Use Of Plerixafor Research Articles

Bilateral exudative retinal detachment with subretinal light-chain protein in a patient with multiple myeloma -case report-

BackgroundExudative retinal detachment in patients with multiple myeloma is exceedingly rare. Only two Cases are known to us. We successfully identified light-chain proteins in subretinal fluid, allowing for a more precise understanding of the pathogenesis of this complication.Case presentationA 68-year-old patient presented with bilateral exudative retinal detachment. The visual impairment was reported one day after stem cell mobilization by granulocyte-colony stimulating factor (G-CSF) and the additional administration of Plerixafor. The symptoms began during stem cell apheresis. The patient underwent surgical treatment for both eyes through vitrectomy and silicone oil tamponade. Light-chain proteins were detected in the collected subretinal fluid through electrophoresis in one eye.ConclusionsWe successfully identified light-chain proteins in subretinal fluid, allowing for a more precise understanding of the pathogenesis of this complication. The pathomechanism likely involves damage to the outer blood-retina barrier due to the deposition of light-chain proteins. Whether mobilization of bone marrow cells with Plerixafor led to a breakdown of the outer blood-retina barrier in these patients is a topic for discussion and has to be considered in the use of Plerixafor.

Comparison of the efficacy of a generic plerixafor versus Mozobil as adjunct peripheral blood stem cell mobilization agents in multiple myeloma patients.

Plerixafor is an adjunct peripheral blood stem cell (PBSC) mobilization agent with well-demonstrated safety and efficacy. The routine use of the originator brand drug (Mozobil) has been limited by cost. This retrospective study was conducted to compare the mobilization efficacy of a lower-cost generic plerixafor and Mozobil in multiple myeloma (MM) patients. The study included two near-concurrent cohorts of MM patients mobilized with brand (n = 64) or generic (n = 61) plerixafor in addition to filgrastim. Collection and early engraftment outcomes were compared. The two cohorts had comparable distributions of sex, age, and weight. Previous treatment histories and proportions of upfront versus just-in-time plerixafor use were similar. There was no significant difference in their median overall cumulative total yield (106 CD34+ cells/kg) (brand, 5.91; generic, 5.80; p = .51). However, the generic cohort had a significantly higher median yield after the first dose (4.79 vs. 3.78, p = .03), and consequently lower median numbers of plerixafor doses (p = .001) and collection days (p = .002). Only 31.1% of patients in the generic arm required more than one dose versus 59.4% of patients in the brand arm (p = .006). All transplanted patients in the brand and generic arms (90.6% and 85.2% respectively, p = .42) achieved engraftment. There was no significant difference in their median times to platelet and neutrophil engraftment, nor their transfusion requirements during the first 30 days post-transplant. The generic plerixafor produced comparable cumulative collection yields and early engraftment outcomes as Mozobil, but fewer doses and collection days were needed to reach collection goal.

Preemptive Approach to Plerixafor Use Is Optimal in Patients With Relapsed/Refractory Germ Cell Tumors Undergoing Peripheral Blood Hematopoietic Stem Cell Collection: Effect on Collection Days, Yields, and Cost.

Evidence describing the use of plerixafor in the off-label population of relapsed/refractory germ cell tumors (GCT) is limited. Weaim to describe the effect of rescue versus preemptive plerixafor use on apheresis collection days, collection yields, and cost. We retrospectively collected data on 77 consecutive patients (at least 15 years of age) with GCT who underwent peripheral blood stem cell (PBSC) collection for autologous stem cell transplant between January 1, 2020 and May 1, 2022. Depending on insurance approval, plerixafor was given either as "rescue" (after a first apheresis collection of < 5 × 106 CD34+ cells/kg) or as "preemptive" on Day 4 of granulocyte-colony stimulating factor (G-CSF) prior to the first apheresis collection, if the Day 4 peripheral blood CD34+ count was < 40 cells/μL. A total of 66% of patients who received preemptive plerixafor completed collection in 1 day, similar to good mobilizers who only needed G-CSF (71%, p = 0.366). In contrast, all poor mobilizers in the rescue group required at least 2 days of collection and had lower CD34+ cell yields than the preemptive group (7.15 vs. 9.81 × 106/kg, p = 0.0055). A cost analysis revealed that preemptive plerixafor may save approximately $7000 per patient compared with a rescue approach. Preemptive plerixafor in GCT patients undergoing PBSC collection allows relatively poor mobilizers to collect in fewer days and with lower overall cost. Fewer apheresis procedures result in less risk to the patient, increased patient satisfaction, and the ability to schedule more patients within the constraints of staffing.

Analysis of apheresis outcomes in a cohort of Chilean patients treated with autologous stem cell transplantation: A single center real-world experience

Adequate stem cell harvesting is required for autologous hematopoietic transplantation. In deficient mobilizer patients, the collection of stem cells can be challenging because of the impossibility of achieving satisfactory CD34 cell counts with GCSF + - chemotherapy. Plerixafor is a potent and expensive drug that promotes the release of stem cells from the medullary niche to the peripheral blood and allows satisfactory harvests. We performed a retrospective analysis of 370 patients with myeloma and lymphoma harvested at our institution. 99 % of patients achieved satisfactory apheresis using Plerixafor in 45 %. Satisfactory harvests were obtained in patients mobilized with GCSF or plerixafor. In patients who used plerixafor, it was necessary to perform fewer apheresis procedures (P = 0.05). In multivariate analysis, the only factor that predicted the need for plerixafor was the presence of less than 30,000 CD34 / ul on the day of apheresis (OR 0.3. p < 0.001). Since we adopted the plerixafor protocol guided by CD34 counts, the number of patients with harvest failure has decreased. In conclusion, the rational and standardized use of plerixafor favors satisfactory harvest in patients who require autologous transplantation in South-American patients.

