Greiner, Carl

AbstractBackgroundSince FDA approval in 2017, CAR‐T therapy has seen rapid clinical adoption. Shifting clinical trends have emerged with increasing utilization of CAR‐T therapies and a downward trend in HSCTs. Given the overlapping resources required for the manufacture and storage of these products, we sought to examine trends over a 6‐year period.MethodsThe apheresis patient database and Lab database were reviewed to compile a list of patients that underwent either CAR‐T or HSCT (autologous) collections, and/or received CAR‐T or autologous HSCT infusions between January 1, 2018 and December 12, 2023. This was further examined by year and disease group.ResultsThe total number of patients collecting for CAR‐T increased from 52 in 2018 to 150 in 2023 (slope = 21.97; p = .0013), accompanied by a decrease in the number of patients collecting for HSCT, from 425 in 2018 to 341 in 2023 (slope = −21.2; p = .0177). Neither total number (calculated as number of HSCT + CAR‐T) of patients collected (mean 476 + 20.4 per year), nor collection procedures (mean 972 ± 75.8 per year) changed significantly over the 6‐year period. The total number of CAR‐T infusions increased from 24 in 2018 to 111 in 2023 (slope = 17.7; p = .004), with a decrease in auto‐HSCT from 400 to 289 (slope = −28.7; p = .008). The overall number of infusions (calculated as number of HSCT + CAR‐T) did not change significantly (slope = −10.9; p = .13) over the 6‐year period.DiscussionOur findings confirm the increasing adoption of CAR‐T therapy occurring alongside a decreasing stem‐cell transplants, with stable overall resource utilization.

Background: Upfront autologous stem cell transplant (ASCT) is the standard-of-care for newly diagnosed multiple myeloma (MM) patients. However, relapse and the development of therapy-related myeloid neoplasms (t-MN) post ASCT results in considerable morbidity and mortality. We hypothesized that enrichment of abnormal myeloid progenitors and immune effector cells (IEC) in peripheral blood stem cells (PBSCs) of patients with MM is associated with a higher risk of relapse and development of t-MN. Methods: After institutional review board approval, we screened patients with active MM that were evaluated at Mayo Clinic, Rochester, MN between 01/01/2003 and 12/31/2020. Patients that underwent an ASCT and had cryopreserved PBSC product available for research were included. Using mass cytometry, we performed a comprehensive immunophenotyping of mobilized cryopreserved PBSCs from 54 MM patients undergoing 1 st ASCT, using validated antibody panel of 37 lymphoid- and myeloid-based markers each. Flow cytometry standard files were normalized and concatenated using the Fluidigm acquisition software. Flow cytometry standard files were uploaded to the OMIQ software from Dotmatics (www.omiq.ai, www.dotmatics.com), where transformation and cleaning (doublets, debris) were performed. To correct for between-sample technical variations (“batch effects”), we used fdaNorm within the omiq.ai platform. Clustering and visualization of normalized and concatenaded flowcytometry files were performed within the omiq.ai platform using PhenoGraph and UMAP, respectively. We performed principal component analysis (PCA) to identify major immunomic drivers of variability across patients. We explored the associations between immune subsets and the dichotomized clinical outcomes of interest: progression-free (PFS), myeloid neoplasm-free (MNFS) and overall survival (OS) from ASCT. A 2-sided false discovery rate adjusted P-value of <0.05 was considered significant when multiple comparisons were performed; otherwise, a P-value of <0.05 was considered significant. Results: The most abundant cell populations were T-cells (49% of the CD45 +) and myeloid cells (43% of the CD45 + cells). Clustering on the CD45 + cells revealed 30 unique lymphoid clusters and 27 unique myeloid clusters. Subclustering on NK-cells identified an additional 16 NK-cell clusters. On PCA, principal components-1 (PC-1) and 2 (PC-2) explained 15.2% and 12.5% of the variability in the data, respectively. A high PC-2 score was associated with inferior median PFS (20 vs. 52 