient group.

Low baseline platelet count predicts poor response to plerixafor in patients with multiple myeloma undergoing autologous stem cell mobilization

Background aimsBaseline platelet count has been shown to be a sensitive predictor of autologous peripheral blood progenitor cell collection yield in patients with multiple myeloma mobilized with granulocyte colony-stimulating factor (G-CSF). Patients who mobilize poorly with G-CSF are often treated with plerixafor to enhance mobilization. There are no surrogate markers available to predict response to plerixafor. MethodsWe retrospectively analyzed data from 73 patients with multiple myeloma who did not have adequate mobilization with G-CSF alone and were treated with plerixafor as a rescue agent. ResultsWe found that baseline platelet count directly correlated with peripheral blood CD34+ (PB-CD34+) count after plerixafor treatment (r = 0.36, P < 0.0001) and the number of PB-CD34+ cells collected on the first day of apheresis and inversely correlated with the number of apheresis sessions needed to collect the target number of PB-CD34+ cells (P = 0.0015). Baseline platelet count of 153 000/µL or less was associated with 90% specificity of predicting poor response to plerixafor with a sensitivity of 33%. ConclusionsBaseline platelet count is a good predictor of mobilization response to plerixafor in patients with multiple myeloma.

Impact of Plerixafor Use at Different Peripheral Blood CD34+ Thresholds on Autologous Stem Cell Collection in Patients with Multiple Myeloma.

Patients with multiple myeloma (MM) scheduled for autologous stem cell transplantation must undergo autologous stem cell mobilization; unfortunately, however, many do not obtain an adequate collection yield. Despite the availability of plerixafor, its widespread and uniform use is limited by its cost, and consequently, many institutions have adopted various risk-adapted algorithms. We report our mobilization experience as we have modified our plerixafor algorithm to a more liberal one, with the expectation of greater collection efficiency and mobilization success with higher plerixafor use. A total of 344 mobilization attempts were analyzed over 3 time periods and using 3 different peripheral blood CD34+ cell counts to guide plerixafor use: <15/µL (n=66), <20/µL (n=130), and <40/µL (n=148). The primary endpoints were evaluation of changes in mean plerixafor utilization and apheresis days and assessment of the impact on overall mobilization costs. Secondary endpoints were a description of the impact of lenalidomide use on mobilization and evaluation of the rate of mobilization failure. We found that mean plerixafor use increased from 1.32 to 1.65 to 1.74 doses per mobilization (P=.026) and the mean days of apheresis decreased from 2.15 to 2.17 to 1.89 days per mobilization for the <15/µL, <20/µL, and <40/µL cohorts, respectively (P=.011). The combined cost of plerixafor and apheresis procedures at a threshold of 40/µL is close to that at a threshold of 15/µL, while saving 26 apheresis days per 100 patients. In general, there were low rates of mobilization failure across all thresholds. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization and required more apheresis sessions (P < .013) and greater plerixafor use (P < .001) to achieve target stem cell yields. Overall, using plerixafor in patients with MM, with a day 4 pCD34 count of <40/µL is a reasonable and cost-effective strategy to optimize apheresis utilization.

Yf-H-2015005, a New CXCR4 Antagonist, in the Mobilization of Hematopoietic Stem Cells in Patients with Non-Hodgkin Lymphoma: A Randomized-Controlled Phase 3 Study