Predictive factors for peripheral blood stem cell mobilization in multiple myeloma in the era of novel therapies: A single‐center experience

AbstractObjectiveMultiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of mobilization failure and characterize the risk factors associated with poor mobilization (PM) of MM patients in novel therapies era.MethodsWe conducted a retrospective study of 211 MM patients who received their first peripheral blood stem cells (PBSC) mobilization at our single center. The following data were collected: age, gender, clinical stage, disease status, complete blood cell count, induction regimen, CD34+ cell count in peripheral blood (PB), and PBSC collections.ResultsIn addition to conventional drugs, 22 (10.4%) patients received daratumumab containing induction, and 33 (15.6%) patients used plerixafor for poor mobilization (pre‐apheresis PB CD34+ cells &lt;20/μL). Failure of collection occurred in 24 (11.4%) patients and was correlated with low white blood cell (WBC), ≥3 cycles of lenalidomide treatment before mobilization, steady‐state mobilization and nouse of plerixafor are associated with mobilization failure. Daratumumab‐based induction treatment ≥2 courses, albumin &gt;41 g/L before mobilization, and steady‐state mobilization were risk factors for PM in subgroups of patients treated with lenalidomide for &lt;3 courses. In addition, Hepatitis B virus infection at baseline, thalassemia and measurable residual disease positivity were recognized as predictive factors for PM in subset of chemo‐mobilization patients.ConclusionIn addition to some well‐recognized risk factors, baseline WBC count and daratumumab exposure ≥2 courses before mobilization were revealed as the predictive factors of mobilization failure, providing consultation for preemptive use of plerixafor.

Daratumumab during Myeloma Induction Therapy Is Associated with Impaired Stem Cell Mobilization and Prolonged Post-Transplant Hematologic Recovery.

Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, n = 110; D-RVd, n = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, p = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, p = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 106/L, p = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 106/kg BW, p = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, p = 0.0164; and 16 vs. 14 days, p = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, p = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; p = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT.

Abstract 732: Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia

Abstract Introduction: CXCR4 is a chemokine receptor for CXCL12 that plays a critical role in homing of hematopoietic stem cells (HSCs) to the bone marrow microenvironment. The CXCR4 inhibitor plerixafor is used to increase mobilization of peripheral blood stem cells in combination with filgrastim. This pathway has also been investigated for applications in hematologic malignancies such as acute myeloid leukemia (AML), including clinical trials, with the goal of disrupting AML from the protective marrow environment. These have included use of plerixafor with 7+3 or MEC, BL-8040 with cytarabine, and ulocuplumab with MEC. For the ulocuplumab trial, at the study site of the authors, CR/CRi correlated with &amp;gt;10% CXCR4 expression (Becker et al. ASH 2014). The objective of this preclinical study is to identify the AML patient population most likely to respond to CXCR4 inhibition, and the role of combined beta-adrenergic blockade, as the latter has been shown pre-clinically to augment mobilization of HSCs when combined with a CXCR4 inhibitor, GPC-100 (Sukhtankar et al. PLoS One, 2023). Procedures: AML patient samples (N=124 including 90 blood and 34 bone marrow samples, and 21 with both) were obtained with informed consent on an IRB approved protocol. Multicolor flow cytometry was performed with sequential gating on blasts (by FSC/SSC, CD45/SSC, CD34 or phenotype), and leukemia stem cells (LSCs:CD34+CD38−,CD123+), then analysis for CXCR4 and beta-2 adrenergic receptor (ADRB2) surface expression. Correlations between CXCR4 expression and clinical characteristics including age, gender, new diagnosis vs. relapse, ELN2022 risk, cytogenetics, FLT3/NPM1 mutation status, CR1 duration, and overall survival were performed. GraphPad Prism9 was used for statistical analysis, and Mann Whitney test (two groups) and ordinary one-way ANOVA (&amp;gt;2 groups) were used for comparisons. Results: The range of CXCR4 expression by AML blasts is 0.05 to 99.7% (median 13.1%; mean 16.2%), and by AML LSCs 0 to 99% (median 2%, mean 15.7%). The expression by blasts and LSCs for each patient exhibited tight correlation, R2=0.88 p=1.23 × 10e-25). There was higher % expression of CXCR4 by both blasts and LSCs for new diagnosis, as compared to relapsed, patient samples (p=0.002). There was no correlation between level of CXCR4 expression and the other clinical features. For a subset of 20 patient samples analyzed for both CXCR4 and ADBR2 expression by AML blasts, ADBR2 expression ranged from 0.4 to 20.1%. For the samples that express ADBR2, there was high level expression of CXCR4, range 35.9 to 98.7% (median 78.4%, mean 76%). Conclusion: These studies support further investigation of whether simultaneous blockade of CXCR4 and ADBR2 may potentiate chemotherapy response in AML by limiting microenvironment mediated chemotherapy protection and reveal that patients with new diagnosis may be more susceptible to this approach. Citation Format: Brenda Loera, Chunxiao Zhang, Pina M. Cardarelli, Niña G. Caculitan, Sylvia Chien, Jin Dai, Vivian G. Oehler, Jianying Zhang, Guido Marcucci, Pamela S. Becker. Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 732.

