Day Of Apheresis Research Articles

Seven-Day Vein-to-Vein Point-of-Care Manufactured CD19 CAR T Cells (GLPG5101) in Relapsed/Refractory NHL: Results from the Phase 1 Atalanta-1 Trial

Background Chimeric antigen receptor (CAR) T-cell therapies improve survival for patients (pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Recent studies highlighted the importance of shortening time from leukapheresis to infusion to improve clinical outcomes (Chen et al., 2022; Locke et al., 2022). A novel decentralized and automated point-of-care (PoC) manufacturing model was developed to administer fresh autologous CAR-T treatments within 7 days of apheresis. This avoids the need for cryopreservation and complex logistics, and potentially makes CAR-T therapy accessible for pts with rapidly progressive disease. Here we provide an update on the Phase (Ph) 1 Atalanta-1 trial of PoC manufactured GLPG5101 in pts with R/R NHL. Methods Atalanta-1 (CTIS: 2022-502661-23-00) is a Ph1/2, multicenter trial of PoC-manufactured GLPG5101 in pts with R/R diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) or mantle cell lymphoma (MCL). GLPG5101 is an anti-CD19/4-1BB CAR-T therapy, administered as a fresh product after fludarabine/cyclophosphamide lymphodepleting chemotherapy. Primary Ph1 objectives are safety and establishment of a recommended Ph2 dose. The primary Ph2 objective is efficacy (objective response rate [ORR]). Secondary objectives include feasibility of PoC manufacturing, safety, additional efficacy endpoints, and pharmacokinetics. Results As of May 2, 2023, 14 pts were enrolled in the Ph1 study at dose level (DL) 1 (50×10 6 CAR+ T cells, n=7) or DL2 (110×10 6 CAR+ T cells, n=7); no screen failures occurred. Pts were diagnosed with R/R MCL (n=3), DLBCL (n=7), FL (n=3), or MZL (n=1). Median age was 65 years (range 50-77), 11/14 pts were male. Median prior lines of therapy was 4 (range 1-8). GLPG5101 was manufactured for all pts and administered as a fresh infusion; 13 pts were infused within 7 days of leukapheresis, 1 within 8 days. Three pts received DL1 instead of the intended DL2 due to a lower CAR+ T-cell yield during manufacturing. GLPG5101 showed a preserved early memory phenotype for both CD4+ and CD8+ CAR T cells in the final product, compared to apheresis starting material ( Figure). Most treatment-emergent adverse events (TEAEs) were of Grade 1-2; the majority of Grade ≥3 events were hematological ( Table). Seven (50%) pts experienced cytokine release syndrome (CRS), all but 1 of Grade 1-2; 1 patient had Grade 3 CRS (DL2). Neurotoxicity was seen in 6 (43%) pts, all Grade 1. Grade 3-4 infections occurred in 2 pts. Dose-limiting toxicities (DLTs) were reported for 4 (29%) pts (DL1, n=1; DL2, n=3). Three pts had Grade 4 neutropenia, manageable with granulocyte colony-stimulating factor; these did not limit dose escalation. One Grade 5 intra-abdominal hemorrhage occurred 12 days post infusion (DLT at DL2), caused by Grade 4 disseminated intravascular coagulation, in a pt with multiple comorbidities. One Grade 5 sepsis was recorded >6 months after infusion while the pt was in ongoing complete response (CR). In the efficacy-evaluable pts (n=13), 11 responded to treatment (best ORR 85%). CRs were observed for 9 pts (CR rate 69%). Seven (54%) pts had an ongoing response at time of analysis, with duration reported up to 12 months post-infusion (median follow-up 4.5 months; range 1-12 months). Three pts progressed after an initial response, 1 pt with a CD19−negative relapse. ORR and CR rate were 86% and 57% at DL1, and 83% and 83% at DL2, respectively. Robust CAR T-cell expansion was observed in all pts by qPCR with a median maximum expansion of 2.8×10 5 copies/µg DNA (C max). Median T max was 14 days (range 7-28 days) across doses. The median AUC 0-28d was 3.1×10 6 copies/µg DNA × days. GLPG5101 was detected in peripheral blood up to 9 months post-infusion. Conclusion Data from 14 pts with NHL enrolled in the Ph1 Atalanta-1 study demonstrate that PoC CAR-T manufacturing with a short vein-to-vein time is feasible. GLPG5101 is administered as a fresh product with a median vein-to-vein time of 7 days. The safety profile of GLPG5101 is comparable to other CAR-T therapies, and high CR rates across both DLs in a heavily pre-treated pt population are demonstrated. With this novel PoC manufacturing model, an early phenotype of less differentiated CAR T cells is preserved, demonstrating rapid GLPG5101 in vivo expansion and durable persistence post-infusion . The trial is ongoing, and updated data will be presented.