months; P=0.005, Figure 1A), MNFS (52 vs. 85 months, P=0.03, Figure 1B) and OS (64 vs. 106 months, P=0.01) from ASCT. Immune subsets enriched in the high PC-2 cohort included the ‘NKT-like’ (CD56 +) T-cell subset which expressed the inhibitory CD159a receptor and TIGIT; a terminally differentiated (CD27/CD28 -, CD57/KLRG1 +) and exhausted (TIGIT/PD-1 +) T cell subset, 2 exhausted (TIGIT/PD-1 +) T cell subsets; an immunosenescent (CD27/CD28 -, CD57/KLRG1 +) T cell subset as well as a terminally exhausted (C27/C28 -, KLRG1/PD-1/TIGIT +) TCRgamma-delta subset. Immune subsets with high loadings within PC-1 (associated with improved clinical outcomes) consisted exclusively of CD4 + cells with early memory phenotypes (CD27/CD28/CD127 +). Abnormal expression of CD7 and HLA-DR expression on myeloid progenitor cell subsets was associated with an inferior PFS, MNFS, and OS. A NK-cell subcluster, characterized by an immature (CD56 high), inhibitory (CD159a +, NKG2A) phenotype, was enriched in patients developing t-MN (0.33% vs. 0.17%, P=0.006). Conclusion: We identify abnormal myeloid and immune effector cells in the PBSCs of patients with MM, even prior to ASCT. Patients with a PBSC product that is enriched in immunosuppressive T and myeloid cell subsets, and with a lower proportion of antigen presenting cells, progenitor populations, and anti-tumor macrophages have a shorter PFS and MNFS. This suggests that the predisposition to t-MN and inferior outcomes for MM are possibly determined early in the disease course. These findings need external validation and have the potential to guide sequencing of future treatment modalities.

Abstract Introduction: Peripheral blood hematopoietic progenitor cell collection is a more popular source of stem cells for transplantation than bone marrow harvest. A number of automated cell separators exist which can be used to perform mononuclear cell collections. These separators collect varying amounts of other cells during the collection process, including them in the mononuclear cell product. Because of this, collection of mononuclear cells can result in significant reductions in platelet count and loss of red blood cells during the procedure. In order to minimize platelet transfusion support, we developed an algorithm to optimize mononuclear cell collections while minimizing platelet losses using the Gambro COBE Spectra and the Baxter Amicus Methods: Previously, patients were assigned randomly to any available apheresis machine. Starting August 2nd 2002, patients with a WBC count higher than 35×10 (9)/L were preferably assigned to Amicus for 5 hour collection with processing 1000 ml/cycle or as second choice Spectra for 5 hours run with maximum draw rate 65 ml/Min., for both instruments. If the WBC was lower than 35×10 (9)/L, the preferred machine would be Amicus for 5 hours run at 1400 ml/cycle with maximum draw rate 90ml/Min. or Spectra for 5 hours run with maximum draw 100 ml/Min. We reviewed the difference of pre and post procedure platelet counts of non Hodgkin’s Lymphoma patients undergoing stem cells collection for 6 months before and after the implementation of the above protocol from February 2002 till February 2003. All CBC were performed on the same Coulter analyzer. Results: 14 patients (2 on Amicus and 12 on Spectra) underwent stem cells collection before August 2nd, 2002. 13 patients (8 on Amicus and 5 on Spectra) were collected after this date. The Fisher’s exact test was used for this study. The median and mean differences in the first group were 141.5 ×10(9)/L and 135 ×10 (9)/L respectively (95% CI, p 0.0183). The second group had a median and mean of 45 ×10 (9)/L and 51 × 10(9)/L (95% I, p 0.0183). The minimum and maximum differences were 36 × 10(9)/L and 200 × 10(9)/L respectively in the first group and −19 ×10(9)/L and 121×10(9)/L for the second group. There was no difference in the numbers of the collections days in both groups in regard to the type of automated cell collector. Discussion: The implemented algorithm showed a net advantage. Even though none of the patients required blood transfusions, there was lesser drop of platelets counts with the new settings.