Outcomes of upfront plerixafor use for mobilization in germ cell tumor patients

High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) improved 5-year overall survival rates in relapsed/refractory germ cell tumors (GCTs) from 10% to 52%. Nearly 30% of GCT patients are deemed poor mobilizers after receiving several lines of prior therapy. There is limited data available regarding upfront plerixafor use in GCT patients. We predicted upfront plerixafor use would increase the amount of stem cells collected preventing subsequent mobilizations and improve time to curative therapy. A retrospective, single center, chart review of adult GCT patients who received plerixafor upfront for mobilization at a single center between January 1, 2013 and August 31, 2021 was performed.The primary objective was to evaluate the rate of successful peripheral blood CD34+ cell collections. Secondary objectives consisted of describing the impact of plerixafor use on mobilization and assessing auto-HSCT related outcomes. Sixteen patients received plerixafor upfront after an average of three prior lines of therapy (range: 2-5 lines). Successful collection (≥4 × 106 CD34+ cells/Kg collected within four days) was achieved in 15 (94%) patients in a median of one apheresis day (interquartile range: 1-2 days). All patients proceeded to an initial auto-HSCT and 12 patients (75%) completed both transplants as planned. Survival at 12 months was 50%.The significantly higher amount of CD34+ cells collected over less apheresis days demonstrated the clinical utility of upfront plerixafor and its potential to facilitate more efficient stem cell mobilization. There is a need for larger randomized studies with upfront plerixafor use in this unique patient population.

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

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

PLERIXAFOR FOR HEALTHY PERIPHERAL BLOOD HEMATOPOIETIC STEM CELL DONORS IN PEDIATRIC ALLOGENEIC HSCT.

Data on use of plerixafor for peripheral blood stem cell(PBSC) mobilization in children with cancer undergoing autologous hematopoietic stem cell transplantation(HSCT) is there in literature. The use of plerixafor for normal healthy allogeneic donors is not reported much, especially in the pediatric setting. In this retrospective analysis from a single tertiary care centre in India, we report the efficacy and safety of the use of plerixafor in five healthy allogeneic PB-HSC donors and compare the outcomes with five others allogeneic HSCT’s in which plerixafor was not used. Ten allogeneic HSCT were included in the analysis, 5 in which the donor received plerixafor and in the other five the donor did not get it. In all the HSCT, PB HSC were the product.&#x0D; No significant difference in terms of recipients age and weight; donors age and weight and the CD- 34 count in PB before plerixafor were there between the two groups. However, the CD-34 HSC count in the harvested product was significantly higher in the group that received plerixafor (p=0.032). The stem cell dose transfused to the patient was also higher when the donor got plerixafor, although the difference was not significant. None of the donors suffered any side effects and underwent the subsequent apheresis uneventfully.&#x0D; The use of plerixafor in healthy stem cell donors (both pediatric and adult) for allogeneic stem cell transplant allowed a better yield of stem cells. In our experience the use of plerixafor was safe for the donors.

Immune Graft Composition Is Important for Deepening Response and Outcome after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma Who Do Not Receive Maintenance Therapy

Maintenance therapy with Lenalidomide or proteasome inhibitors after autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is an important component of first line treatment, resulting in deepening response (DR), converting PR to VGPR/CR or VGPR to CR in most patients and, in significantly longer PFS and OS. Of note, randomised clinical trials and real-world data confirm that DR also occurs in about 30% of patients receiving placebo or no maintenance at all. We analysed 90 patients with MM treated with first line ASCT in Hammersmith Hospital between 2017 - 2020, who did not receive maintenance therapy. We observed DR in 20 patients (22%) in the first two years. Patients achieving a DR had significantly higher PFS at 36 months post ASCT (89.4% v 41.1%, p=0.001 - Figure 1A). Baseline and ASCT characteristics, including high-risk cytogenetics, ISS, induction therapy and conditioning were comparable in DR and non-DR patients, however the use of the CXCR4 antagonist Plerixafor plus G-CSF vs G-CSF alone in the mobilisation regimen was associated with a higher probability for DR in the first 24 months post ASCT (58.3% v 23.2%, p=0.011 - Figure 1B). We suggest that improvement in depth of response after ASCT without pharmacological intervention indicates an immune anti-MM effect, underpinned by the immune composition of autologous grafts. We used 14-colour flow cytometry to analyse the immune cell frequencies in graft in 59 of the above patients, including 17 patients mobilised with Plerixafor plus G-CSF and 42 with G-CSF alone. The cell dose of each cell population was calculated from the relative frequency of CD34 cells in the graft and the CD34 cell dose infused in ASCT. In line with previous reports, the use of Plerixafor results in higher frequency and cell dose (in x10^6 cells/kg) of T cells in the graft (70.6% v 61.3%, p=0.015 and 306.2 v 161.4, p=0.007), driven mostly by a higher frequency (67.8% v 48.7%, p= 0.001) and dose (224 v 78.2, p=0.001) of central memory (CM) CD4 T cells. On the contrary, frequency and cell dose of effector memory (EM) CD4 T cells in Plerixafor plus G-CSF mobilised grafts were lower (6.7% v 21.5%, p=0.006 and 15.5 v 34.7, p=0.063). Apart from mobilisation regimen, univariate analysis showed a higher probability of achieving DR in grafts with high frequency of CD4 CM T cells (p= 0.012), NK cells (p=0.018 , Figure 1C), CD8 CM cells (p=0.06), higher dose of CD8 memory stem cells (p=0.033), lower frequency and dose of CD4 EM (p= 0.017 and p=0.007) and a lower dose of CD4 terminal effectors (TE) (p=0.039). In multivariate analysis, only a high NK cell frequency (p=0.011) and low CD4 TE cell dose (p=0.01), driven by their PD1 expression, predicted a higher probability for DR. Tregs frequency and cell dose were not affected from mobilisation regimen. However, Tregs dose was the stronger predictor of PFS at 36 months (75% with dose &amp;lt;5.06 x10^6/kg v 34.5% with dose &amp;gt;5.06 x10^6/kg, p= 0.001). Similarly, lower cell doses of CD4 EM (p=0.012) and frequency of CD4 TE (p=0.034) predicted a higher probability of PFS, but only Tregs cell dose retained significance in multivariate analysis (Figure 1D, p=0.001). In conclusion, spontaneous DR occurs in the first 2 years post ASCT in the absence of maintenance therapy and is associated with better PFS. CD4 memory subsets and NK cell graft composition appears significant for a potential immunological effect in DR. Additionally, a lower cell dose of immunosuppressive Tregs appears more important for sustaining long-term remission post ASCT.