Adaptive Manufacturing of LV20.19 CAR T-Cells for Relapsed, Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by the presence of t(11;14) and bright CD20 expression. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL is limited by both relapse and high rates of Grade 3+ cytokine release syndrome (CRS) and ICANS with 15% and 31% patients (pts) experiencing such toxicities, respectively. To improve outcomes we utilized dual targeted lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T-cells with an adaptive manufacturing (MF) process to optimize the final CAR product as part of a Phase 1/2 clinical trial in R/R MCL. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report results of MCL pts from a fully enrolled Phase I safety run-in and Phase II efficacy cohort. The primary outcome for the Phase II cohort was day 90 complete response (CR) rate. The Phase II cohort utilized an adaptive 8/12 day MF process to enhance the percentages of T-SCM (stem cell-like memory) and T-CM (central memory) CAR T-cells in the final product by shortening culture time. CAR T-cells were harvested either on day 8 of MF or extended to a 12-day MF process depending on achieving target cell dose in culture. Fludarabine/cyclophosphamide lymphodepletion was started during MF to facilitate fresh infusion in eligible pts. Descriptive statistics were utilized for demographic data and the Kaplan Meier methodology for survival analysis. Results: In total 17 pts with R/R MCL received LV20.19 CAR T-cells (Phase 1=3 pts and Phase 2=14 patients). All pts achieved target cell dose. 13 pts received an 8-day product while 4 received a 12-day product. 14/17 pts received a fresh (non-cryopreserved) infusion. 8-day products were enriched for T-SCM/CM phenotype cells with significantly lower number of terminally differentiated effector memory (EMRA) T-cells in the CD4 compartment (p<0.05) than 12-day products. The median age was 63 (50-74 years) and 15 (88%) were cisgender male. The median number of lines of therapy was 4 (3-8). p53 deletions or mutation were present in 7 pts. Day 28 overall response rate (ORR) was 100%; CR rate=76% and partial response (PR) =24%. Initial ClonoSEQ MRD assay performed within the first 90 days of LV20.19 CAR T (n=13) was negative in 10 pts (77%). Among Phase II patients with day 90 results available (n=12) the ORR was 100%, CR rate=92% and PR rate=8% exceeding the Phase II efficacy threshold. Two pts have relapsed to date, +8 months and +2 years after infusion. There were two non-relapse mortality (NRM) events that occurred beyond day 28: gram negative rod sepsis & COVID19 infection resulting in a 1-year NRM rate of 12%. The 1-year progression free survival (PFS) was 77%, 1-year duration of response (DOR) was 92%, and 1-year overall survival (OS) of 84%. Median PFS/DOR/OS have not been met with median follow-up of 14 months of surviving pts (Figure 1). In terms of safety, 94% (n=16) experienced CRS, all grade 1-2. 18% (n=3) had ICANS in the first 28-days, 2 pts with Grade 3 toxicity. There were two pts with late (>day 28) episodes of Grade 1 neurological toxicity. Both pts had immense expansion of lymphocytes in the CSF (total nucleated cell count of 386/µLand 1005/µL) with CAR+ T cells present. Both received only a single dose of intrathecal hydrocortisone (no systemic steroids) with resolution of neurotoxicity within 24 hours of administration. Conclusions: Bispecific LV20.19 CAR T-cells with adaptive MF process is feasible, safe, and efficacious for R/R MCL with ORR 100%, no Grade 3+ CRS and low rates of Grade 3+ ICANS (12%). Adaptive MF enriched the final product with higher percentages of T-SCM/T-CM CAR cells and allowed most pts to receive CAR-T cells within 8 days of apheresis. Dual targeting of CD20 and CD19 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL.

Efficacy of Chimeric Antigen Receptor T-Cell Therapy Is Not Impaired By Previous Bispecific Antibody Treatment in Patients with Large B-Cell Lymphoma

Introduction: Potential T-cell exhaustion after bispecific antibody (BsAb) treatment remains an open question, raising the theoretical concern that prior BsAb exposure could affect subsequent chimeric antigen receptor (CAR) T-cell efficacy. Clinical data on CAR T-cell outcomes after prior BsAb treatment in the setting of large B-cell lymphoma (LBCL) are scarce and highly awaited to better define treatment sequencing in relapsed/refractory (R/R) patients. Methods: We conducted a retrospective, international study including R/R LBCL patients treated with CD19-targeted CAR T-cells at 15 centers between July 2018 and January 2023 who had been exposed to BsAbs prior to apheresis. Then, we identified a control cohort from patients included in the DESCAR-T Registry (n=764). We carried out a 1:1 propensity score matching (PSM) to achieve balance between cohorts; 13 baseline covariates were included in the PSM. We compared response rates, survival outcomes and toxicity after CAR T-cell therapy, according to previous BsAb exposure. Results: We identified 47 LBCL patients who received BsAb therapy prior to CAR T-cell apheresis. Median age was 65 years (range 31-82), with a male predominance (66%), and median prior lines of therapy before BsAb were 2 (IQR 2-3) (Table). The BsAbs targeted CD20/CD3 (91%) or CD22/CD3 (9%), either in monotherapy (n=41, 87%) or in combination with other agents (n=6, 13%) (lenalidomide [n=2], polatuzumab [n=1], chemotherapy [n=2], missing [n=1]). The median time on BsAb treatment was 98 days (IQR 56-160) with a best overall (complete) response rate (ORR [CRR]) of 47% (19%). Median progression-free survival (PFS) and duration of response (DOR) were 3.1 months (95% CI 2.7-4.4 months) and 8.8 months (95% CI 2.2-NR), respectively. Cytokine release syndrome (CRS) occurred in 59% of patients (grade 3 in 4%). No neurologic toxicity (NT) was reported. In 26 (55%) patients, bispecific antibody was the last line before CAR T-cell therapy. Median washout between the last BsAb dose and lymphocyte apheresis for CAR T-cell manufacturing was 43 days (range 34-103 days). In terms of the subsequent CAR T-cell therapy, patients received axi-cel (n=22, 47%), tisa-cel (n=20, 43%) or liso-cel (n=5, 11%). Most patients developed CRS after infusion (79%, 6% grade >2), with a low rate of NT (23%, 2% grade >2). Neutropenia and thrombocytopenia grade >2 were reported in 66% and 45% of patients, respectively. Regarding efficacy, ORR after infusion was 83% (CR 43%). Median PFS and overall survival (OS) were 6.6 months (95% CI 2.6-not reached [NR]) and NR (95% CI 9.0-NR), respectively. The rate of overall (complete) response was similar between patients who had previously responded (CR or PR) or not (SD or PD) to BsAb therapy (82% [41%] vs 84% [44%], respectively, p=0.64). However, all 9 patients achieving CR after BsAb achieved subsequent response to CAR T-cells. Given the wide variability in the washout between last BsAb dose and lymphocyte apheresis, we evaluated the impact of this interval on CAR T-cell efficacy. The 6-month PFS and OS of patients previously exposed to BsAb within 45 days of lymphocyte apheresis was similar to patients who had a longer washout (59% vs 47% [p=0.25] and 83% vs 67% [p=0.21], respectively). In the second part of the analysis, we matched our cohort with a control group of CAR T-cell recipients not previously exposed to BsAbs. The final analysis included 2 sets of 42 patients with comparable characteristics. Median follow-up from CAR T-cell infusion was 11.5 months for the BsAb cohort (CI 95% 6.4-19.0 months) and 18.8 months for the control cohort (CI 95% 10.9-23.0 months). Patients with previous BsAb exposure showed a similar PFS (p=0.10, Figure) and OS (p=0.08) after CAR T-cell infusion in comparison to the control group. In terms of toxicity, there were no differences in the incidence of CRS (p=0.41) or NT (p=1.0) after infusion. Conclusions: Previous exposure to bispecific antibody treatment targeting different antigens does not have a negative impact on survival outcomes after CAR T-cell therapy. Lack of response to a previous BsAb does not predict for lower response rates after CAR T-cell infusion.