Abstract Abstract 4228 Background Peripheral blood stem cells (PBSC) are the preferred graft type for autologous stem cell transplantation (ASCT) and mobilization is typically done using growth factor (GF) alone or a combination of chemotherapy (CTX) and GF. The success of mobilization is influenced by several factors such as prior therapy, mobilization strategy, underlying disease, among others. Patients (Pts) failing to mobilize successfully often have GF dose increased and if unsuccessful, mobilization is reattempted with chemotherapy + GF or G-CSF (Granulocyte Colony-Stimulating factor) + GM-CSF (Granulocyte–Macrophage Colony-Stimulating factor). More recently, plerixafor, a CXCR4 inhibitor, has been found to enhance G-CSF based collection allowing potential early intervention in poor mobilizers. However, this approach requires valid cut-points for peripheral CD34 counts (pCD34) for cost efficient use. Methods We studied 656 first time, G-CSF based PBSC mobilizers with Non-Hodgkin Lymphoma (562; 86%), or Hodgkin's Disease (94; 14%). Salvage attempts were excluded, as were first attempts using CTX+GCSF, plerixafor or GF combinations. Sensitivity-specificity analysis (Receiver operating characteristic) was used to define ideal cut-points for predefined outcomes. We used a CD34 yield of 2 million/kg as the minimum required collection and 5 million/kg as the ideal collection for the current analysis. Our current practice is to initiate collection at a pCD34 of 10/uL. Results We first determined the best day 1 pCD34 cutoff for being able to collect at least 2 million/kg PBSC to be 9/uL. Among those with ≥9/uL, only 6.6 % failed to collect at least 2 million compared to 55% among the rest (P < 0.001). These numbers were 6.3% and 50% respectively using the traditional cutoff of 10/uL. We then examined how the pCD34 on day 2 predicted collection, among those failing to reach the current threshold of 10/uL. Among this group, a pCD34 on day 2 of 9.1/uL was the best cutoff to predict a collection of 2 million/kg. Among those with >=9.1/uL, only 22% failed to collect at least 2 million compared to 79% among the rest (P < 0.001). Among those with day 1 pCD34 < 10, 49% achieved a count of 9.1/uL on day 2. We then examined what pCD34 on day 1 can best predict a pCD34 ≥ 9.1 on day 2 and found this to be 5.2/uL. Among those with day 1 pCD34 ≥ 5.2/uL, 79% reached day 2 pCD34 ≥ 9.1 compared to 24% among the rest (P < 0.001). We then determined cutoffs based on ideal targets using only those patients achieving pCD34 count > 10/uL by day 2, since these patients would have started collection without any change in the mobilization technique. We used a maximum of 5 collections to achieve the goal as being ideal, taking into account the most commonly used practice of collecting during weekdays. We examined cutoffs for a target of 5 million/kg for one transplant. The best day 1 or day 2 pCD34 predicting a 5 million/kg yield in 5 collections was 17/uL. Among those with day 1or 2 pCD34 ≥ 17/uL, 4% failed to reach 5 million in ≤ 5 days compared to 96% among the rest (P < 0.001). Conclusions This study provides an estimate of optimal pCD34 count thresholds for early identification of patients with lymphoma at high risk of collection failure. It is reasonable to use the first or second day pCD34 count, since a substantial proportion of patients will achieve the threshold value by day 2 and these patients appear to have similar outcome as those reaching the threshold by day 1. Based on the results here, interventions such as addition of plerixafor can be considered if pCD34 count is < 6/uL on day 1 or < 10/uL by day 2, to achieve the minimum collection of 2 million/kg. However, in order to achieve the ideal targets, a higher threshold should be considered and the recommendation based on the current study would be 17/uL for a target of 5 million. Such a target-adapted strategy may be more appropriate. Disclosures: Kumar: Celgene,Genzyme,Millenium,Novartis,Bayer,: Honoraria, Research Funding. Gertz:Genzyme: Research Funding. Micallef:Genzyme: Research Funding.