Comparison of different plerixafor-based strategies for adequate hematopoietic stem cell collection in poor mobilizers

Objectives: The main objective of the present study was to evaluate whether the use of plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) or subsequent use of isolated G-CSF and then plerixafor following disease-specific chemotherapy, and whether it would allow for adequate peripheral stem cell collection in patients. Methods: The retrospective study evaluated 54 patients with previous mobilization failure who were administered plerixafor in 2 centers. In patients without any side effects, CD 34+ cell counts, the percentage of patients who were found eligible for autologous transplantation, the engraftment kinetics of the patients who underwent transplantation, and their overall survival results were compared between the two groups where G-CSF was used with plerixafor, or where plerixafor was used after isolated G-CSF following chemotherapy. Results: The median age of the patients was 49 years (range: 17-70), and 64.8% (n = 35) were males. It was identified that 31 (57.4%) patients underwent mobilization treatment with isolated G-CSF and plerixafor, and 23 (42.6%) patients underwent mobilization treatment with chemotherapy plus G-CSF and plerixafor. In all patients, mean hemoglobin level (11.3 ± 1.5 g/dL vs. 9.3 ± 1.3 g/dL; p &amp;lt; 0.001) and median platelet level (129.2 ×103/µL vs. 58.4 ×103/µL) were found to be higher, while febrile neutropenia rate (3.3% vs. 60.9%), the percentage of replacement patients (6.7% vs. 65.2%), and median days of G-CSF (6 vs. 9) were found to be lower on the day of plerixafor administration in the isolated G-CSF and plerixafor group compared to the chemotherapy and G-CSF and plerixafor group. Conclusions: In conclusion, our study demonstrated that administration of plerixafor is generally safe and well-tolerated. Regardless of the underlying disease, it offers an effective alternative for patients with previous failed mobilization attempts using conventional regimens, and allows stem cell collection with fewer apheresis sessions.

Autologous STEM Cell Collection after Daratumumab, Bortezomib, Thalidomide and Dexamethasone Versus Bortezomib, Thalidomide and Dexamethasone in NEWLY Diagnosed Multiple Myeloma: A Real-Life Monocentric Italian Experience

Introduction In newly diagnosed multiple myeloma (NDMM) patients (pts), induction followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) remains the standard of care. The addition of an anti-CD38 antibody, daratumumab, to an established frontline protocol based on bortezomib, thalidomide and dexamethasone (D-VTd), improves efficacy but could hamper peripheral blood stem cell collection (PBCS). Methods The aim of our study is to evaluate the possible impact of the addition of daratumumab to induction therapy prior to ASCT on PBCS and hospitalization parameters a real-world population with NDMM. We hereby, retrospectively analyzed 28 NDMM pts who received 6 cycles of D-VTd as induction therapy before ASCT and compared them with a consecutive series of 32 VTD-treated NDMM pts who were matched for cytogenetic abnormalities and age, managed at the Hematology Department of Sapienza University in Rome. Results Patient baseline characteristics were equally distributed among both groups, as summarized in Table 1. After induction therapy, a combination of cyclophosphamide (CTX) with granulocyte colony stimulating factor (G-CSF) at standard dose of 10 mg/sqm/day was used as the first mobilizing regimen attempt in both groups. The median time between the last day of induction therapy and the first day of mobilization therapy was 30 days for D-VTd groups and 22 days for VTD groups (p=0.041). Overall, 94% of pts treated with VTd met the desired collection goal after first mobilization therapy, compared to 68% of pts treated with D-VTd (p=0.01). In the VTd arm, 1 pts required a second mobilization attempt, and 1 pts required a further one. In the D-VTd arm, 5 pts required a second mobilization attempt, and 4 pts also required a further one. Overall, 3 pts in the D-VTd arm did not meet the collection goal. In pts with impaired mobilization, plerixafor was used in 4/32 pts in the VTd arm (13%), compared to 29% of pts treated with D-VTd (p=0.195). In the D-VTd arm, 12/28 pts (43%) had received a higher dose of CTX as mobilization therapy (3 g/m 2) compared to the standard dose of 2.4 g/m 2 in 16/28 pts (57%). Nevertheless, no difference was observed in the rate of PBSC collection at the first attempt (p=0.7). No baseline clinical or disease characteristics were observed to have negative impact on the PBSC at first mobilization attempt, including treatment response at the end of induction therapy. Nevertheless, a significantly lower pre-mobilization level of platelet was detected in the group of D-VTd treated pts (173.000/mm 3 vs 210.000/mm 3, p=0.012) that did not meet the desired collection goal after first mobilization therapy. The median PBSC collection was 9.1x10 6 CD34+ cells/Kg in the whole cohort, with no significant difference in the two groups. A lower pre-mobilization level of neutrophils (p=0.028) and platelets (p=0.004) was observed in the D-VTd arm compared to the VTd arm, possibly reflecting prolonged daratumumab-related hematological toxicity. No significant difference was observed in the leucocyte (WBC) azimuth value in the two arms. However, the two groups reached this value on two different days. In the VTd arm the median day was 8, and in the D-VTd arm it was 11 (p=0.034). The use of G-CSF for more days did not result in an increase in CD34+ and the median azimuth value of CD34 was significantly lower in the D-VTd group than in the VTD group (p&amp;lt;0.001). The median collection volume from apheresis devices was significantly higher in the D-VTd group (372 ml) compared to VTd arm (301 ml) (p=0.05), possibly related to a higher WBC azimuth in D-VTd arm, resulting in a prolonged apheresis procedure. Pts receiving D-VTd had slightly delayed hematopoietic neutrophil (11 vs 14 days, p=0.030) and platelet (15 vs 14 days, p=0.018) engraftment, but no requiring a higher number of red cell (p=0.6) and platelet (p=0.3) transfusions and a longer hospitalization (20 vs 17 days, p=0.2) after the first ASCT, compared to pts treated with VTd. No difference in the two groups regarding rate of febrile neutropenia (65% vs 45%, p=0.2) and use of antibiotics (53% vs 57%, p=0.8) were observed. Conclusions In conclusion, frontline induction daratumumab-based therapy is likely to affect PBSC collection after first mobilization attempt, even if not clinically relevant, and potentially mitigated with higher use of plerixafor. Furthermore, the inclusion of daratumumab in pretransplant therapy regimens did not impair ASCT.