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.

Inflammation-related mRNA expression in patients with multiple myeloma undergoing hematopoietic stem cell mobilization

Mobilization of CD34+ cells is a key element in the therapy of patients with multiple myeloma undergoing autologous stem cell transplantation. The use of chemotherapy and the granulocyte colony-stimulating factor can significantly affect the expression of inflammation-related proteins and the migration of hematopoietic stem cells. We assessed the mRNA expression of selected proteins involved in the inflammatory landscape in MM patients (n=71). The aim of the study was to evaluate C-C motif chemokine ligand 3, 4, 5 (CCL3, CCL4, CCL5), leukocyte cell-derived chemotaxin 2 (LECT2), tumor necrosis factor (TNF), and formyl peptide receptor 2 (FPR2) levels in the course of mobilization and their role in the CD34+ collection efficacy. mRNA expression from peripheral blood plasma was evaluated by RT-PCR. We observed a deep decline in CCL3, CCL4, LECT2, and TNF mRNA expression on the day of the first apheresis (day A) as compared to baseline. A negative correlation was observed between CCL3, FPR2, LECT2, TNF level, and the CD34+ cells count in peripheral blood on day A, and the number of CD34+ cells obtained at first apheresis . Our results indicate that the investigated mRNAs significantly alter and may regulate the migration of CD34+ cells during mobilization. Moreover, in case of FPR2 and LECT2, the results obtained in patients differ from the murine models.

Impact of gemtuzumab ozogamicin consolidation on hematopoietic stem cells (HSCs) mobilization in AML: analysis of 20 patients.

Gemtuzumab ozogamicin (GO), is an anti-CD33 monoclonal antibody, approved for AML CD33 + , those patients with low and intermediate-risk who obtain a complete response may also be candidated for consolidation with autologous stem cell transplantation (ASCT). However, there are scant data on the mobilization of hemopoietic stem cells (HSC) after fractionated GO. We retrospectively studied data from five Italian centers and identified 20 patients (median age 54years, range 29-69, 15 female, 15 NPM1mutated) that attempted HSC mobilization after fractionated doses of GO + "7 + 3" regimen and 1-2 cycles of consolidation (GO + HDAC + daunorubicin). After chemotherapy and standard G-CSF, 11/20 patients (55%) reached the threshold of 20 CD34 + /µL, and HSC were successfully harvested, while 9 patients (45%) failed. The median day of apheresis was Day + 26 from the start of chemotherapy (range 22-39days). In good mobilizer patients, the median circulating CD34 + cells were 35.9 cells/µL and the median CD34 + harvested were 4.65 × 106/kg of patients' body weight. With a median follow-up of 12.7months, at 24months from the first diagnosis, 93.3% of all 20 patients were alive and the median overall survival was 25months. The 2-year RFS rate from the timepoint of the first CR was 72.6%, while the median RFS was not reached. However, only five patients underwent ASCT and achieved full engraftment.In conclusion, in our cohort of patients, the addition of GO reduced HSC mobilization and harvesting, which was reached in about 55% of patients. Nevertheless, further studies are warranted to evaluate the effects of fractionated doses of GO on HSC mobilization and ASCT outcomes.

Mobilization and Hematopoietic Stem Cell Collection in Poor Mobilizing Patients with Lymphoma: Final Results of the German OPTIMOB Study

Introduction: Successful mobilization and collection of peripheral hematopoietic stem cells (HSCs) are necessary for lymphoma patients eligible for myeloablative chemotherapy with subsequent autologous stem cell transplantation (ASCT). Albeit G-CSF alone or combined with chemotherapy is well-established methods for HSC mobilization, up to 40% of the patients fail to mobilize (poor mobilizer, PM). Plerixafor (PLX) is commonly used in PM patients resulting in increased migration of HSCs into peripheral blood and thus improves the collection outcome. Methods: The prospective, multicenter, open-label, non-interventional OPTIMOB study assessed mobilization and collection parameter of patients with lymphoma or multiple myeloma to get deep insights in the treatment of those patients in clinical routine focusing on PM patients. PM was defined as follows: (1) no achievement of ≥20 CD34+ progenitor cells/µL before first apheresis, (2) PLX administration at any time point during the observational period, (3) reduction of the initially planned CD34+ progenitor cell yield as necessity due to failed mobilization or HSC collection, and (4) no performance of apheresis due to low CD34+ progenitor level. Primary objective of the study was to assess mobilization success by the proportion of PM patients achieving >2 × 106 CD34+ progenitor cells/kg body weight on the first day of apheresis. Here, the data of the lymphoma cohort are presented. Results: Out of 238 patients with lymphoma documented in the study, 32% were classified as PM. 87% of them received PLX. Demographic data revealed no obvious differences between PM and good mobilizing (GM) patients. All patients were treated highly individualized prior to mobilization. Majority of all PM patients were able to undergo apheresis (95%) and reached their individual requested CD34+ progenitor cell target (72%). 57% of the PM patients achieved >2.0 × 106 CD34+ progenitor cells/kg body weight on day 1 of apheresis and nearby 70% of them underwent ASCT. Median time to engraftment was similar in PM and GM patients of the lymphoma cohort. Conclusions: Majority of PM patients with lymphoma were successfully mobilized and underwent ASCT. Most of them received PLX during the study.

Despite Use of Upfront Plerixafor and G-CSF, Daratumumab Exposure Reduces Stem Cell Mobilization in Patients with Multiple Myeloma