Abstract Abstract 3231 Poster Board III-168 Background Peripheral blood stem cells (PBSC) are the preferred graft type for autologous stem cell transplantation (ASCT) and mobilization is typically done using growth factor (GF) alone or a combination of chemotherapy (CTX) and GF. The success of mobilization is influenced by several factors such as prior therapy and mobilization strategy. Patients (Pts) failing to mobilize successfully often have GF dose increased and if unsuccessful, mobilization reattempted with chemotherapy + GF or G-CSF (Granulocyte Colony-Stimulating Factor) + GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor). More recently, plerixafor, a CXCR4 inhibitor, has been found to enhance G-CSF based collection allowing potential early intervention in poor mobilizers. However, this approach requires valid cut-points for peripheral CD34 counts (pCD34) for cost efficient use. Methods We studied 910 first time, G-CSF based PBSC mobilizers with MM (565; 62%), or light chain amyloidosis (345; 38%). Salvage attempts were excluded, as were first attempts using CTX+GCSF, plerixafor or GF combinations. Sensitivity-specificity analysis (ROC) was used to define ideal cut-points for predefined outcomes. We used a CD34 yield of 2 million/kg as the minimum required collection and 4 million/kg as the ideal collection for this analysis. Our current practice is to initiate collection at a pCD34 of 10/uL. Results We first determined the best day 1 pCD34 cutoff for being able to collect at least 2 million/kg PBSC to be 9.2/uL. Among those with ≥9.2/uL, only 1.6% failed to collect at least 2 million compared to 27% among the rest (P < 0.001). These numbers were 1.7% and 25% respectively using the traditional cutoff of 10/uL. We then examined how the pCD34 on day 2 predicted collection, among those failing to reach the current threshold of 10/uL. Among this group, a pCD34 on day 2 of 8/uL was the best cutoff to predict a collection of 2 million/kg. Among those with >8/uL, only 9% failed to collect at least 2 million compared to 48% among the rest (P < 0.001). Among those with day 1 pCD34 < 10, 65% achieved a count of 8/uL on day 2. We then examined what pCD34 on day 1 can best predict a pCD34 ≥ 8 on day 2 and found this to be 5/uL. Among those with day 1 pCD34 ≥ 5/uL, 92% reached day 2 pCD34 ≥ 8 compared to 36% among the rest (P < 0.001).We then determined cutoffs based on ideal targets using only those patients achieving pCD34 count > 10/uL by day 2, since these patients would have started collection without any change in the mobilization technique. We used a maximum of 5 collections to achieve the goal as being ideal, taking into account the most commonly used practice of collecting during weekdays. We examined cutoffs both for a target of 4, 8 and 12 million/kg for one, two or three transplants respectively. Among those with a day 1 or day 2 pCD34 > 10/uL 98% collected 4 million/kg in 5 collections. The best day 1 or day 2 pCD34 predicting a 8 million/kg yield in 5 collections was 21.4/uL and a 12 million/kg yield was 27.9/uL. Among those with day 1or 2 pCD34 ≥ 21.4/uL, 90% collected 8 million compared to 54% among those with pCD34 < 21.4/uL. Similarly, among those with day 1 or 2 pCD34 ≥ 27.9/uL, 79% reached 12 million in ≤ 5 days compared to 17% among those with pCD34 < 27.9/uL (P < 0.001).Finally we examined if poor collection on first day, despite a pCD34 > 10 predicts for poor overall yield. A ratio of day 1 collection (million/kg) to pCD34 day 1 or 2 < 5×104 was highly predictive of failure to get eventual yield of 2 million/kg, with 38% below the cutoff failing to reach the goal compared to 2% for those above the cutoff. Conclusions This study provides an estimate of optimal pCD34 count thresholds for early identification of patients at high risk of collection failure. It is reasonable to use the first or second day pCD34 count, since a substantial proportion of patients will achieve the threshold value by day 2 and have similar outcome as those reaching the threshold by day 1. Based on the results here, interventions such as plerixafor can be considered if pCD34 count is < 5/uL on day 1 or < 9/uL by day 2, to achieve the minimum collection of 2 million/kg. However, in order to achieve the ideal targets, a higher threshold should be considered and the recommendation would be 17/uL, and 28/uL for target of 8 or 12 million respectively. Finally, identification of poor mobilizers after start of collection potentially provides another time point for early intervention, and this needs to be prospectively studied. Disclosures Micallef: Genzyme: Research Funding. Gertz:Genzyme: Research Funding. Kumar:Celgene,Genzyme,Millenium,Novartis,Bayer,: Honoraria, Research Funding.

