Mobilization Failure Rate Research Articles

A retrospective study on the efficacy of pegfilgrastim-filgrastim combination regimen in the mobilization for autologous stem cell transplantation in lymphoma patients

BackgroundThe high mobilization failure rate with the mobilization strategy of combining chemotherapy and filgrastim (rhG-CSF) in autologous hematopoietic stem cell transplantation (auto-HSCT) in lymphomas is one of the unresolved issues. Whether the combination of polyethylene glycol filgrastim [pegfilgrastim (PEG-FIL), PEG-rhG-CSF] and filgrastim (FIL) improves the mobilization success rate and the timing of combination therapy has not been studied. Methods107 lymphoma patients who received auto-HSCT were retrospectively enrolled and divided into groups of PEG+FIL and FIL. The group of PEG+FIL received pegfilgrastim (9 mg) on the third day of the chemotherapy, followed by filgrastim (10 μg/kg/day) based on the counts of peripheral blood stem cells (PBSC). The group of FIL received filgrastim 10 μg /kg/day depending on the number of PBSCs. ResultsThe incidence of neutropenic fever in the group of PEG+FIL was significantly lower than in the group of FIL. The mean recovery time of leukocytes at autologous stem cell transplantation was significantly shorter in the group of PEG+FIL than in the group of FIL. Compared to the groups of FIL, the group of PEG+FIL had lower hospitalization costs. We found that the combination therapy is more recommended for patients with a bone marrow hematopoietic area of less than 30 %. Filgrastim is best administered 5–6 days after pegfilgrastim administration. ConclusionsCompared to conventional filgrastim mobilization, the combination of pegfilgrastim and filgrastim schedule has high efficacy, non-inferior safety, and superior health economic benefits during auto-HSCT.

The Combination of Pegfilgrastim and Filgrastim Improves the Outcomes of Mobilization and Engraftment after Transplantation of Autologous Hematopoietic Stem Cells for the Treatment of Lymphoma

BACKGROUND : Hematopoietic stem cell transplantation (HSCT) is broadly utilized for the treatment of lymphoma. Autologous peripheral blood stem cell (PBSC) transplantation (ASCT) requires mobilization of hematopoietic stem cell/ hematopoietic progenitor cell (HSC/HPC) in peripheral blood (PB) to collect HSCs. The high mobilization failure rate with the mobilization strategy of combining chemotherapy and filgrastim (rhG-CSF, recombinant human granulocyte colony-stimulating factor) in ASCT is one of the unresolved issues. Whether the combination of polyethylene glycol filgrastim [pegfilgrastim (PEG-FIL), PEG-rhG-CSF] and filgrastim (FIL) improves the mobilization success rate and the timing of combination therapy has not been studied. METHODS: To test the hypothesis that the combination of pegfilgrastim and filgrastim schedule has superiority, we retrospectively investigated a cohort of 107 lymphoma patients who received auto-HSCT and collection in the First Hospital of Jilin University from Jan 1st 2015 to Dec 1st 2022. These patients were categorized into PEG+FIL group and FIL group. The group of PEG+FIL received pegfilgrastim (9 mg) on the third day of the chemotherapy, followed by filgrastim (10 μg/kg/day) based on the counts of peripheral blood stem cells (PBSC). The group of FIL received filgrastim 10 μg /kg/day depending on the number PBSCs. Demographic information, laboratory results, and treatment plans were collected for these two groups of patients. RESULTS：We compared their mobilization efficacy (mononuclear cell [MNC] and CD34 + cell counts) and transplantation efficacy (days to leukocyte and platelet recovery post-transplantation). Successful ASCT mobilization was achieved in 93 patients (86.9%), with the PEG+FIL group exhibiting a higher success rate compared to the FIL group (89.2% [58/65] vs. 83.3% [35/42], p = 0.032). The PEG+FIL group also demonstrated significantly higher CD34+ cell counts [MNC: 8.9 (6.9, 11.2) vs. 7.8 (6.2, 9.8) × 10 8 cells/kg, p = 0.024; CD34 + cell count: 7.5 (5.6, 13.0) vs. 4.9 (3.2, 9.2) × 10 6 cells/kg, p = 0.008] and a lower incidence of neutropenic fever compared to the FIL group (11.8% vs. 24.3%, p = 0.038). The PEG+FIL group also demonstrated a shorter mean leukocyte recovery time in autologous stem cell transplantation than the FIL group (10.02 ± 0.73 vs. 10.9 ± 1.1 days, p < 0.001). To delve deeper into the safety considerations of both groups, we evaluated the advantages of each regimen and the methodologies for selecting time windows. A bone marrow aspiration and biopsy were performed on all patients before stem cell collection. Among 18 patients who had a hematopoietic area less than 30% and a fat area greater than 40%, 10 were in the PEG+FIL group and 8 in the FIL group. For patients who required only one collection, the durability was 80% in the PEG+FIL group compared to 0% in the FIL group (p < 0.01), indicating a superior recommendation for patients with a bone marrow hematopoietic area of less than 30%. In the PEG+FIL group, monitoring was carried out for PB CD34 + percentage and WBC count following pegfilgrastim administration, with subsequent computation of CD34 + cells in PB. Filgrastim administration was found to be optimal 5-6 days post-pegfilgrastim administration. CONCLUSIONS: In conclusion, relative to conventional filgrastim mobilization, the conjunctive use of pegfilgrastim and filgrastim demonstrates superior efficacy, non-inferior safety during ASCT. The schedule enhanced the the outcomes of mobilization in the patients of less hematopoietic area. KEY WORDS: Pegylated recombinant human granulocyte-stimulating factor (pegfilgrastim, PEG-rhG-CSF), recombinant human granulocyte-colony stimulating factor (filgrastim, rhG-CSF), lymphoma, hematopoietic stem cell transplantation (HSCT) autologous hematopoietic stem cell mobilization.