Introduction Daratumumab is an anti-CD38 IgG1k monoclonal antibody with direct tumor killing and immunomodulatory mechanisms of action which was shown to have clinical benefits when added to the standard-of-care induction regimen in transplant eligible multiple myeloma (MM) patients. However, prior studies have indicated a potential reduction in stem cell yield in patients exposed to daratumumab prior to stem cell mobilization. Additionally, prior studies have not utilized combination mobilization regimens with G-CSF and the CXCR4 antagonist plerixafor as standard-of-care, which may overcome the deleterious effect of daratumumab. In this study, we investigated the stem cell yield of plerixafor-treated patients with daratumumab exposure compared to those without. Methods We conducted a retrospective study of patients with MM at our institution who underwent autologous stem cell mobilization and collection during first-line treatment over a 15-month period from 2021-2022. Following induction, patients underwent mobilization with a regimen of G-CSF for 5 days with plerixafor on the 4th day. Circulating CD34+ stem cells were enumerated on the 5th day, after which patients underwent approximately 20L apheresis with a collection goal of 5x106 CD34+ cells/kg of body weight. The primary endpoint of this study was the comparison of circulating CD34+ cells between patients who received daratumumab during induction and those who did not. Secondary endpoints included collection CD34+ yield and proportion who met the collection goal. Results 123 patients were included in the analysis. The median age was 65 (range: 34-77), 54% were male, and 84% were White. Twenty-two percent were stage I, 58% stage II, and 19% stage III by the Revised International Staging System. Forty-seven percent received daratumumab during induction. Of those, the median number of cycles administered was 4 (range: 1-5). Ninety percent received daratumumab in combination with bortezomib, lenalidomide and dexamethasone. The two cohorts were balanced in terms of age, gender, race, and exposure to lenalidomide, alkylators and radiation during induction. Patients with daratumumab exposure had a mean mobilization of 57.5 CD34+ cells/mcl compared to 96.4 for those without (p < 0.001). The mean CD34+ cell collection yield in 1 apheresis procedure was 6.0 x 106 cells/kg compared to 10.6 x 106 cells/kg (p < 0.001). Fifty-three percent of patients with daratumumab exposure met the collection goal compared to 80% of patients without (p < 0.001). Of the patients who did not meet the goal in one apheresis procedure, the majority were able to meet the goal with 1-3 additional days of apheresis (Figure 1). However, only 86% of patients with daratumumab exposure met the collection goal compared to 97% of those without (p < 0.001). Ten patients failed to collect 2.0 x 106 cells/kg, the institutional minimum for transplantation, 9 of which received daratumumab during induction. Eight were able to collect the minimum with an additional 1-3 days of apheresis; 2 patients required an additional mobilization procedure and collection but were able to proceed to transplantation. After adjusting for covariates including age, gender, race, weight, and exposure to lenalidomide, alkylators, and radiation, daratumumab exposure was associated with a 37.9 cells/mcl decrease in mean mobilization of CD34+ and 4.2 x 106 cells/kg decrease in CD34+ cell collection (both p < 0.001). Alkylator exposure was associated with a 43.3 cells/mcl decrease in mean mobilization of CD34+ (p = 0.040) and 4.1 x 106 cells/kg decrease in CD34+ cell collection (p = 0.057). Lenalidomide exposure was associated with a 103.4 cells/mcl decrease in mean mobilization of CD34+ (p <0.001) and 8.7 x 106 cells/kg decrease in CD34+ cell collection (p <0.001). Conclusion Inclusion of daratumumab in the induction regimen for transplant-eligible patients with MM resulted in a significant reduction in stem cell mobilization and stem cell yield, even with the use of plerixafor-containing mobilization regimens. This reduction was similar to alkylator exposure but less than lenalidomide exposure. With the increasing use of quadruplet induction regimens, the frequency of mobilization failure is likely to increase in the future and new mobilization regimens and approaches are needed to guarantee adequate cell yields without the need for additional days of apheresis and/or mobilizations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost-Effectiveness Analysis of Motixafortide Versus Plerixafor in Stem Cell Mobilization for Autologous Transplantation in Patients with Multiple Myeloma

Introduction: The Phase 3 GENESIS trial (NCT03246529) compared the efficacy and safety of motixafortide and granulocyte-colony stimulating factor (M+G) to placebo + G (PBO+G) for the mobilization of hematopoietic stem cells (HSCs) prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Compared with PBO+G, M+G significantly increased the proportion of patients who were able to successfully mobilize ≥6x106 CD34+ cells/kg for ASCT within 2 apheresis days (92.5% vs. 26.2%; p<0.0001). In a cost-effectiveness model (CEM) based on the GENESIS trial, M+G yielded additional quality-adjusted life years (QALYs) and cost savings relative to G alone from a United States (US) healthcare payer perspective (Lamotte et al. (2022) Value Health 25(7): S346). Plerixafor + G (P+G) is also used for HSC mobilization prior to ASCT in patients with MM. To date, M+G and P+G have not been directly compared in head-to-head trials; therefore, the relative efficacy and cost effectiveness of these therapies is currently unknown. Methods: The Bucher method was used to assess the relative efficacy of M+G in the GENESIS trial and P+G in the Phase 3 AMD-3102 trial (NCT00103662), with the PBO+G arms of both trials used as a common comparator. Risk ratios (RRs) were derived for binary trial endpoints (i.e., proportion with mobilization of ≥6x106 CD34+ cells/kg within 1-4 apheresis days, successful engraftment, use of rescue therapy, proportion who underwent ASCT, incidence of serious adverse events [SAEs]) and mean differences were derived for continuous trial endpoints (i.e., number of study drug doses received, frequency and amount of G doses, and number of apheresis sessions). The RRs were then used to update the CEM to compare the cost effectiveness of M+G and P+G from a US healthcare payer perspective over a lifetime horizon; model assumptions and sources for unit costs and quality of life scores were unchanged from the previously published CEM. Results: The mean age at baseline was 59-60 years in GENESIS and 58 years in AMD-3102; heterogeneity was observed for the mean time since diagnosis (6-7 vs. 11-12 months), prior radiotherapy (10%-11% vs. 27%-31%), and the ethnic and sex distribution of the PBO+G arms (White: 95% vs. 83%; males: 57% vs. 70%). Notably, prior lenalidomide use was markedly lower in AMD-3102 (<10%) than in GENESIS (70%), which likely contributed to the higher mobilization rates in the AMD-3102 PBO+G arm than in the GENESIS PBO+G arm. In the Bucher analysis, healthcare resource utilization (HRU) outcomes significantly favored M+G during primary mobilization, including less frequent administration of G (mean difference [MD]: -0.97; 95% CI -1.43, -0.50; p=0.0001), lower G doses (MD: -920 mcg; 95% CI -1,368, -471; p=0.0001), and fewer apheresis sessions (MD: -0.98; 95% CI -1.34, -0.63; p<0.0001) (Table 1). The proportion of patients with successful mobilization of ≥6x106 CD34+ cells/kg within 1 apheresis day was significantly greater with M+G (88.8%) than with P+G (54.2%; RR 2.97; 95% CI 1.08, 8.17; p=0.0341). Similar results were observed between groups for other outcomes, including ASCT rates (RR 1.06; 95% CI 0.93, 1.21; p=0.4124), engraftment durability by 100 days (RR 0.98; 95% CI 0.87, 1.11; p=0.7894), and SAE rate (RR 2.36; 95% CI 0.26, 21.05; p=0.4521); analyses were limited to publicly available data for P+G, and were not feasible for the use of rescue therapy because of insufficient sample size. In the cost-effectiveness analysis, M+G was dominant to P+G over a lifetime horizon, resulting in additional QALYs (+0.0358) and lower total costs (-$17,378 USD; Table 2) as per base case deterministic results. The key cost drivers were the probability of successful transplantation, long-term maintenance costs, and the time to engraftment in poor mobilizers. In a probabilistic sensitivity analysis, M+G was dominant in 66% of simulations and 92% cost effective at a WTP threshold of $50,000 per QALY. Conclusions: The results of this analysis show that the use of M+G was associated with significantly lower HRU relative to P+G for the mobilization of HSCs prior to ASCT in patients with MM, as well as significantly greater successful mobilization of ≥6x106 CD34+ cells/kg within 1 apheresis day. Cost-effectiveness analysis results showed that M+G was dominant to P+G, yielding additional QALYs and net cost savings over a lifetime horizon from a US healthcare payer perspective. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Haematopoietic Progenitor Cell Mobilisation Following Blinatumomab Therapy