Background: Autologous hematopoietic stem cell transplantation (AHSCT) is an important therapy for non-Hodgkin's lymphoma (NHL). This study evaluated the safety and efficacy of YF-H-2015005, a new CXCR4 antagonist, when used to mobilize hematopoietic stem cells in patients with NHL eligible for treatment with AHSCT. Methods: This phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study enrolled patients (age range, 18 to 65 years) with NHL, and who were in their first or second complete or partial remission. The patients received granulocyte colony-stimulating factor (G-CSF, 10 mg/kg/day) each morning for up to 8 days. Treatment with YF-H-2015005 (0.24 mg/kg/day) or placebo was initialed during the evening of the fourth day of G-CSF administration, and then continued for up to 4 days. Starting on day 5, apheresis was performed for 9 to 10 hours after each dose of YF-H-2015005 or until ≥ 5 × 106 CD34+ cells/kg had been collected. The primary endpoint was the percentage of patients who collected ≥ 5 × 106 CD34+ cells/kg during the course of 4 or fewer apheresis days. The secondary endpoints were the percentage of patients who collected ≥ 2 × 106 CD34+ cells/kg during the course of 4 or fewer apheresis days, the number of apheresis days required to reach ≥ 2 × 106 CD34+ cells/kg, the number of apheresis days required to reach ≥ 5 × 106 CD34+ cells/kg, and patient safety. Results: A total of 101 patients with NHL were randomly assigned to the YF-H-2015005 group (n = 51or placebo group (n = 50), respectively. The percentage of patients who met the primary endpoint was 57% (29/51) in the YF-H-2015005 group and 12% (6/50) in the placebo group (P &amp;lt; 0.001). A larger proportion of patients in the YF-H-2015005 group (86%) achieved the secondary endpoint of collecting ≥ 2 × 106 CD34+ cells/kg in 4 or fewer apheresis days when compared with the placebo group (38%, P &amp;lt; 0.001). Patients in the YF-H-2015005 group required shorter time periods to collect ≥ 2 × 106 CD34+ cells/kg (1 days vs. 4 days) and ≥ 5 × 106 CD34+ cells/kg (3 days vs. not reached). Treatment-related adverse event were observed in 37 patients (20 in the YF-H-2015005 group and 17 in the placebo group). The most common adverse events in the YF-H-2015005 group were diarrhea (14%), hyperhidrosis(6%), elevated alkaline phosphatase (6%). No serious treatment-related adverse event occurred. Conclusions: The combination of YF-H-2015005 and G-CSF was a tolerable regimen for use in rapidly mobilizing and collecting CD34+ cells for transplantation in patients with NHL. Disclosures Zhu: Mundipharma: Research Funding.

Are We Choosing Mobilization Regimens for Autologous Stem Cell Transplantation in Multiple Myeloma Wisely?: A Single Centre Comparison of GCSF+/-Plerixafor Vs Cyclophosphamide/GCSF+/- Plerixafor

Background: Autologous stem cell transplantation (ASCT) as consolidation post induction is standard of care for eligible multiple myeloma patients. Multiple strategies are employed for mobilization of stem cells in ASCT. Cyclophosphamide/GCSF is an effective standard regimen. However there are reported toxicities associated with cyclophosphamide including risk of febrile neutropenia. Since plerixafor was introduced in Canada, this mobilization agent has been increasingly used as needed with GCSF at Kingston Health Science Centre (KHSC), with elimination of cyclophosphamide. There is however high cost associated with plerixafor. To date, there is no standard mobilization regimen across Canada. This retrospective study evaluates mobilization and ASCT outcomes of multiple myeloma patients who had undergone stem cell mobilization with GCSF+/-plerixafor (GP) vs cyclophosphamide/GCSF+/-plerixafor (CyGP) at KHSC. The goal is to analyze the efficacy of each regimen balanced with adverse events to guide optimal mobilization regimen choice. Method: Patient with multiple myeloma who had ASCT at KHSC were selected consecutively based on date of ASCT in a reverse chronological order starting from Jan 2019. From Oct 2015 to March 2018, CyGP was the mobilization regimen used at KHSC. From March 2017 to January 2019, cyclophosphamide was eliminated and GP was used. Both groups could have received plerixafor as needed based on Cancer Care Ontario funding criteria such as failure to achieve target CD34+ cell count. Retrospective chart review was conducted to collect data on demographics, plerixafor use, days of apheresis, total cell collected, rate of febrile neutropenia, length of transplant hospital stay, time to engraftment, and transfusion requirement. Chi-Square, t-test, or Mann Whitney methods were used for test of statistical significance where appropriate. Results: Total 97 patients were included with 47 in the GP group and 50 in the CyGP group (Table 1). Average age was 64 and 63 respectively. 32% of patients in GP group and 36% of CyGP group required plerixafor rescue. No difference in the number of apheresis days were noted in the two groups. Total cell collection was significantly higher in the CyGP group (P&lt;0.001). Day 1 and 2 cell collections were also significantly higher in the CyGP group (P&lt;0.05) (Fig 1). The cell dose target varied in the CyGP group due to changing practices over time which is a confounding factor. There were no cases of febrile neutropenia in the GP group and 3 cases in the CyGP group (P=0.243). All 3 febrile neutropenia patients required hospitalization with 1 requiring ICU. There was no clinically significant difference in transfusion requirement during ASCT (Fig 2). Median time to engraftment of neutrophil and platelet after ASCT were less by 1 day in the CyGP group (P&lt;0.05) (Fig 3), although there was no difference in length of transplant hospital stay. Conclusions: Stem cell mobilization with CyGP resulted in significantly higher total collection cell count, and more efficient collection with higher yield on the first 2 days of apheresis. However, there was no difference in the total number of apheresis days. It also did not lead to less plerixafor usage and was associated with possibly higher rate of febrile neutropenia. There was no clinically significant difference in transplant outcomes in terms of transfusion support required, days to engraftment, or length of hospitalization for ASCT. Mobilization with GCSF+/-plerixafor without cyclophosphamide is a non-inferior regimen. Disclosures Bhella: Celgene: Consultancy, Honoraria.