Primary Endpoint Analysis from a Response Adaptive Phase II Clinical Trial of Carfilzomib, Lenalidomide, Dexamethasone Plus Daratumumab (KRd-Dara) in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Background Minimal residual disease (MRD) status has prognostic significance for progression-free survival (PFS) and overall survival (OS) in NDMM, but its value in guiding therapy remains unclear. We conducted a 2-stage, phase II trial evaluating the quadruplet regimen of KRd-Dara as induction therapy followed by MRD adapted KRd consolidation +/- autologous stem cell transplantation (ASCT) and maintenance versus observation. We previously reported the results of our stage I analysis at ASH 2022 (n=23; Blood 2022;140:4440-4441). Here we provide an updated analysis of the primary endpoint after completed enrollment of stage 2. Methods Eligible patients had NDMM with measurable disease. The induction phase allowed 8 cycles of KRd-Dara. Post-induction treatment assignment was informed by ASCT eligibility and MRD status by next generation sequencing (NGS at 10 -5), and included Group A (MRD negative, transplant-eligible and -ineligible, optional lenalidomide maintenance), Group B (MRD positive, transplant eligible, ASCT) and Group C (MRD positive, transplant ineligible, KRd consolidation for up to 12 cycles). Patients in Group B could receive up to 12 cycles of KRd consolidation therapy after ASCT if MRD positive. All groups could receive optional lenalidomide maintenance therapy after achievement of MRD negativity after induction ± consolidation. The primary endpoint was ≥complete response (CR) rate at the end of induction. The secondary endpoints were safety, MRD status, stem cell mobilization failure, and survival outcomes. Efficacy endpoints including MRD were evaluated with the intent to treat principle. Results Thirty-nine patients were enrolled: 23 in stage 1 and 16 in stage 2. Median age was 62 (range 34-78), 31% were female and 31% were African American. R-ISS stage 3 was present in 4 (10%), high-risk cytogenetics (including 1q21 gain) in 15 (39%). At the end of induction, ≥CR was achieved in 22/39 (56%, 90% CI: 42%-70%) patients including stringent CR (sCR) in 17 (44%), VGPR in 14 (36%) and PR in 1(3%). Of note, 2 patients did not complete induction therapy; one died during cycle 2, while another was withdrawn from study after an SAE during cycle 1. Evaluating by NGS, 62% achieved MRD negativity at 10 -5 and 41% MRD negativity at 10 -6 post-induction. MRD negativity by next generation flow cytometry (NGF) was 74% at 10 -5 and 31% at 10 -6. Concordance of MRD by NGS/ NGF at 10 -5 was 26/34 (76% in agreement and 24% disagreement, Cohen's kappa: 0.436), and by NGS/ NGF at 10 -6 was 17/25 (68% in agreement and 32% disagreement, Cohen's kappa: 0.351). 39 patients (100%) experienced treatment emergent AE, with grade ≥ 3 AE in 31 (80%). The most common (≥ 25%) any grade treatment related AE (TRAE) were diarrhea (39%), fatigue (36%), neutropenia (28%), and constipation (26%). Grade 3-4 TRAE (≥10% of patients) included neutropenia (21%) and hypophosphatemia (13%). Covid infection occurred in 10 (26%); only one patient needed hospitalization. Other infections (any grade) were seen in 20 (51%) patients. Fourteen (36%) patients experienced at least one SAE, of which 8 patients had a treatment-related SAE, including one death. Thromboembolic events were observed in 3 (8%) patients. Of 23 patients who collected stem cells upon completion of induction (7-8 cycles of KRD-Dara), 7 (30%) failed to collect an optimal target (3 million CD34+ cells/kg) on first attempt. Comparatively, 0 of 11 patients who collected after 3-5 cycles experienced stem cell collection failure (Fisher's exact: p=0.07). Post-induction, 24 patients were assigned to Group A, 8 to Group B, and 5 to Group C. After a median follow up of 26 months (95% CI: 17 - 27; data cut off 7/6/2023), 28 remain on treatment, 9 are in follow up, and 2 are off study. The 2-year PFS is 85.3% (95% CI: 71.6% - 99.1%); median PFS is not reached. Updated data on the best MRD/ CR/ sCR responses achieved post-induction will be presented at the meeting. Conclusions Our data confirm high rates of sCR and MRD negativity of the quadruplet regimen of KRd-Dara in NDMM. The safety data was in alignment with known safety profile of investigational products. With modification of the protocol to allow earlier stem cell collection, we were able to reduce the rate of stem cell mobilization failure from 30% to 0%. Based on our results, we recommend further testing of this MRD-based platform in randomized studies with stem cell collection after 3-4 cycles of KRd-Dara. Clinical trial: NCT04113018