Abstract Abstract 1178 Poster Board I-200 Background: High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has been shown to be of value in selected patients with malignant lymphoma and multiple myeloma (MM). Both granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF) are widely used following stem cell transplantation to support accelerated myeloid recovery and potentially shorten hospital stay. In the recent years, PBSCT is increasingly done in an ambulatory care setting and it is not clear if routine growth factor use has any potential benefit. We undertook this study to compare engraftment kinetics, incidence of febrile episodes, hospitalization duration and other outcomes among transplants done with or without growth factor support Patients and Methods: We included adult patients undergoing PBSCT for myeloma and lymphoma between May 2007 and June 2009 in an ambulatory care setting. Prior to April 2008 (Group-1) all patients received GMCSF 500 mcg/ day starting on day 6 routinely. Since April 2008, there was a shift in clinical practice and routine use of GMCSF was discontinued due to lack of clear evidence regarding benefit. Patients transplanted between April 2008 and June 2009 did not routinely receive GMCSF (Group-2). Typical conditioning regimen for lymphoma was BEAM (BCNU, Etoposide, Cytosine Arabinose, Melphalan) and for multiple myeloma was melphalan 200mg/m2. Patients' demographics details, indication for PBSCT, duration of neutropenic fever, hospital stay, and neutrophil and platelet engraftment were collected from electronic medical records. Neutrophil engraftment is defined as the first day of 2 consecutive days when ANC was > 0.5 × 109/L and platelet engraftment is defined as first of 7 consecutive days on which patient's unsupported platelet count was greater than 20× 109/L. Results: A total of 309 were included in this study, 126 (40%) patients in group-1 (69 with MM, 57 with lymphoma) and 183 (60%) in group-2 (100 with MM, 83 with lymphoma). In group-1, 73 (58%) and in group-2 130 (71%) were male patients. Median age was 59 (29-74) years in group 1 and 58 (24-76) years in group-2. Patients in group 1 received a median of 3.65 (1.1-8.7) versus 4.37 (1.1-9.54) CD34+ x106/kg in group 2 (P =0.005). Median time to neutrophil engraftment was 12 (95% CI 12, 12) for group-1 and 14 (95% CI; 13-14) for group-2 (Kaplan Meier analysis; log rank P < 0.0001). Median estimated time to platelet engraftment was 14 days (95% CI; 13, 15) for group 1 and 13 days (95% CI; 13-13) for group 2 (Kaplan Meier analysis; log rank P 0.007). In group-1 98 (78%) patients developed febrile episodes compared to 117(64%) in group-2 (P = 0.009). Median duration of fever was 2 days (range, 1-8) in group-1 compared to 1 day (range, 1-8) in group-2 (P = 0.0003). The median (range) duration of hospital stay was 7 (1-40) days for group-1 compared to 8 (2-56) days for group-2 (P=NS). There was no significant difference in mortality between these two groups. Conclusion: Routine use of granulocyte growth factors is associated with a shorter time to neutrophil engraftment, but associated with a delay in platelet engraftment. The longer time to neutrophil engraftment without growth factor use does not translate into any increase in frequency of febrile episodes. On the contrary, higher number of febrile days is seen with use of growth factors, likely explained on the basis of drug fever. No difference in the frequency of engraftment syndrome or treatment related mortality was seen. Disclosures: No relevant conflicts of interest to declare.

BackgroundThe use of hematopoietic progenitor cell (HPC) transplant has risen over the past two decades. A variety of adverse events (AEs) of varying severity have been noted during HPC infusions. These AEs have been associated with several factors such as the amount of dimethyl sulfoxide and white blood cells in the HPC product. We performed a single‐institution retrospective analysis to determine the effect of two different HPC infusion techniques, manual push with syringes versus infusion from bags with the aid of gravity, on the occurrence of infusion‐related AEs.Study Design and MethodsInfusions between December 2008 and November 2010 involving peripheral blood HPCs were reviewed. Pertinent clinical and HPC product–related information was recorded. Data were analyzed to determine the incidence of infusion‐related AEs and its association with patient and product‐related variables.ResultsWe found 461 AEs in 645 patients during the study period. A total of 325 (50%) experienced at least one AE. Flushing was the most common type of AE followed by nausea and hypertension. The use of syringe infusion was more commonly associated with AEs (odds ratio, 1.82 [95% confidence interval, 1.32‐2.50]; p = 0.002). Other independent risk factors were cryopreserved products and the amount of polymorphonuclear leukocytes in the product.ConclusionTo our knowledge, this is the first study examining the effect of two different infusion techniques on infusion‐related AEs. Our findings suggest that the use of bags for infusion protected the patients from AEs.