Safety and Toxicity Profile of Pembrolizumab (PEM) in Combination with ICE Chemotherapy Followed By Autologous Stem Cell Transplantation for Relapsed/Refractory Classical Hodgkin Lymphoma: No Impairment in Stem Cell Mobilization or Engraftment

Background: Despite excellent outcomes in the front-line management of classical Hodgkin lymphoma (cHL), patients with relapsed or refractory disease typically undergo second-line cytotoxic chemotherapy before proceeding to consolidation with autologous hematopoietic stem cell transplant (autoHSCT). Pre-transplant F18-FDG-PET imaging is a well-established predictor of outcomes following autoHSCT; a complete metabolic response (CMR) to second-line therapy defined as a Deauville score 1-3 predicts a favorable outcome and is a requirement for transplant at many centers. The PD-1 pathway plays an important role in the pathogenesis of cHL and checkpoint inhibition with agents including PEM and nivolumab have shown efficacy as monotherapy in heavily pretreated disease. We hypothesized that the addition of PEM to ICE (ifosfamide, carboplatin, and etoposide) chemotherapy will increase the rate of CMR by PET-CT prior to autoHSCT without impairing the mobilization of peripheral blood progenitor cells (PBPC) or engraftment. Here we present interim safety and toxicity data from this ongoing trial (NCT03077828) including the yields of PBPC mobilization and engraftment. Methods: Enrollment criteria include patients age &gt;18 years medically fit for autoHSCT with relapsed/refractory cHL and excludes those with prior PD-1 inhibitor exposure, CNS involvement, more than 2 prior regimens or history of autoimmune disease. Patients are treated with 2 cycles of PEM 200 mg IV on day 1 in combination with ICE chemotherapy (ifosfamide 5000 mg/m2 day 2 CIV over 24hr, carboplatin AUC 5 IV day 2, etoposide 100 mg/m2 IV days 1-3) on a Q21 day cycle. PBPC mobilization and harvest are performed per institutional protocol on recovery post-cycle #2. A cycle of PEM 200 mg IV is then administered as monotherapy followed by response assessment with PET-CT. Patients with Deauville scores ≤3 proceed to autoHSCT per institutional protocol. A third cycle of PEM+ICE is optional following the PET-CT assessment. Neither the conditioning regimen nor management during transplantation is dictated by the protocol. Results: As of July 2019, 23 of 40 planned patients have evaluable safety and toxicity data. One patient had inconclusive pathology and was removed from study after one cycle of PEM-ICE but is included for this report. The median age was 32 (range 19-62) and 17 of 23 patients were females (74%). 8 patients were refractory to first-line therapy, and 9 relapsed within one year of treatment. 19 patients had received ABVD. Following protocol directed therapy, all but one patient had successful mobilization and collection; one had a severe allergic reaction to filgrastim and underwent bone marrow harvest instead. 16 patients collected in a single day of apheresis; the remainder collected within 4 days. The median number of stem cells harvested was 12.6 x 106 CD34+ cells/kg (range 4.2 - 46.1 x 106/kg). 3 patients underwent the 3rd cycle of PEM + ICE chemotherapy. 3 patients had Deauville scores &gt;3 on FDG-PET response assessment; two had biopsies showing only benign processes and proceeded to transplant. Following stem cell reinfusion, all patients successfully engrafted, with a median time to absolute neutrophil and platelet recovery of 11 days (range: 9 - 24) and 12 days (range: 9 - 23), respectively. The combination of PEM + ICE chemotherapy was well tolerated. There were no reports of pneumonitis, colitis, hepatitis, or endocrinopathies. The most common toxicities were cytopenias, mucositis, diarrhea and febrile neutropenia. A single death on protocol was deemed secondary to advanced cardiovascular disease discovered mid-treatment during the patient's pre-transplant assessment. There was no clinical evidence to suggest an inflammatory process resulting in the cardiac arrest. Conclusions: The combination of PEM with ICE chemotherapy in relapsed / refractory cHL appears tolerable and safe. We found no significant hindrance to peripheral blood stem cell harvest and PEM- related AEs were uncommon. Additionally, pre-treatment with a checkpoint inhibitor prior to autoHSCT appears safe thus far and does not appear to delay engraftment. Disclosures Casulo: Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Karmali:Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Pro:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Mehta:Millennium/Takeda, Celgene; stock in Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. Gordon:Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Gilead: Other: Advisory Board; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Winter:Merck: Consultancy, Research Funding.