Background: Our institution routinely performs autologous back-up haematopoietic progenitor cell (HPC) harvest prior to unrelated donor transplantation, particularly in the post-pandemic era, or in other circumstances if there is risk of graft failure. This practice is influenced by our relative geographical isolation and significant challenges in obtaining emergency allogeneic products. As the treatment landscape for paediatric acute lymphoblastic leukaemia (ALL) has expanded to incorporate immunotherapy, many patients proceeding to transplant receive the bispecific T-cell engager blinatumomab. Little is known about HPC mobilisation outcomes in patients following blinatumomab therapy. Here we report our experience with HPC mobilisation for autologous back-up harvest in paediatric patients with ALL treated with blinatumomab. Methods: We reviewed HPC mobilisation attempts in patients with ALL at The Children's Hospital at Westmead, Sydney, Australia from 1 January 2012 to 30 June 2022. Patients were analysed in two groups: those mobilised following blinatumomab and those mobilised following chemotherapy or from steady state. Patients were mobilised according to our institutional practice. Following chemotherapy or blinatumomab, granulocyte-colony stimulating factor (G-CSF) was given subcutaneously at a dose of 5 µg/kg/day after chemotherapy, or 10 µg/kg/day after blinatumomab or from steady state haematopoiesis. Records were assessed retrospectively for demographics, mobilisation strategy, G-CSF days, apheresis days, final HPC yield in CD34+ cells/kg, transplant characteristics, and outcomes. Successful mobilisation was defined as proceeding to apheresis and successful harvest at the patient level by achieving an HPC yield of at least 2 x 106 CD34+ cells/kg. Results: Over the 10.5 year (y) study period, 30 patients with ALL underwent 34 HPC mobilisation attempts for the purpose of autologous back-up HPC harvest prior to allogeneic transplant; 7 (23%) after blinatumomab and 23 (77%) after chemotherapy. Mobilisation and apheresis characteristics of the two groups are summarised in Table 1. There were no differences in age, weight, gender, disease status or prior exposure to radiotherapy between the blinatumomab and chemotherapy groups. Successful mobilisation was less likely in the blinatumomab group with 5/8 (63%) proceeding to apheresis vs 24/26 (92%) in the chemotherapy group, P=.037. In 29 successful mobilisations, the blinatumomab group had a lower median number of days of G-CSF (6 (range 5-7) vs 11 (3-24), P=.006), and greater utilisation of plerixafor (2/5 (40%) vs 0/24 (0%), P=.001). On day 1 of apheresis, the blinatumomab group had a lower median CD34+ count x 106/L (27 (20-32) vs 57 (13-636), P=.021) and a higher median white cell count x 109/L (37.4 (24.5-79) vs 15.6 (1.3-63.5), P=.015). Although the median total HPC yield of CD34+ cells x 106/kg was significantly lower in the blinatumomab group (2.2 (2-4.7) vs 5.6 (1.4-35.2), P=.033), there was no difference in the proportion of patients achieving the collection target of 2 x 106 CD34+ cells/kg (5/5 (100%) vs 21/23 (91%), P=.494). With a median follow up of 1.6y for the blinatumomab group and 7y for the chemotherapy group, there was no difference in 2y relapse-free (83% vs 57%, P=.310) or overall (83% vs 67%, P=.5903) survival between the groups. Of 28 patients who proceeded to transplant, 3 (11%) required autologous HPC reinfusion for secondary graft failure, 2/3 after 9/10 matched unrelated donor transplants without serotherapy, and all from the chemotherapy group. Neutrophil engraftment for these 3 patients occurred at a median of 13 days (range 11 - 14). One patient died 35 days after salvage reinfusion without achieving platelet engraftment. The 2 surviving patients achieved platelet engraftment at 18 and 29 days post reinfusion and remain alive in continuous complete remission more than 3y following HPC re-infusion. Conclusions: HPC mobilisation for autologous back-up harvest is feasible for ALL patients following blinatumomab. However, these patients are at risk of failed mobilisation and may benefit from pre-emptive strategies such as the use of plerixafor to optimise mobilisation success. Our relatively high rate of salvage reinfusion of autologous HPCs in ALL patients underlines the utility of universal back-up harvests for patients undergoing unrelated donor transplant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development and validation of a predictive model to guide the use of plerixafor in pediatric population

Plerixafor, a CXCR4 receptor antagonist, reduces the binding and chemotaxis of hematopoietic stem cells to the bone marrow stroma, resulting in predictable peak of cluster of differentiation 34+ (CD34+) cells in the peripheral blood (PB) approximately 10 h after its administration. We developed a model that could predict the CD34+ harvest volume on the first day of apheresis (AP-CD34+) based on PB-CD34+ counts immediately prior to commencing apheresis in pediatric population. In all, data from 45 pediatric patients from the MOZAIC study who received either granulocyte colony-stimulating factor (G-CSF) alone or G-CSF plus plerixafor were included. The modeling of the data exhibited a strong and highly predictive linear relationship between the counts of PB-CD34+ cells on the first day of apheresis and AP-CD34+ cells collected on the same day. It is predicted that there are approximately 13 new collected CD34+ cells for 100 new circulating CD34+ cells before apheresis. Our predictive algorithm can be used to quantify the minimal count of PB-CD34+ cells that enables to collect at least 2 × 106 or 5 × 106 AP-CD34+ cells/kg with sufficient assurance (probability = 0.90) and can guide the use of plerixafor in patients at higher perceived risk for mobilization failure. Trial registration of MOZAIC study: ClinicalTrials.gov, NCT01288573; EudraCT, 2010-019340-40.