Impact of Daratumumab on Hematopoietic Stem Cell Mobilization with G-CSF and on-Demand Plerixafor in Newly-Diagnosed Multiple Myeloma Patients

Introduction Autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients with newly diagnosed (ND) multiple myeloma (MM); therefore, an adequate hematopoietic stem cell (HSC) collection is crucial to allow patients to proceed to ASCT and ensure optimal hematologic recovery. A more frequent use of plerixafor (PLX) and lower HSC yields have been reported in patients treated with daratumumab, a backbone of induction therapy for NDMM patients. Chemotherapy-free mobilization with G-CSF and on-demand PLX is an effective mobilization strategy lacking chemotherapy-related toxicities. Here we present the results of a multicenter, retroprospective and prospective, observational study, aiming to compare the impact of daratumumab on HSC mobilization with G-CSF + on-demand PLX in patients with NDMM treated with bortezomib-thalidomide-dexamethasone (VTd) or VTd plus daratumumab (D-VTd). Methods NDMM patients undergoing a first HSC mobilization attempt with G-CSF (10 mcg/kg/day) were enrolled and observed up to 30 days after ASCT. According to its label, on-demand PLX was administered in patients with &amp;lt;20 CD34 + cells/µL after ≥ 4 days of G-CSF or in case &amp;lt;1×10 6 CD34 + cells/kg were collected on the first day of apheresis. The primary endpoint of the study was the rate of poor mobilizing patients (≤2x10 6 CD34 + cells/Kg collected or need for PLX to reach an adequate HSC harvest). Key secondary endpoints included: the rate of suboptimal (2 to 4 CD34 + cells/kg) and optimal (≥4 CD34 + cells/Kg) collection; the median number of apheresis required to obtain ≥2x10 6 CD34 + cells/Kg; the impact of daratumumab on HSC engraftment. Results A total of 190 NDMM patients (median age, 62 years) were enrolled in 2 Italian centres (IRCSS Istituto Clinico Humanitas and Città della Salute e della Scienza di Torino) and analyzed; of these, 70% (133/190) were treated with VTd and 30% (57/190) with D-VTd. The median number of induction cycles was 4 in both groups. Best response after the induction phase was at least very good partial response (VGPR) in 87/133 (65%) and 41/57 (72%) of patients treated with VTd or D-VTd, respectively (p=0.4). The median time from the end of induction to G-SCF administration was 24 days in the VTd group and 29 days in the D-VTd group (p=0.5). The rate of poor mobilizing patients was 31% (41/133) in the VTd group and 54% (31/57) in the D-VTd group (p=0.002), mainly due to a higher rate of PLX use in the D-VTd as compared to the VTd group (53% vs. 28%; p=0.001), while the rate of patients who failed HSC mobilization (≤2x10 6 CD34 + cells/kg collected) was similar in the two groups (2% vs. 3%; p=1). Despite a numerically higher median number of CD34 + cells collected in the VTd group (7.9) as compared to the D-VTd group (7.1; p=0.009), no difference in the rate of patients who collected 2-4 (5% vs. 5%; p=1) and ≥4 CD34 + cells/Kg (95% vs. 95%; p=1) was observed in the VTd and D-VTd groups, respectively. A higher median number of CD34 +/µL on the first day of count was observed in the VTd as compared to the D-VTd group (24.5 vs. 19, p=&amp;lt;0.001). Among patients who had &amp;lt;20 CD34 +/µL [32% (43/133) vs. 51% (29/57)] on the first day of count, a similar increase in the CD34 +/µL (48.5 vs. 55) was observed in the two groups after PLX administration. The median number of apheresis session needed to complete the harvestwas 1 fo the VTd group and 2 in the D-VTd group (p=0.1). Neutrophil and platelet recovery were achieved in 100% of patients with a median time to neutrophil recovery of 15 and 13 days in the VTd and D-VTd groups, respectively (p=&amp;lt;0.001) and a median time to platelet recovery of 16 and 14 days in the VTd and D-VTd groups, respectively (p=0.001). Conclusion G-CSF plus on-demand PLX for HSC mobilization demonstrated to be an effective strategy in NDMM patients treated with VTd with or without daratumumab, resulting in very low rates of mobilization failures irrespective of the use of daratumumab during induction. Despite a higher rate of patients requiring PLX for HSC collection and lower CD34 + yields, the incorporation of daratumumab as part of the induction treatment did not negatively impact the possibility to achieve an optimal HSC collection. Our results, along with the lack of chemotherapy-associated toxicity, support the use of a chemotherapy-free HSC mobilization with G-CSF and on-demand plerixafor also in patients receiving daratumumab upfront.