A Randomized Evaluation of Vinorelbine Versus Gemcitabine Chemotherapy Mobilization of Stem Cells in Myeloma Patients

Background: In myeloma patients, a non-myelosuppressive regimen combining a single dose of vinorelbine chemotherapy together with G-CSF is safe and effective to harvest peripheral blood progenitor and stem cells (PBSC) before autologous stem cell transplantation (ASCT). Considering its neurotoxic potential, vinorelbine may aggravate pre-existing bortezomib-induced polyneuropathy, and gemcitabine represents an alternative mobilization regimen. We have reported that monotherapy with gemcitabine together with G-CSF can be used as a promising alternative mobilization chemotherapy to vinorelbine, even more so as gemcitabine avoids neurotoxicity associated with vinorelbine Methods: In this prospective phase-II study (ViGeM Trial; NCT# 02791373), we compared in a 1:1 randomization the efficacy and toxicity of vinorelbine or gemcitabine with G-CSF (and, if needed, plerixafor) in 130 evaluable myeloma patients in first remission. The objective of the study is to demonstrate the non-inferiority of gemcitabine versus vinorelbine. The primary endpoint is mobilization success, which is defined as a collected apheresis product comprising at least 6.0×106 CD34+ cells/kg b.w. at day 8 after chemotherapy (vinorelbine or gemcitabine) together with G-CSF in the absence of plerixafor. Results: We observed successful CD34+ mobilization in 75% [95% confidence interval (CI): 63%-85%] of patients in the vinorelbine group versus 49% [95% CI: 36%-62%] with gemcitabine; the pre-specified non-inferiority margin -15% was not reached. More vinorelbine recipients achieved the collection goal in a single-day procedure (78% vs 60%). The median CD34+ yield was 11.4×106/kg b.w. in vinorelbine versus 8.7×106/kg in gemcitabine (P=0.001). At apheresis as well as day +100 following ASCT, polyneuropathy occurred more frequent in vinorelbine recipients. Special attention should be given to the fact that no patients with gemcitabine was observed with grade ≥ 3 polyneuropathy (Table 1). Finally, less patients in the vinorelbine group (1%) needed two apheresis days as compared to 14% in the gemcitabine group, respectively (P=0.007), whereas the use of rescue plerixafor was similar (11% versus 10%). Conclusion: This prospective comparison indicated that non-inferiority of gemcitabine as compared to vinorelbine chemotherapy together with G-CSF stimulation regarding CD34+ mobilization was not reached. Polyneuropathy was aggravated in the vinorelbine cohort, but not in gemcitabine recipients. Our study allows individualization of CD34+ mobilization regimens in myeloma patients. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Vinorelbine and gemcitabine are used for stem cell mobilization in this study and, thus, off-label.

Single-dose etoposide is an effective and safe protocol for stem cell mobilization in patients with multiple myeloma.

Single-dose etoposide was used an outpatient-based protocol for mobilization in patients with multiple myeloma (MM) for autologous stem cell transplantation (ASCT). Thus, we retrospectively analyzed the efficacy and safety of our one-day protocol in comparison with that of previous methods. We retrospectively analyzed 168 patients with MM who underwent peripheral blood stem cell collection for upfront ASCT between 2008 and 2018. The mobilization protocols included G-CSF alone (G-mobilization), one-day 375 mg/m2 of etoposide (E375), two-days of 375 mg/m2 of etoposide (E750), or one-day high-dose (3.5 g/m2 ) cyclophosphamide (HD CY). For comparison of efficacy of each protocol, collected CD34+ cells over 4 × 106 /kg and under 2 × 106 /kg were defined as "adequate harvest" and "harvest failure," respectively. The median number of collected CD34+ cells was 5.58 × 106 /kg in patients receiving single-dose etoposide, and the percentage of uncomplicated optimal harvest of E375 (65.6%, 21/32) was significantly higher than that of E750 (41.9%, 13/31) and HD CY (31.3%, 15/48). The E375 showed the highest rate of adequate harvest (96.9%, 31/32) compared to that of E750 (87.1%), HD CY (75.0%), and G-mobilization (59.6%). Most E375 patients achieved adequate harvest without complication (29/32, 90.6%), the CD34+ cell collection yield on apheresis days one and two of E375 was not significantly different from that of E750, and no harvest failures occurred for E375. Neutrophil and platelet engraftments were significantly faster in E375 than other groups (P < .001). The use of single-dose etoposide could be an effective and safe method for mobilization in patients with MM.