P932: ON-DEMAND PLERIXAFOR WITH CYCLOPHOSPHAMIDE AND G-CSF FOR HEMATOPOIETIC STEM-CELL MOBILIZATION IN MULTIPLE MYELOMA PATIENTS: FINAL RESULTS OF THE MOZOBL06877 STUDY

Background: High-dose melphalan and autologous stem-cell transplant (ASCT) are pillars for the upfront treatment of ASCT-eligible newly diagnosed multiple myeloma (ND)MM patients (pts) or as salvage strategy at relapse. Failure to collect an adequate number of hematopoietic stem cells (HSC) to receive ASCT (<2×106 CD34+ cells/kg) occurs in 5%-15% of MM pts undergoing HSC mobilization with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY). Aims: We report the final results of the observational MOZOBL06877 study (NCT03406091; partially supported by Sanofi investigation funds) to prospectively assess the performance of HSC mobilization with G-CSF/CY plus on-demand CXCR4 inhibitor plerixafor (PLX) in NDMM pts treated with novel agents. Methods: NDMM pts undergoing HSC mobilization with CY (2-4 g/m2) and G-CSF (5-10 mcg/kg/day) were enrolled and observed up to 30 days after mobilization. According to its label, “on-demand” PLX was administered in pts with <20 CD34+ cells/ul after ≥4 days of G-CSF or in case <1×106 CD34+ cells/kg were collected on the first apheresis day. Pts gave written informed consent. The primary endpoint was the poor mobilizer rate, defined as the rate of pts collecting <2×106 CD34+ cells/kg or requiring PLX. Secondary endpoints were the identification of predictive factors for PLX use and safety during mobilization. Results: 301 NDMM pts were enrolled and analyzed; 72% received induction with bortezomib-thalidomide-dexamethasone, 9% a lenalidomide (Len)-based and 3% a daratumumab (Dara)-based regimen. Overall, 48 pts (16%) were poor mobilizers: 14 (5%) failed to yield ≥2×106/Kg CD34+, while 34 (11%) required rescue with PLX. Among pts yielding <2×106/Kg CD34+ cells, 4 received PLX, while 10 did not. Among pts who successfully collected ≥2×106/Kg CD34+ (n=287, 95%), 34 (12%) required PLX: 23 (68%) due to a CD34+/uL count ≤20 after ≥4 days of G-CSF and 11 (32%) to a collection <1×106/Kg after the first apheresis day. In pts mobilized with PLX, median number of CD34+×106/L cells increased from 17.5 (IQR 10.8-25.6) before PLX to 58.3 (IQR 34.2-100.2) after PLX. Median number of CD34+/Kg collected in pts who did not require PLX was 10.2×106 (IQR 8.3-13.2). In pts who required PLX, a median of 6.5×106 CD34+/Kg (IQR 4.6-9.6) was collected. An adequate HSC yield for ≥2 ASCTs (≥4×106/Kg) was obtained in 96% and 85% of pts not receiving or receiving PLX, respectively. Median number of apheresis days was 1 (IQR 1-2) in pts not requiring PLX and 2 (IQR 1-2) in pts requiring PLX. In a multivariate analysis (Table), factors predicting PLX use were advanced disease stage (R-ISS 3 vs 1-2, OR 5.5, P=0.01), bone marrow (BM) plasma cell (PC) infiltration at diagnosis (PC>60% vs ≤60%, OR 4.2, P<0.001), pre-mobilization absolute neutrophil count (ANC, < vs >2500/mmc, OR 2.8, P=0.01), and the use of Len-based (Yes vs No, OR 3.4, P=0.02) or Dara-based induction regimens (Yes vs No, OR 5.3; P=0.04). Grade 3 infections occurred in 3 pts (1%), with no grade 4-5 reported. Image:Summary/Conclusion: Among NDMM pts treated with novel-agent-based induction and undergoing HSC mobilization with CY/GCSF, “on-demand” PLX in case of low CD34+ cell count or insufficient HSC yield was a safe and effective rescue strategy, reducing mobilization failure from 16% to 5%. Predictive factors for PLX use were advanced disease stage, high BM plasmacytosis, low ANC values before mobilization and the use of Len/Dara during induction. Preemptive PLX in pts with ≥1 risk factors should be investigated to further reduce the risk of mobilization failure.

P1362: FEASIBILITY OF HAEMATOPOIETIC STEM CELL MOBILIZATION AFTER CONSOLIDATION WITH GEMTUZUMAB OZOGAMICIN AND INTERMEDIATE-DOSES ARA-C AND DAUNORUBICIN IN AML