Impact of the Addition of Daratumumab to the Standard Bortezomib-Thalidomide-Dexamethasone Regimen on Hematopoietic Stem Cell Mobilization and Collection, Post-Transplant Engraftment and Infectious Complications: A Case-Control Multicentre Real-Life Analysis

Background The pivotal clinical trial CASSIOPEIA established the quadruplet Daratumumab-Bortezomib-Thalidomide-Dexamethasone (Dara-VTD) as superior with regards to the standard Bortezomib-Thalidomide-Dexamethasone (VTD) regimen as induction therapy in newly diagnosed transplant-eligible (NDTE) multiple myeloma (MM) patients. As a matter of facts, Dara-VTD is currently the approved induction scheme in NDTE MM patients in Italy. Previous reports showed that adding Daratumumab in induction therapy patients yielded to a higher number of poor mobilizers, with a lower median number of collected hematopoietic stem cells (HSC). However, these reports included different types of induction therapies, merging patients on and off clinical trials, and real-life data focusing exclusively on Dara-VTD is lacking. We report our experience on the impact of Dara-VTD on HSC mobilization and collection, with a retrospective comparison with a cohort of patients treated with VTD and we also provided data concerning post-transplant engraftment and infectious complications. Methods From January 2022 to June 2023, 109 NDTE MM patients from 5 Haematology Institutions received Dara-VTD treatment induction according to the approved doses and schedule. The control group consisted of 116 age-matched patients treated with VTD in the years 2015-2016. Mobilizing therapy consisted of cyclophosphamide 1-3 gr/sqm followed by granulocyte colony-stimulating factor (G-CSF) 10 mcg/kg starting the 5th day thereafter, with HSC harvest planned on the 11th day. Patients received only G-CSF 10 mcg/kg if they were older than 70 years or had renal impairment (i.e., eGFR &amp;lt; 50 ml/min). Poor mobilizer was defined as having less than 20 CD34+/µL in peripheral blood on the 11th day after cyclophosphamide and G-CSF or on the 4th day of G-CSF alone administration. In that case, plerixafor was added at the standard dose of 0.24 mg/kg. Results In the Dara-VTD group, 96/109 patients received cyclophosphamide and G-CSF; among them, 3 patients had failed a previous G-CSF mobilizing therapy, even with the addition of plerixafor. Thirteen patients received G-CSF only. In the VTD group, all patients had received cyclophosphamide and G-CSF. Pre-harvest median number of CD34+/mL in the Dara-VTD group was 26 (range 0.8-279) vs 76 (range 20-294) in the VTD group and the incidence of poor mobilizing patients was 41.7% vs 5.9%, respectively (OR 0.3, 95% CI 0.16-0.54, P &amp;lt; 0.0001). Baseline disease characteristic did not have an impact on poor mobilizing events. On the contrary, patients who developed hematologic toxicity during induction turned out to be poor mobilizers (OR 3.5, 95% IC 1.36-9.59, p= 0.011). Plerixafor was used in 54/109 patients in the Dara-VTD group and in 16/116 patients of the VTD group. Two patients failed HSC mobilization both with G-CSF and cyclophosphamide and G-CSF. All patients that received G-CSF only resulted in poor mobilizers and required plerixafor before HSC harvest; therefore, cyclophosphamide showed to be superior with regards to G-CSF as mobilizing therapy (p= 0.011). The median number of collected HSC was significantly lower in the Dara-VTD group vs VTD group: 5.17 x 10^6/Kg (IQR 3.9-5.47) vs 8.7 x 10^6/kg (IQR 6.35-11.15), respectively (p &amp;lt; 0.0001). 33% of patients in Dara-VTD group collected at least 6 x 10^6 CD34+/Kg). Median time to neutrophils and platelets engraftment were different between the two groups (13 and 11 days, respectively, P &amp;lt; 0.0001), but we did not observe any difference in terms of infection incidence. Notably, post-transplant infections incidence in Dara-VTD group was 43%. Although the second transplant was planned for 36 patients treated with Dara-VTD, it was performed in 10 patients only, mainly because of insufficient HSC harvest. Conclusions Our experience with Dara-VTD confirms an increased number of poor mobilizers, a higher need for the use of plerixafor and a lower number of collected HSC. We observed a slightly lower engraftment in Dara-VTD group, probably because of a lower number of infused HSC. The lower number of collected HSC hampers the possibility of a double transplant.

Engraftment Syndrome during Autologous Stem Cell Transplant in Hodgkin Lymphoma Patients Treated with Checkpoint Inhibitors: A Multi-Center Retrospective Analysis