Comparison of Efficacy and Safety of Generic Plerixafor Vs Original Plerixafor in the Mobilization of Myeloma Patients

Introduction The commonest indication for an Autologous Stem Cell Transplantation (ASCT) is still Multiple Myeloma. A successful mobilization of hematopoietic stem cells (HSC) is a sine qua non of ASCT. The introduction of Plerixafor, which is a partial agonist of the alfa-chemokine receptor CXCR4 has added an important value and impact on mobilization. Plerixafor is successfully integrated into both growth factor-only and cyclophosphamide and growth factor mobilization strategies with significantly reducing the mobilization failure rate in myeloma patients. In addition, plerixafor + G-CSF has also been shown to successfully mobilize the majority of patients who previously failed to mobilize with either growth factor alone or in combination with chemotherapy. Even a Just-in-Time algorithm which induces plerixafor in patients who lacks a certain threshold of CD34 positive HSCs on the day of mobilization led to a cost-effective and successful mobilization with highly restricted rates of mobilization failure. In this study we tried to demonstrate the efficacy and safety of a novel generic Plerixafor (Pleksor - Gen Ilac) and to compare it with original one (Mozobil - Sanofi) in a retrospective manner. Method Patients who were transplanted in two centers who adopted the same mobilization standard operating procedures (SOP) were included in the study. An age and sex matched cohort of patients who received Mozobil (from 2020-2022 - Group A) were compared with the ones who received Pleksor (2021-2022 Group B) as a Just-in-Time conjunct to GCSF alone or chemo mobilization. Poor mobilization was defined as a final yield of 2 million CD34 positive HSCs per kg. Our aim was to collect enough stem cells for at least two ASCTs, thus our current SOP's indicated a minimum CD34 positive HSC threshold of at least 4 million per kg and an ideal HSC threshold of 6 million per kg. Results A total of 28 patients were included and they were equally distributed among Group A (n=14) and B (n=14). Median age of the patients at the time of mobilization were as follows, 60 (35-72) in Group A and 61 (38-70) in Group B. 14 patients who received Pleksor achieved a median yield of 8.40 million CD34 positive HSCs per kg (4.8-21) and the patients who received Mozobil have ended with a yield of 6.7 million CD34 positive HSCs per kg (4.5-13) (p=0.210). None of the patients in both groups were named to be a poor mobilizer according to the threshold of 2 million CD34 positive HSCs per kg but 3 of the patients in Group A and 2 of the patients in Group B ended with a yield of 6 million CD34 positive cells which was below to the ideal threshold for two transplants. Regarding lenalidomide exposure before mobilization, history of radiotherapy, line of the therapies received before mobilization, number of leukapheresis and the mobilization policy (chemo vs gcsf alone) there were no statistically significant difference between two groups (p=0.120, 0.702, 0.842, 0.769 and 0.420 respectively). The median neutrophil engraftment time in days were as follows for Group A and B, 11(10-14) vs 11 (10-16), p=0.541 and the median platelet engraftment time in days were 17 (10-30) in Group A and 16 (10-28) in Group B with a p value of 0.571. In none of the cases any specific side effects were noted which could be attributable to Pleksor or Mozobil. Conclusion Our study demonstrated a comparable efficacy of a generic form of Plerixafor when compared with the originator. This would lead to a decrease in the cost of total process of mobilization with a similar efficacy and toxicity profile. We are now planning to initiate a prospective trial to validate these results in a larger patient population. Up to our knowledge this is the first study comparing the efficacy of a generic Plerixafor in a sole myeloma patient cohort.

Stem Cell Mobilization Characteristics for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) Treated with Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab (KRd-Dara)