Background: Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate Antibody is currently approved in combination with 7 + 3 in low- and intermediate risk acute myeloid leukaemia (AML). These patients are candidate for consolidation with autologous stem cell transplantation (ASCT) particularly when MRD- is obtained. GO can improve the rate of MRD negativity. There are limited data on the effect of its addition on the mobilization of Hemopoietic Stem Cells (HSC). Aims: To assess the feasibility of mobilization of HSC after re-introduction into market of GO at 3mg/m2 in 2019. Methods: We retrospectively studied AML patients undergoing 3 + 7 + GO induction and Ara-C + Daunorubicine + GO, consolidation (doses are derived from label instructions and ALFA0701 study) and mobilization on day +20 using G-CSF 10µg/kg. CD34+ were monitored, and patients were harvested when a threshold of 20 cells/µL was reached in peripheral blood. Results: In 2020 and 2021, also considering constrains caused by COVID-19 pandemics, we attempted mobilization in our 3 Italian centres of 14 patients with a diagnosis of CD33+ de novo-AML. The median age was 52 years (range 29-65 yrs.), 4 were males and 10 females; 11 patients carried a mutation of NPM1 and all had a normal karyotype except one with t(10p12;11q14) (Table 1). All received 3 + 7+GO induction and achieved a CR. Therefore, we started consolidation (total ARA-C 8g/m2) + GO as inpatient. Ten patients (71%) reached the established threshold of 20 CD34+ /µL and were successfully harvested, while 4 patients (29%) failed mobilization. The median day of apheresis was D+26 from the start to chemotherapy (range 22-39). The median number of circulating CD34+ cells on the day of collection was 35.9 cells/µL (range 20-2153 cells/µL). The median CD34+ harvested was 4.65 x 106/kg (range 1.8- 44.6 x 106/kg). In our cohort, 4 patients (28% of the entire cohort and 40% of the harvested patients) underwent ASCT, 3 achieved favourable engraftment, while in the last patient ASCT is ongoing. Several reasons prevented ASCT in the remaining 6 patients: 3 patients underwent allogeneic SCT (2 had positive MRD on harvested apheresis; 1 was reclassified as high-risk ELN2017 due to RUNX1 mutation resulting from NGS panel), 2 refused ASCT and one suffered early relapse. Image:Summary/Conclusion: In our patients, the addition of GO did not impair HSC mobilization and harvesting that was reached in about 71% of cases, similarly to the AML-10 trial of the EORTC and GIMEMA Leukemia Groups where 70% of patients were successfully harvested. Our data are particularly interesting because in the pivotal ALFA0701 study, only one patient underwent Autologous-SCT, but in the control arm. An important limit of our case-series is that only 4 patients were auto-transplanted, so we have scant data on engraftment. In particular, evaluating day to engraftment of platelets would be interesting, given the known increase of thrombocytopaenia in patients treated with GO. In conclusion, mobilization with GO is feasible and further studies are warranted to evaluate the effects of fractioned doses of GO on HSC mobilization and ASCT outcome; the ongoing trial GIMEMA AML1819 - EudraCT number 2019-003871-20 - will prospectively assess the effect of GO, but with lower doses of ARA-C (total ARA-C 6 g/m2).

The Influencing Factors for Stem Cell Apheresis in Pediatric Cancer Patients

Objective: Pediatric cancer patients comprise a fragile patient group regarding age and intensive therapy. It is known that factors like apheresis machine, characteristics of patients, primary disease, and cellular parameters before the process impact the efficacy of stem cell apheresis. In this study, we aim to evaluate the characteristic features of stem cell apheresis and the influencing factors of the process. Patients and Methods: This study involves 42 patients who received a total of 88 aphereses, between August 2012-March 2021in our pediatric stem cell transplantation unit. All of the patients received chemotherapy and GCSF for mobilization. The patients received plerixafor in case of unsuccessful mobilization. Results: For most of the patients (n= 23, 55%), targeted cell numbers could be reached on the second day of apheresis. Especially the patients with neuroblastoma and lymphoma need to have more than one apheresis. Our results indicate that median MNC and CD 34 + cell counts before the apheresis were significantly associated with successful apheresis (p&lt; 0.01 and p= 0.03 respectively). Regarding the influence of primary disease, we showed that successful apheresis was less in neuroblastoma and lymphoma compared to other pediatric cancers (p= 0.01). We reported successful apheresis with plerixafor for six patients who had unsuccessful apheresis before. Conclusion: In this study, it is shown that median MNC counts before apheresis, median CD 34 + cell counts before apheresis, and primary disease are influencing factors for successful apheresis. This study indicates that plerixafor may enhance the apheresis efficacy even in unsuccessful apheresis attempts with standard mobilization protocol. Identifying the influencing factors on apheresis for such a fragile patient population may help the procedure to be more efficient and safe for the children.

Prolonged Lenalidomide Induction Does Not Significantly Impair Stem Cell Collection in Multiple Myeloma Patients Mobilized With Cyclophosphamide or Plerixafor: A Report From The Covid Era

IntroductionInduction therapy for multiple myeloma is traditionally capped at 6 cycles of lenalidomide due to concerns that longer treatment compromises the ability to collect sufficient stem cells for autologous stem cell transplantation (ASCT). However, during the COVID-19 pandemic, many of our patients received prolonged lenalidomide induction due to concerns about proceeding to ASCT. We investigated whether prolonged induction with lenalidomide affects the efficacy of stem cell collection among patients mobilized with cyclophosphamide and/or plerixafor. Patients and methodsThis single center, retrospective study included patients who were treated with lenalidomide induction regimens, received mobilization with cyclophosphamide or plerixafor, and underwent apheresis in preparation for ASCT. 94 patients were included, 40 of whom received prolonged induction with >6 cycles of lenalidomide containing regimen. ResultsPatients who received prolonged induction were more likely to require >1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (R2 = 0.06423, P = .0148). However, there was no significant difference between patients who received prolonged induction and those who did not with respect to CD34+ stem cell yields at completion of apheresis (9.99 vs. 10.46 cells/Kg, P = .5513) or on the first day of collection (8.29 vs. 9.59 cells/Kg, P = .1788). ConclusionAmong patients treated with >6 cycles of lenalidomide, mobilization augmented with cyclophosphamide and/or plerixafor will likely facilitate sufficient stem cell harvest to permit ASCT.

Are we choosing mobilization regimens for autologous stem cell transplantation in multiple myeloma wisely: A single center comparison of GCSF+/-plerixafor vs cyclophosphamide/GCSF+/-plerixafor.

Autologous stem cell transplantation (ASCT) is a standard consolidation treatment for eligible patients with multiple myeloma (MM). There is no standardized mobilization regimen for collection of CD34+ stem cells, which is crucial to the success of ASCT. Cyclophosphamide/GCSF is an effective regimen, although reported associated toxicities include risk of febrile neutropenia (FN). Since plerixafor was introduced in Canada, this mobilization agent has been increasingly used as needed with GCSF at Kingston Health Science Centre (KHSC), with elimination of cyclophosphamide. This single center, retrospective, quality improvement study evaluates mobilization and ASCT outcomes of MM patients who had undergone stem cell mobilization at KHSC with cyclophosphamide/GCSF+/-plerixafor without antibiotics, cyclophosphamide/GCSF+/-plerixafor with antibiotics, and GCSF+/-plerixafor without antibiotics. A retrospective chart review was conducted evaluating 137 patients. The primary outcome measure was FN rates with mobilization. Balancing measures include CD34+ cell collected, plerixafor usage, days of apheresis and transplant outcomes. Chi-square, ANOVA, or Kruskal-Wallis methods were used to test statistical significance where appropriate. Our study noted a higher total and day one CD34+ count in the two groups utilizing cyclophosphamide in mobilization. All nine cases of FN occurred in these two groups (P < .05). Addition of antibiotics decreased, but did not eliminate risk of FN. There were no significant differences in the rate of plerixafor usage and number of apheresis days. Difference in transplant outcomes, including engraftment and transfusion support, were statistically but not clinically significant. A larger sample size may be needed to explore this fully. There was no significant difference in length of transplant hospital stay. The elimination of cyclophosphamide from mobilization regimens for MM appears to significantly reduce FN rates, without increasing balancing measures such as total number of apheresis days, plerixafor usage, duration of transplant hospitalization or mortality outcomes.