Background: Engraftment Syndrome (ES) has traditionally been considered a rare complication of autologous stem cell transplant (ASCT) in patients (pts) with relapsed/refractory Hodgkin lymphoma (HL). There have been several attempts to define ES, but diagnostic criteria have not been unified. Diagnosis of ES is considered in pts developing non-infectious fever coinciding with neutrophil recovery, typically with at least one other inflammatory finding such as pulmonary infiltrates, diarrhea, rash, or transaminitis. The proposed pathogenesis of ES involves production of inflammatory cytokines by activated leukocytes, which may ultimately be suppressed by treatment with systemic corticosteroids. Recent clinical trials in HL have suggested that exposure to immune checkpoint inhibitors (ICI) before ASCT may increase the risk of developing ES. Methods: We conducted a retrospective study at several U.S. academic institutions to better characterize ES in HL pts undergoing ASCT in the era of ICIs. Eligibility criteria included age &amp;gt; 18, diagnosis with relapsed/refractory HL, treatment with an ICI as part of pre-transplant salvage therapy, and ASCT between January 1, 2015 and February 1, 2023. Inflammatory symptoms and timing of symptom onset were assessed by medical record review. ES was defined by Maiolino criteria (Maiolino et al. Bone Marrow Transpl, 2003) as at least two symptoms within 48 hours of engraftment not attributable to other causes, including fever in combination with diarrhea, rash, or pulmonary infiltrates. We assessed the incidence of inflammatory symptoms and ES, and evaluated potential risk factors associated with developing these symptoms. Results: A total of 53 pts with HL were identified. Pts had a median age of 33 (range 19-72), 49% were female, 75% White, and 11% Black. The majority (87%) had the nodular sclerosis subtype and were treated with ABVD (68%) or BV-AVD (23%) in the frontline setting, with a majority achieving CR (53%) or PR (15%). At relapse, 57% received BV-nivolumab and 13% received pembrolizumab-GVD. Overall, 70% received nivolumab prior to ASCT, and 30% received pembrolizumab. None of the pts in this reported cohort were treated on a clinical trial. On pre-ASCT PET, 77% achieved CR, after which all were mobilized with GCSF, with 42% also receiving plerixafor. An average of 9.57 million CD34+ cells/kg (median 7.28) were infused on day 0. Pts were hospitalized for an average of 20 days (range 2-99). All pts successfully engrafted, with a median time-to-engraftment (ANC 500) and time-to-platelet-recovery of 10 days. A majority of pts (70%) experienced at least one non-infectious inflammatory finding at engraftment, but only 21% met Maiolino criteria for ES. The frequency of non-infectious inflammatory findings is described in Figure 1. Of the 11 pts clinically diagnosed with ES by the treating physician, 7 received high-dose steroids for treatment, for a median of 8 days. There were no deaths attributed to ES. Following transplant, 91% achieved CR, with 5 pts experiencing progressive disease. Over a median follow-up of 15 months (range 1-57 months), 5 pts relapsed and 4 died. The outcomes of the entire cohort were excellent, with 2-year PFS of 78% (95% CI: 67-90%) and 2-year OS of 90% (95% CI 81-100%). There were no differences in survival based on ES status. We explored potential risk factors for developing ES, including number of cells infused, duration of ICI exposure/timing in relation to ASCT, and plerixafor use, but none achieved statistical significance. Conclusions: In this non-trial cohort of HL pts receiving ICI-based salvage before transplant, a minority of patients (21%) developed ES by traditional diagnostic criteria, but the majority of pts (70%) developed non-infectious inflammatory findings in the peri-engraftment period. Most pts experiencing ES were treated with steroids and had favorable outcomes similar to those without ES. With increasing use of ICI-based regimens in the pre-transplant setting, further studies with larger patient cohorts are needed to better characterize this entity, develop unified reporting and diagnostic criteria, identify pts at high risk for severe ES, and develop effective prophylactic and therapeutic strategies.

Real-World Mobilization, Harvest, and Transplant Outcomes in Newly Diagnosed Multiple Myeloma Patients Receiving D-VTd: A UK Centre Experience

Introduction In newly diagnosed multiple myeloma (NDMM) patients eligible for autologous stem cell transplantation (ASCT), daratumumab plus, bortezomib, thalidomide, and dexamethasone (D-VTd) followed by high-dose melphalan with ASCT, is considered standard of care in Europe. The CASSIOPEIA trial reported a lower stem cell (SC) yield and higher plerixafor (PLX) use, but no impact over ASCT feasibility and safety for the D-VTd group. However, real-world data from clinical experience after its approval is scarce. In the United Kingdom, the National Institute for Health and Care Excellence approved D-VTd as frontline treatment in November 2021. Our aim was to describe the real-world experience regarding mobilization, harvest, and ASCT outcomes in NDMM patients receiving D-VTd. Methods We included all consecutive NDMM patients referred from 10 haematology centres to our institution and subsequently to apheresis, from June 2022 to May 2023. Patients received D-VTd as induction and had achieved at least partial response at time of referral. Patients underwent SC mobilisation with cyclophosphamide 1.5g/m 2 D+1, GCS-F 5µg/kg D+5 to D+10, and apheresis D+11 and D+12. Additional VTd cycles were given when length of waiting for apheresis was more than 6 weeks. Pre-emptive PLX was given for pre-apheresis CD34+count between 5-15cells/µL. After a successful harvest (≥2.0x10 6 CD34+cells/kg) ASCT was scheduled in 4-6weeks. Results A total of 95 patients were included. The median age was 63 years (range 34-74), 71.6% were male, 16.8% were ISS-III, 9.2% were R-ISS-III, and 28.9% had high-risk cytogenetics. Regarding induction treatment patients received 4 cycles of D-VTD; additionally 11 (11.6%) received radiotherapy, and 36 (37.9%) additional VTD pre-apheresis,th a median of 2 (range 1-4). MM response pre-apheresis was ≥VGPR in 80%. The median time from the start of D-VTd to apheresis was 6 months (range 4-10). A total of 87 patients underwent apheresis; 21 (22.1%) received pre-emptive PLX and 71 (81.6%) underwent two apheresis procedures. The mean pre-apheresis and total dose CD34+cells were 29.2/µL (range 0.4-220.7) and 4.5x10 6/kg (range 1.2-12.6), respectively. From the 14 patients that failed to collect ≥2.0x10 6cell/kg on first attempt, 8 underwent a second attempt. Overall harvest success rate was 92.6% ( n = 88) (Figure 1). Regarding the additional VTd versus non-VTd groups, mean total CD34+cell dose was 5.1x10 6/kg (range 1.3-10.7) versus 4.8x10 6/kg (range 1.2-12.6) ( p = 0.61) and PLX was used in 25% versus20.3% ( p = 0.28). After a median of 7 weeks (range 4-32), 68 patients (77.3%) proceeded to ASCT, 11 (12.5%) are awaiting, and 9 (10.2%) were cancelled. A 54.4% (n = 37) of patients experienced a delay for ASCT, 7 due to second harvest attempt. Mean CD34+cells infused was 3.7x10 6/kg (range 2.0-6.7). All patients achieved neutrophil and platelet engraftments after a median of 13 days (range 9-17) and 19 days (range 13-29), respectively. One patient died after engraftment, day +49, due to pneumonia. MM response at 100-days after ASCT was ≥VGPR in 97.1% and MRD-neg in 85.2% of the evaluated patients (Table 1). Conclusions Based on our results, we confirm that compared to published data the addition of daratumumab to VTd in NDMM patients, results in a lower SC yield and higher pre-emptive PLX administration. As expected, when reflecting the real-world practice timely interventions are difficult to maintain leading to delays on harvesting and ACST procedures. Herein we report the implementation of a “bridging” strategy with additional VTd cycles between D-VTd induction and apheresis, this did not influence our harvest outcomes. Although longer follow-up is desirable, our results regarding harvest success (92.6%) and ASCT outcomes, including engraftment and MM response at 100-days, are comparable to those reported by the CASSIOPEIA trial.