Introduction: CD38 monoclonal antibody (mAb)-containing quadruplet regimens have been shown to improve depth and duration of response in patients with NDMM eligible for autologous stem cell transplant (ASCT). However, some studies have raised concerns about the detrimental effect of combined lenalidomide and CD38 mAbs on stem cell mobilization. As an exploratory endpoint, we evaluated the effect of KRd-Dara on stem cell mobilization and collection in the Levine Cancer Institute (LCI) KRd-Dara study (NCT04113018) that permits up to 8 cycles of induction with KRd-Dara followed by an MRD-directed treatment algorithm for transplant-eligible and transplant-noneligible patients (Bhutani et al, Blood 2020 Abstr 1388). We provide a table summarizing our results from stage 1, along with two other phase II studies, the MANHATTAN (Landgren et al, JAMA Oncol 2021) and the MASTER (Costa et al, JCO 2021) studies that used variable numbers of KRd-Dara induction cycles prior to stem cell apheresis. Patients and study design: Eligible patients had NDMM and an ECOG performance status score of 0-2. Induction treatment consisted of 28-day cycles of KRd-Dara with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); lenalidomide orally, 25 mg (days 1-21); dexamethasone weekly; daratumumab (subcutaneous) per standard approved dosing schedule. One pre-study cycle with non-protocol therapy was allowed. During stage I of the study, stem cell collection for transplant-eligible patients was performed after 8 cycles of induction. All patients were mobilized with granulocyte-colony stimulating factor (G-CSF, 10 µg/kg) daily for 5 days. Preemptive Plerixafor was administered in the evening of Day 4 if the blood CD34+ cell count was <50/µl. Collection was done over 2 days in some patients who failed to collect sufficient CD34+ cells during the first day. A second mobilization attempt after a few weeks of additional wash-out was allowed. Our center-specific minimum required collection target is 3 x 106 CD34+ cells/kg, below which the stem cell dose is considered inadequate to perform a single ASCT. Physicians requested collection for potentially 2 or 3 transplants per patient, with a collection goal of 8 -12 x 106 CD34+ cells/kg. Mobilization failure was defined as the proportion of patients with Day 4 CD34 count <1/µl or collection of <3 x 106 CD34+ cells/kg (considered inadequate for even one ASCT) during the first mobilization attempt. Results: Among the 22 mobilized patients during stage 1 analysis, the median age was 60 years (range, 34 to 72) and 32% were African Americans. Eighteen patients received plerixafor, 3 did not based on futility as their Day 4 blood CD34 count was zero, and only one patient met the threshold of not receiving Plerixafor. The median total CD34+ cells collected were 7.73 x 106/kg (range, 0.00-19.18). Six (27%) patients had mobilization failure after their first attempt. Four of these patients underwent a second attempt after a median of 56 days (range, 36-98 days), with only one patient collecting enough CD34+ cells for one ASCT. Of the 10 patients whose collection goal was 2 transplants (8 million CD34 cells/kg), 9 patients did not meet the goal. Of the 12 patients whose collection goal was 3 transplants (12 million CD34 cells/kg), 8 patients did not meet the goal. Conclusions: The stem cell mobilization failure rate was high in patients collecting after 7 or 8 cycles KRd-Dara. Second remobilization with G-CSF and plerixafor was successful in only 1 of the 4 patients. We have modified stage 2 of the protocol to allow stem cell collection after cycle 3 of KRd-Dara induction. We plan to do combined analyses of LCI, MANHATTAN and MASTER to determine predictive factors associated with poor stem cell mobilization after KRd-Dara induction. Based on our results, we recommend stem cell collection after 3-4 cycles of KRd-Dara regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A comparison of four leukapheresis methods to harvest an optimal dose of CD34+ cells: A single center experience

Chemokine receptor CXCR4 antagonist plerixafor (Px) as well as high volume (HV) leukapheresis have been shown to reduce hematopoietic stem progenitor cell (HSPC) mobilization failure rates. However, no direct comparisons of such methods currently exists. We compared the HSPC collection yield based on basal peripheral blood CD34+ cell numbers in patients diagnosed with multiple myeloma or non-Hodgkin's lymphoma undergoing autologous stem cell transplantation in a retrospective chart review. The leukapheresis methods used included HV versus regular volume (RV) with or without Px. There were 116 patients in the study group while the historical control group had 34 patients. Control group underwent RV leukapheresis without Px. Addition of Px or HV in the study group failed to display significant improvement in CD34+ cell collection yield; however, when basal CD34+ cell numbers were taken into account, both Px + RV and HV without Px increased CD34+ cell collection yield. The collection failure rates of HV without Px group were comparable to Px + RV when the basal CD34+ cell numbers were over 20/μl. Of interest, multivariate linear regression analysis did not detect any significant difference between HV versus Px + RV or other leukapheresis methods in CD34 yields or collection failure rates from a single collection after controlling for other factors (sex, age, or underlying disease). In multivariate analysis, pre apheresis CD34+ cell number was significantly and positively associated with the CD34+ cell yields from a single apheresis. In our studies, the majority of patients can be rescued without Px by HV alone as a potential cost saving approach. In summary, trend in our studies reflects that both Px and HV are capable of reducing the mobilization failure rates except the poorest mobilizers, which will need to be validated in larger studies.

Analysis of Factors Influencing Autologous Peripheral Blood Stem Cells Mobilization in Patients with Lymphoma and Multiple Myeloma

To analyze the factors influencing the mobilization of autologous peripheral blood stem cells (auto-PBSCs) in patients with lymphoma and multiple myeloma, and provide reference for optimizing the autologous stem cell mobilization regimen. Clinical data of 33 multiple myeloma and lymphoma patients received auto-PBSCs mobilization in our center from January 2015 to December 2018 were collected, the correlation of mobilization failure rate with gender, age, courses of chemotherapy before mobilization, does of recombinant human granulocyte colony stimulating factor (rhG-CSF), type of disease, and chemotherapy regimen were retrospectively analyzed. Type of disease and course of pre-mobilization chemotherapy could affect the mobilization failure rate (P<0.05). The mobilization failure rate of lymphoma patients was 42.1%, which was significantly higher than 7.1% of multiple myeloma patients (P=0.026). The mobilization failure rate was higher in the group with chemotherapy courses≥5 before mobilization (P=0.016). Age, gender, dose of rhG-CSF, and chemotherapy regimen had no significant correlation with mobilization failure rate (P>0.05). Multi-course chemotherapy before collection and lymphoma patients are poor factors negatively impacting on auto-PBSCs mobilization.