SIRT1-SIRT7 Expression in Patients with Lymphoproliferative Disorders Undergoing Hematopoietic Stem Cell Mobilization.

Simple SummaryOne of the treatment lines of patients with lymphoproliferative disorders is autologous transplantation, preceded by an effective mobilization of hematopoietic stem cells from the bone marrow niche into the peripheral blood. Sirtuins (SIRT1-SIRT7) are members of the NAD + -dependent class III histone deacetylase family, which affect the inflammatory response, hematopoiesis, angiogenesis, and the behavior of hematopoietic cells during mobilization and transplantation. In our work, we wanted to investigate how sirtuins expression changes on the day of the first apheresis as compared to the period before mobilization and how they can influence the efficacy of CD34+ cell collection. Our study revealed a significant increase in sirtuin expression on the day of the first apheresis as compared to the baseline. We demonstrated that the expression of SIRT5, SIRT6, and in particular SIRT7, on the day of first apheresis, may be associated with the efficacy of hematopoietic stem cell mobilization.Sirtuins are involved in the fate of hematopoietic stem cells (HSCs), including their metabolism, stress response, differentiation, migration, and apoptosis. The aim of this study was to explore SIRT1-7 expression during HSC mobilization. The study included 50 patients with lymphoproliferative disorders (39 multiple myeloma, 11 lymphoma). Samples were taken before mobilization (day 0) and on the day of first apheresis (day A). The sirtuin expression was evaluated by the Droplet Digital PCR (ddPCR) method. A significant increase of the SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7 levels measured at day A as compared to baseline was observed. The study revealed a positive correlation between SIRT5, SIRT6, and SIRT7 expression and the CD34+ peak value in peripheral blood and the number of CD34+ cells collected on day A. Patients from the SIRT7 “high expressors” group collected more CD34+ cells on day A than “low expressors”. Upregulated expressions of SIRT3 and SIRT7 on the day of first apheresis were observed in patients in complete remission status (CR) as compared to the non-CR group. Our results suggest that the investigated sirtuins may influence the HSC migration and hematopoietic landscape during mobilization. SIRT5, SIRT6, and SIRT7 may be associated with the efficacy of HSC mobilization.

High Efficacy of Stem Cell Mobilization With Etoposide+Cytarabine Plus G-CSF in Patients With Multiple Myeloma.

BackgroundEfficient mobilization of CD34+ hematopoietic stem cells plays a vital role in successful autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM), especially in cases with high-risk cytogenetic recommended for tandem ASCT. However, the optimal mobilization strategy remains a matter of debate in the era of lenalidomide. The combination of etoposide with Cytarabine plus G-CSF as a novel mobilization regimen in MM has not been reported previously.MethodsThis research retrospectively studied mobilization efficacy and safety using etoposide combined with Cytarabine (etoposide 50–100 mg/m2, qd d1–3; AraC 0.5 g/m2, q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 128 patients with MM. 70(54.7%) patients received lenalidomide-based induction regimens treatmentResultsA median of 27.75×106 CD34+ cells/kg was collected in the first apheresis, and 28.23×106 CD34+ cells/kg were collected overall. Of the 128 patients, all achieved adequate collection (≥2×106 CD34+ cells/kg), 121(94.5%) achieved optimal collection for single ASCT (≥5×106 CD34+ cells/kg), and 114(89.1%) harvested optimal collection for tandem ASCT (≥10×106 CD34+ cells/kg). In particular, the target yield of optimal collection for tandem ASCT was reached in 82.8% (106/128) by a single apheresis procedure. 14 patients obtained deeper response post mobilization. In multivariate analysis, cycles of prior chemotherapy independently affected the optimal achievement of CD34+ cells (p=0.004, OR 0.695, 95% CI 0.544~0.888). Previous lenalidomide exposure did not significantly impair CD34+ cells collection. Although 68% episodes of antibiotic usage were observed, no severe infection or treatment-related mortality occurred.ConclusionStem cell mobilization with Etoposide + Cytarabine plus G-CSF was highly efficient and safe in patients with MM, which could be considered in high-risk MM patients who were referred for tandem ASCT.

Addition of bortezomib to high-dose cyclophosphamide therapy as a conditioning regimen for autologous peripheral blood stem cell harvest leads to an increased yield of hematopoietic stem cells.

Peripheral blood stem cell harvest (PBSCH) is a crucial procedure for autologous stem cell transplantation in patients with multiple myeloma. We herein report a retrospective study to verify the usefulness of bortezomib and high-dose cyclophosphamide therapy (Bor-HDCY) as a conditioning regimen for PBSCH. Thirty-three patients were evaluated. The median age at the first apheresis was 61 (interquartile range, 53-64) years old, and 18 (54.5%) patients were male. Bor-HDCY was performed in 15 patients, and HDCY was performed in 18. In the patients who underwent Bor-HDCY, the CD34+ cell count at the first apheresis was significantly higher than in the others (P<0.01), and the total CD34+ cell count also tended to be high (P=0.0933). In terms of apheresis days, two-thirds of the patients who underwent HDCY had two-day apheresis, whereas most who underwent Bor-HDCY had one-day apheresis. According to univariate analysis, Bor-HDCY (P<0.01), VRd (Bor, lenalidomide, and dexamethasone) as induction therapy (P=0.0529), and ≥VGPR before PBSCH (P=0.0767) were factors associated with a higher CD34+ cell count at first apheresis. Although multivariate analysis showed that there were no independently significant factors influencing the CD34+ cell count at the first apheresis, the stepwise selection method revealed that only the Bor-HDCY regimen remained in the final model (P<0.005). Bor-HDCY may be a useful conditioning regimen for increasing the CD34+ cell yield.