A German-Wide Systematic Study on Mobilization and Collection of Hematopoietic Stem Cells in Poor Mobilizer Patients with Multiple Myeloma prior to Autologous Stem Cell Transplantation

Introduction: In patients with a clinical indication for autologous hematopoietic stem cell transplantation (ASCT), sufficient mobilization of CD34+ precursor cells into peripheral blood is essential to ensure adequate hematopoietic stem cell (HSC) collection prior to intensive therapy. However, with standard granulocyte-colony stimulating factor (G-CSF)-based mobilization schemes, an important minority of patients fail to mobilize sufficient (e.g., >10/µL) CD34+ cell counts into the peripheral blood and are considered as poor mobilizers (PM). Because failure to achieve sufficient CD34+ cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34+ mobilization in PM patients. Methods: The German non-interventional, multicenter, open-label, prospective OPTIMOB study evaluated HSC mobilization strategies prior to planned ASCT in adult patients with hematologic malignancies (lymphomas or multiple myeloma [MM]) focusing on PM patients. PM patients were defined as follows: (1) never achieving ≥20 CD34+ cells/µL before 1st apheresis, (2) receiving PLX at any timepoint of mobilization, (3) their initially planned stem cell yield had to be reduced, or (4) they had not received apheresis due to low CD34+ count in peripheral blood. Results: 168 of 475 MM patients (35%) participating in the OPTIMOB study were classified as PM, and 155 of them (92%) received PLX (PM+PLX) during the study. PM patients were 40–78 years old, slightly more often male (n = 97, 58%), mostly newly diagnosed (n = 146, 87%) and received highly individualized previous treatments. Ninety-four of the PMs underwent chemotherapy mobilization (65%), and 51 patients (35%) received steady-state mobilization with G-CSF only during 1st mobilization attempt. 92% of the total PM population (n = 155) underwent apheresis, 78% of them (n = 117) achieved >2.0 × 106 CD34+ cells/kg body weight on the 1st day of apheresis. PM+PLX had a higher median total collection result than those PM patients without PLX support (7.2 vs. 5.7 × 106 CD34+ cells/kg body weight). In total, ASCT was performed in 136 PM+PLX (88%) versus 8 PM−PLX patients (62%). Conclusion: The OPTIMOB study showed that a considerable proportion of adult MM patients in Germany are PMs. Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs.

The effect of mobilizing large numbers of CD34 + cells (super-mobilizers) on the engraftment and survival in patients undergoing autologous stem cell transplantation

With the use of plerixafor in addition to growth factor for peripheral blood stem cell mobilization, the yield of autologous stem cell harvest has been higher while the length of apheresis days has become shorter. There is still debate whether higher cell collection efficacy in autologous stem cell transplant (ASCT) affect outcomes. In this retrospective study, we defined two groups of patients, group 1, super-mobilizers, with more than double the target cell dose collected (n = 15), while group 2 included all other patients (n = 75). Multiple myeloma (MM) and lymphoma patients were combined. Patients with chemo-mobilization, those needed more than one day apheresis, or with less than 100 days after ASCT were excluded. Correlations were performed between cell collection efficacy and post thaw CD34 cell viability (by 7AAD flow cytometry method), product HCT, and engraftment of neutrophils and platelets. We performed multiple linear regression using the above variables in addition to age, sex and disease type. We used Kaplan Meier’s curves to show effect of cell collection efficacy on 1-year overall survival (OS). Our results show that all super-mobilizers received plerixafor in addition to G-CSF, while 83% did in group 2. Correlations between cell collection efficacy and neutrophil and platelet engraftment in group 1 and 2 was modest and better in group 1 (R=0.449 Vs 0.233 for neutrophils; R=0.464 Vs 0.110 for platelets, respectively). However, multiple linear regression showed statistically significant association between cell collection, as a continuous variable, with disease type (P < 0.001), product HCT (P < 0.001), post thaw viability (P = 0.003), and age (P = 0.013). MM patients were more likely to be super-mobilizers, while the product HCT was higher in the super-mobilizers. No significant effect of cell collection efficacy was found on engraftment of neutrophils or platelets. With relatively short post ASCT follow up, 6 patients in group 2 died of any cause while no deaths were recorded in the super-mobilizers group (P = 0.1892 by log-rank test). In conclusion, stem cell collection efficacy in ASCT is more frequent in MM than lymphoma patients, but is not predictive of faster engraftment. On the other hand, 1-year OS was 100% in the super-mobilizers group versus 93% in the other group.

Fifty years of BMT: risk stratification, donor matching, and stem cell collection for transplantation.

In this review, we discuss recipient risk assessment for allo-HCT regarding comorbidities present at baseline to predict non relapse mortality. We further reviewed the incorporation of remission status and cytogenetic risk prior to allograft transplantation to predict relapse rates for hematologic malignancies. HCT-CI and DRI are tools available to physicians to assess the risk-benefit of allo-HCT in patients referred for transplantation. Next, we discuss our algorithm for donor selection and criteria for donor selection in case matched donors are not available. Finally, we discuss our approach for stem cell mobilization, especially in donors failing G-CSF, and our approach for the use of plerixafor and data supporting its use.