Comparison of Peripheral Blood Stem Cell Mobilization with Etoposide or Cyclophosphamide in Patients with Multiple Myeloma

▪For successful autologous stem cell transplantation, collection of the sufficient number of hematopoietic stem cells is essential after induction therapy for transplant candidates in multiple myeloma (MM). In this study, we compared the efficacy and safety of stem cell mobilization with etoposide (VP-16; 375 mg/m2 on days 1 and 2) or cyclophosphamide (CY; 3.0 g/m2 on day 1) in patients with MM. Granulocyte-colony stimulating factor (G-CSF, 10 mg/kg/day, subcutaneously) was administered from the development of neutropenia to the final collecting day. Mobilization failure was defined as total collected CD34+ cell count < 4.0 x 106 cells/kg in three apheresis procedures. Seventy-six patients were mobilized with CY and G-CSF, and 46 patients were mobilized with VP-16 and G-CSF between February 2008 and July 2017. Median total collected number of CD34+ cells was significantly higher in patients who were mobilized with VP-16 compared with those who were mobilized with CY (27.6 x 106 cells/kg vs. 9.5 x 106 cells/kg, P < 0.001). In addition, the rate of mobilization failure was significantly lower in VP-16 group compared with CY group (2.2% vs. 23.7%, HR 0.072, 95% CI 0.009-0.557, P = 0.001). One patients who were mobilized with VP-16 showed mobilization failure and did not achieve the sufficient collection of stem cells in subsequent mobilization process with plerixafor. Severe infections during mobilization period were frequently developed in CY group (15.8% in CY group vs. 8.6% in VP-16 group, P = 0.407). The median time to platelet engraftment (> 20 × 109/L) and neutrophil recovery (> 0.5 × 109/L) did not different between two group after autologous transplantation. In conclusion, VP-16 and G-CSF was a very effective and safe method for peripheral blood stem cell mobilization and is considered as a more suitable chemo-mobilization regimen compared to CY and G-CSF in patients with MM. DisclosuresNo relevant conflicts of interest to declare.

Use of Plerixafor for Stem Cell Mobilization in the Setting of Autologous and Allogeneic Stem Cell Transplantations: An Update.

Mobilization failure is an important issue in stem cell transplantations. Stem cells are yielded from the peripheral blood via apheresis. Granulocyte colony-stimulating factor (G-CSF) is the most commonly used mobilization agent among patients and donors. G-CSF is administered subcutaneously for multiple days. However, patients with mobilization failure cannot receive autologous stem cell transplantation and, therefore, cannot be treated adequately. The incidence rate of mobilization failure among patients is about 6–23%. Plerixafor is a molecule that inhibits the binding of chemokine receptor-4 with stromal-cell-derived factor-1, thereby resulting in the release of CD34+ cells in the peripheral blood. Currently, plerixafor is used in patients with mobilization failure with G-CSF and is administered subcutaneously. Several studies conducted on different clinical settings have shown that plerixafor is effective and well tolerated by patients. However, more studies should be conducted to explore the optimal approach for plerixafor in patients with mobilization failure. The incidence of mobilization failure among donors is lower. However, plerixafor is not approved among donors with mobilization failure. Moreover, several clinical studies in donors have shown a beneficial effect of plerixafor. In addition, the adverse events of plerixafor are mild and transient, which can overcome the adverse events due to G-CSF. This review assessed the current role and effects of plerixafor in stem cell mobilization for autologous and allogeneic stem cell transplantations.

Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor versus Granulocyte Colony-Stimulating Factor +/- Plerixafor in the Lenalidomide Era

Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used to treat patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017 and 2020 using either cyclophosphamide (4 g/m2) plus granulocyte colony-stimulating factor (G-CSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. Although total CD34+yield was higher after chemomobilization compared with G-CSF +/- PXF (median, 13.6×106/kg versus 4.4×106/kg; P < .01), achievement of≥2×106CD34+ cells (95% versus 93.7%; P=.61) and rates of mobilization failure (5% versus 6.3%; P=.61) were similar. Fewer patients required PXF with chemomobilization (12.3% versus 49.5%;P < .01), and apheresis sessions were fewer (median, 1 [range, 1 to 4] versus 2 [range, 1 to 5]). The rate of complications, including neutropenic fever, emergency department visits, and hospitalizations, was higher after chemomobilization (30% versus 7.4%;P < .01). Previous use of ≤6 cycles of lenalidomide did not impair cell yield in either group.The median cost of mobilization was 17.4% lower in the G-CSF +/- PXF group (P=.01).Between group differences in time to engraftment were not clinically significant. Given similar rates of successful mobilization, similar engraftment time, and less toxicity and lower costs compared with chemomobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.

Low-Dose Cyclophosphamide versus Intermediate-High-Dose Cyclophosphamide versus Granulocyte Colony-Stimulating Factor Alone for Stem Cell Mobilization in Multiple Myeloma in the Era of Novel Agents: A Multicenter Retrospective Study

The optimal stem cell (SC) mobilization strategy for patients with multiple myeloma (MM) remains a matter of debate. Possible approaches include low or high doses of cyclophosphamide (Cy), other chemotherapeutic agents, or granulocyte colony-stimulating factor (G-CSF) alone. The scope of the study was to compare low-dose Cy plus G-CSF versus intermediate-high-dose Cy plus G-CSF versus G-CSF alone for SC mobilization in MM, in terms of efficacy and safety. We retrospectively analyzed 422 MM patients undergoing SC mobilization in 6 Italian centers, including 188 patients who received low-dose Cy (LD-Cy group, defined as 2 g/m2), 163 patients who received intermediate-high-dose Cy (HD-Cy group, defined as ≥ 3 g/m2), and 71 patients who received G-CSF alone (G-CSF group). The median peak of circulating CD34+ cells was 77/µL in the LD-Cy group, 92/µL in the HD-Cy group, and 55/µL in the G-CSF group (P=.0001). The median amount of SCs collected was 9.1×106/kg, 9.7×106/kg, and 5.6×106/kg in the 3 groups, respectively (P=.0001). The rate of mobilization failure (defined as failure to collect ≥2×106/kg) was 3.7% in the LD-Cy group, 3.4% in the HD-Cy group, and 4.3% in the G-CSF group (P=.9). The target SC dose of at least 4×106/kg was reached in 90.4%, 91.1%, and 78.6% of the patients in these 3 groups, respectively (P=.014). The "on demand" use of plerixafor was higher in the G-CSF group (76%) compared with the LD-Cy group (19%) and the HD-Cy group (6%). In multivariate analysis, G-CSF mobilization and previous use of melphalan or radiotherapy were independently associated with failure to collect the target SC dose of ≥4×106/kg. No impacts of age, blood counts, or previous treatment with lenalidomide, bortezomib, or carfilzomib were observed. Our results suggest that LD-Cy may be considered for successful SC mobilization in patients with MM.

Mobilization of Hematopoietic Stem Cells into Peripheral Blood for Autologous Transplantation Seems Less Efficacious in Poor Mobilizers with the Use of a Biosimilar of Filgrastim and Plerixafor: A Retrospective Comparative Analysis.

IntroductionBiosimilars of granulocyte colony-stimulating factors (G-CSF) have shown similar efficacy to originator filgrastim (Neupogen® [NEU]; Amgen Inc.) as prophylaxis in neutropenia and in the mobilization of stem cells in patients receiving combination chemotherapy with G-CSF.MethodsThis was a retrospective study in which the characteristics of stem cell mobilization treated with a G-CSF alone were compared in 216 patients and 56 donors. The two G-CSF compared were NEU and the biosimilar filgrastim Zarzio® (Sandoz GmbH) (referred to hereafter as BIO). Primary objectives were mobilization rate (minimum of 10 × 103/ml CD34+ on day 4 of treatment [day +4]) and use of the immunostimulant plerixafor (PLEX) in each group.ResultsThe general characteristics of the patients receiving NEU (n = 138) and those receiving BIO (n = 78) did not differ significantly. PLEX was used in 24% of BIO patients and in 25.7% of NEU patients. The median CD34+ cell count on day +4 was significantly lower in BIO patients who needed PLEX than in those who did not (2.4 vs. 4.8 × 103/ml; p = 0.002), as was the final CD34+ cell count (2.5 vs. 3.3 × 106/kg; p 0.03). Mobilization failure rate was higher in the BIO group than in the NEU group (20 vs. 0%; p = 0.01). With respect to donors, more than one apheresis was needed in three BIO donors, one of them with PLEX. The use of BIO was the only risk factor for mobilization failure in patients who needed PLEX (hazard ratio 10.3; 95% confidence interval 1.3–77.8).ConclusionThe study revealed that BIO had a lower efficacy for stem cell mobilization when the only treatment was G-CSF, especially in poor mobilizers needing PLEX.

VTD in comparison with VCD does not affect stem cell yields with G-CSF only mobilization

AbstractTriplet induction regimens are standard of care for newly diagnosed transplant eligible multiple myeloma patients. The combinations of bortezomib and dexamethasone with either cyclophosphamide (VCD) or thalidomide (VTD) are widely used. There are no data available on the impact of the two regimens on stem cell harvest by using G-CSF only mobilization. In this study, we retrospectively analyzed data from our national registry. The outcome measures were mobilization failure, CD34+ cell counts on collection day, number of apheresis procedures, and the number of collected cells. Overall, 72 patients were treated with either VCD or VTD. The mobilization failure rates were 7% and 9% (p = 0.771) and the total number of collected stem cells were 7.0 × 106 and 6.7 × 106 per kg body weight (p = 0.710) for VCD and VTD, respectively. We found no statistically significant difference between the treatment groups in the outcome measures. The addition of thalidomide to bortezomib and dexamethasone (VTD) does not adversely affect stem cell harvest in patients mobilized with G-CSF only.

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.

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.

Can high volume leukapheresis substitute plerixafor to yield an optimal dose of CD34+ vells from poor mobilizers?

Background & Aim Both chemokine receptor CXCR4 antagonist plerixafor (P) as well as high volume (HV) leukapheresis have been shown to reduce mobilization failure rates. However, no direct comparisons of such collection methods currently exist. In this single center retrospective study, we compared the collection efficiency in adult patients diagnosed with multiple myeloma (MM) or non-Hodgkins Lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT) comparing yields based on pre apheresis peripheral blood (PB) CD34+ cell number ( 50 cells/µL, Fig 1). Methods, Results & Conclusion The collection methods used included HV vs. regular volume (RV) with or without P. There was a total of 116 patients (78 MM & 38 NHL) in the study group with a total of 191 collections. RV without P was used for patients whose pre-apheresis CD34 count was >50/µL. RV (+P) or HV (+P) or HV without P groups were used to investigate whether HV can substitute RV (+P) for poor mobilizers (

Optimal chemo-mobilization for the collection of peripheral blood stem cells in patients with multiple myeloma

BackgroundFor successful autologous stem cell transplantation, the collection of a sufficient number of hematopoietic stem cells after induction therapy is essential for transplant candidates with multiple myeloma (MM).MethodsIn this study, we compared the efficacy and safety of stem cell mobilization using cyclophosphamide (CY; 3.0 g/m2 on day 1) or etoposide (VP-16; 375 mg/m2 on days 1 and 2) in patients with MM. Granulocyte-colony stimulating factor (G-CSF, 10 μg/kg/day, subcutaneously) was administered from the onset of neutropenia to the final day of collection.ResultsSixty-five patients were mobilized with a combination of CY and G-CSF, and 63 were mobilized with a combination of VP-16 and G-CSF. All patients were mobilized within 7 months of beginning frontline treatment. The median number of CD34+ cells collected was significantly higher in the VP-16 mobilization group than in the CY mobilization group (27.6 × 106 CD34+/kg vs. 9.6 × 106 CD34+/kg, P < 0.001). The rate of mobilization failure, defined as < 2.0 × 106 CD34+/kg collected in three apheresis procedures, was lower in the VP-16 group than in the CY group (1.6% vs. 10.8%, P = 0.062). Severe infections during the mobilization period were more frequent in the CY group than in the VP-16 group (18.5% vs. 7.9%, P = 0.117).ConclusionIn conclusion, an intermediate dose of VP-16 with G-CSF appears to be an effective and tolerable chemo-mobilization method compared to CY and G-CSF, particularly in cases where use plerixafor in MM is difficult.

Thalidomide Does Not Compromise Mobilization with Cytokine Alone in Multiple Myeloma after Triplet Induction Regimen

BackgroundMultiple myeloma (MM) is a hematologic disease characterized by accumulation of malignant plasma cells in the bone marrow. Triplet induction regimens incorporating bortezomib, thalidomid and dexamethasone (VTD) or bortezomib, cyclophosphamide and dexamethasone (VCD) are current standard of care because of improved response and prolonged progression free survival (PFS) and overall survival (OS). Autologous hematopoietic stem cell transplantation (aHSCT), performed in first remission or at relapse, is standard of care for younger fit patients. Successful mobilization and collection of peripheral blood stem cells (PBSC) is required before aHSCT. A target dose of 2 x 106 PBSC per kg body weight is considered a minimum for timely hematopoetic reconstitution, although a higher dose, 3 to 5 x 106 PBSC per kg body weight, is thought to be optimal for earlier engraftment. Mobilization with chemotherapy (intermediate doses of cyclophosphamide) and granulocyte-colony stimulating factor (G-CSF) is a standard in most transplant centers and provides higher stem cell yields in fewer apheresis procedures, at the cost of increased toxicity and less predictable onset date of apheresis in comparison to G-CSF alone mobilization. G-CSF alone mobilization fails to achieve the target doses of PBSC in up to 20 % of patients. There is limited information on possible impact of novel agents on ability to successfully mobilize and harvest PBSC. From available data, the impact of thalidomide on stem cell mobilization is small and probably not of clinical significance, but most of it comes from trials incorporating mobilization with chemotherapy and not G-CSF alone mobilization. Due to feasibility and safety reasons our institution uses G-CSF alone mobilization in MM patients. Mobilization with chemotherapy and/or prelixafor is reserved for poor mobilizers. The aim of our study was to retrospectively evaluate the success of GCSF alone mobilization in patients who received either VTD or VCD induction and possible differences between two groups.Patients and methodsWe retrospectively analyzed data from our national registry from the 1/1/2014 until 12/31/2017. Seventy-two patients with newly diagnosed MM that received induction treatment with VTD or VCD and underwent stem cell mobilization with G-CSF alone were included. VTD treatment consisted of 3 week cycles of bortezomib 1.3 mg/m2 subcutaneous on days 1, 4, 8 and 11, thalidomide 100 mg daily and dexamethasone 40 mg on days 1 - 4 of the first cycle and once per week thereafter. VCD treatment incorporated bortezomib and dexamethasone at the same schedule as for VTD plus cyclophosphamide 500 mg/m2 on day 1, 8 and 15 of each cycle. Following 3 - 4 cycles of induction treatment, stem cells were mobilized using daily subcutaneous injections of G-CSF 10 mg/kg body weight (doses were rounded up according to available 300 mcg and 480 mcg vials) for 5 consecutive days. The number of circulating PBSC was determined in peripheral blood on day 5 by flow cytometry and apheresis was initiated at a CD34+ cell count > 20/μL. A dose of 2 × 106 PBSC per kg body weight and 3 × 106 PBSC per kg body weight were considered the minimal and optimal dose for a single transplant.ResultsTwenty-eight and 44 patients received induction treatment with VCD or VTD respectively (Table 1). The mobilization failure rate between the groups was 7 % and 9 % for VCD and VTD. There was no statistical difference in the number of apheresis procedures, collected PBSC and the ability to collect a minimal and optimal dose for 2 aHSCT between the two groups (Table 2).ConclusionsDue to higher efficacy, VTD is preferred over VCD with no data available on the impact of these regimens on stem cell mobilization with G-CSF alone. The results of our retrospective study showed that thalidomide in the VTD regimen did not influence the number of collected PBSC or the number of apheresis procedures compared to VCD. The failure rate for both groups was low. There was no statistical difference in collecting the optimal dose for two aHSCT between the groups. In conclusion, induction with VTD can be safely used in centers using G-CSF alone mobilization without compromising the ability for stem cell harvest. DisclosuresNo relevant conflicts of interest to declare.

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

Background: Since the introduction of plerixafor, uniform application in mobilization protocols has not been realized. Widespread use of plerixafor is limited by its price. Some institutions have adopted a conservative approach, reserving plerixafor for second mobilization attempts or predicted difficult mobilizations. Our institutional procedure has shifted from using a relatively stringent peripheral blood CD34 threshold to a more generous threshold for plerixafor administration. We report our experience with a risk-adapted strategy for plerixafor use at different pCD34 thresholds. Methods: We retrospectively evaluated patients with multiple myeloma and amyloidosis undergoing autologous stem cell collection with G-CSF mobilization from 1/2012-12/2016. Our algorithm for triggering plerixafor administration has evolved from a pCD34 count of <15/µL to <20/µL to <40/µL. Patients received G-CSF 10 mcg/kg daily for 4 days. On day 4, patients received plerixafor if the pCD34 was below the threshold and was continued until collection was completed. Plerixafor use, days of collection, collection yield, mobilization failure rates, and mobilization costs were calculated. Target collection yield is >4 × 106 CD34+ cells/kg, and an optimal mobilization would allow for two transplants. Results: We identified 348 mobilization attempts. Median age was 59.9 years (range, 28-74) and 60% were male patients. Most patients were in CR (n = 94), VGPR (n = 107), or PR (n = 98). On average, patients received 1.9 prior lines of systemic therapy. Plerixafor use increased from 80% in the <15/µL group to 91% in the <40/µL group, while average number of doses increased from 1.32 to 1.74 per mobilization. The average apheresis days decreased from 2.15 days for the <15/µL group to 1.89 days for the <40/µL group. For patients in the <15/µL and <20/µL groups, 23% completed collection in 1 day, and 65-70% completed within 2 days. For patients in the <40/µL group, 39% completed collection in 1 day and 77% completed within 2 days. A collection yield > 4 × 106 CD34+ cells/kg was reached in 91% of cases in the <15/µL group and 94% in the <40/µL group. More patients (51% vs 41%) collected >8 × 106CD34+ cells/kg in the <40/µL group than <15/µL group and reached that goal within 2 days (49% vs 32%). Mobilization failure rates were <5% across all thresholds. Mobilization costs were comparable. Conclusion: We demonstrate that a liberal strategy for plerixafor administration correlates with fewer apheresis days while having similar mobilization costs. There were 26 fewer days of collection per 100 mobilization attempts with a pCD34 threshold of 40/µL compared to 15/µL at our institution. More patients completed collection in one day, and more reached an optimal collection yield.

Current status of art mobilization in Myeloma

Multiple myeloma is the leading indication of autologous hematopoietic cell transplantation (AHCT) worldwide. Hematopoietic progenitor cell mobilization (HPCM) is the first step of a successful AHCT. A minimum of 2×106 CD34+ cells/kg are needed for successful engraftment. Growth factors have been used both alone or in combination with chemotherapy for HPCM of patients with myeloma. Mobilization failures result in delays in AHCT and increased cost and resource utility. Strategies to mobilize progenitor cells were mainly chemotherapy and growth factor or growth factor-only mobilization until the advent of plerixafor. Plerixafor is successfully integrated into both growth factor-only and cyclophosphamide and growth factor mobilization strategies with significantly reducing the mobilization failure rate in myeloma patients. The best strategy to mobilize progenitor cells with the highest yield and lowest toxicity and cost in patients with multiple myeloma has not yet been determined. This review aims to summarize the current status of art mobilization in myeloma comparing the pros and cons of different mobilization strategies.