Infusion Of Peripheral Blood Stem Cells Research Articles

Trial in Progress: A Phase 1 Umbrella Study of TCR-Engineered T Cells That Target HA-1 (TSC-100) and HA-2 (TSC-101) to Treat Residual Leukemia after Hematopoietic Cell Transplantation

Background: Engineered T cell therapies targeting the lineage-specific antigens CD19 (B cells) or BCMA (plasma cells) are highly effective in patients with lymphoid malignancies and feasible because depleting normal B cells or plasma cells can be tolerated by patients. Targeting lineage antigens in myeloid malignancies is not feasible, however, since depleting normal myeloid cells like neutrophils would lead to serious complications such as febrile neutropenia. To address myeloid malignancies with T cell therapies, one solution is to target antigens that are expressed on the hematopoietic cells of patients undergoing allogeneic hematopoietic cell transplantation (HCT), but not expressed on their donor's cells. Hematopoietic lineage-specific minor histocompatibility antigens (MiHAs) can be targeted by T cell receptors (TCRs), but not chimeric antigen receptors, because they most frequently represent single-amino acid changes in intracellular proteins that are presented on the cell surface by human leukocyte antigen (HLA) binding. TScan has developed the engineered T cell products TSC-100 and TSC-101 that express TCRs targeting MiHAs HA-1 and HA-2 respectively, both presented by HLA-A*02:01. By choosing HCT patients who are HA-1 or HA-2 positive and donors who are mismatched on either the MiHA or HLA-A*02:01, TSC-100 and TSC-101 can eliminate all recipient hematopoietic cells while leaving donor hematopoietic cells untouched. These products are being developed in patients with AML, ALL and MDS undergoing HCT to eliminate any residual hematopoietic cells after HCT and prevent disease relapse that affect ~40% of patients. We describe the clinical trial design and translational assays to generate early evidence of biological activity. Preliminary clinical safety and translational data will be presented. Study Design and Methods: Study NCT05473910 is a multi-center, multi-arm, non-randomized controlled Phase 1 umbrella study evaluating the feasibility, safety and preliminary efficacy of TSC-100 and TSC-101. Key inclusion criteria include adult patients with AML, MDS or ALL who are eligible for reduced intensity conditioning (RIC)-based haploidentical donor transplantation. HLA-A*02:01-positive patients are assigned to the treatment arms, undergo HA-1/ HA-2 testing and receive either TSC-100 or TSC-101 in addition to standard HCT. HLA-A*02:01-negative patients are assigned to the control arm and receive standard HCT alone. Donors in treatment arms undergo two rounds of leukapheresis, one to manufacture TSC-100/101 and one after mobilization to collect stem cells. Patients undergo RIC, peripheral blood stem cell infusion followed by post-transplant cyclophosphamide. Upon count recovery, patients begin treatment with TSC-100 or TSC-101. In Dose Level 1, patients receive a single dose of 5x106 cells/kg. In Dose Level 2, patients receive two doses of 5x106 cells/kg given 40 days apart. In Dose Level 3, patients receive one dose of 5x106 cells/kg and asecond dose of 2x107 cells/kg given 40 days later. Primary endpoints include adverse event profiles of TSC-100/ 101 and dose limiting toxicities. Secondary endpoints measure efficacy including relapse rates, disease-free survival and overall survival. Exploratory endpoints include persistence of TSC-100/ TSC-101, surrogates of efficacy including minimal residual disease (MRD) rates before/ after transplantation, donor chimerism kinetics and rates post-transplantation and markers of T cell activation on TSC-100/ 101. Novel translational assays have been developed for the exploratory endpoints. TSC-100/ 101 persistence is measured by flow cytometry with lower limit of quantification <0.1% of total T cells. MRD is measured by flow cytometry and next-generation sequencing (NGS) the combination of which detects MRD with greater sensitivity than either assay alone. Donor chimerism is measured by standard STR-based assays with a limit of detection of 1-2% and a novel NGS-based assay called Alloheme with a limit of detection of 0.04%. T-cell activation markers on TSC-100/ 101 are measured by flow cytometry, cytokine profiling and single-cell RNA sequencing. Together these translational assays measure elimination of the target hematopoietic cell population, malignant or normal, and provide evidence of potential biological activity well before frank clinical relapses occur. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Non-cryopreserved peripheral blood stem cells as a safe and effective alternative for autologous transplantation in multiple myeloma.

Autologous stem cell transplantation is the standard procedure for multiple myeloma and the grafts are usually cryopreserved. Previous studies reported advantages in the use of fresh peripheral blood stem cells (PBSC) autotransplantation compared to cryopreservation of the grafts. This study compared the transplant-related outcomes of two graft preservation methods: fresh storage (4°C/72 h) and cryopreservation (-80°C). We performed an analysis of 45 patients with multiple myeloma under autotransplantation (17 fresh and 28 cryopreserved) from 2017 to 2021. Fresh PBSC were maintained in the refrigerator for three days in a concentration up to 300 × 103 TNC/μL. Cryopreserved PBSC were concentrated by plasma reduction after centrifugation (950 g/10min/4°C) and an equal volume of cryoprotection solution was added for a final concentration of 300 × 103 TNC/μL, 5% DMSO, 6% hydroxyethyl starch, and 3% human albumin. Neutrophil engraftment was significantly faster with fresh PBSCs (10 vs. 11.5 days, p=0.045). Adverse effects were more common in cryopreserved PBSC transplantation (75% vs. 35.3% patients; p=0.013). Post transplantation hospital stay was 20 and 22 days for fresh and cryopreserved PBSCs respectively (p=0.091). There was no difference in platelet engraftment time (10.5 days for both; p=0.133), number of antibiotics used after transplantation (3 for fresh and 2.5 for cryopreserved; p=0.828), days of antibiotic use after transplantation (12.2 days for fresh and 13.3 days for cryopreserved, p=0.579), and overall survival (p=0.736). The infusion of fresh PBSC refrigerated for up to three days is effective and safe for autologous transplantation in patients with multiple myeloma, which is a useful alternative to cryopreserved PBSC.

IMG-12. Transient atypical brain and spine MRI features after high-dose chemotherapy may represent clumps of CD34+ hematopoietic stem cells

Abstract High-dose chemotherapy is a therapeutic option in selected cases of pediatric high-grade brain tumor (pHGBT). Following high-dose chemotherapy, bone marrow is reconstituted by means of CD34+ peripheral blood stem cell (PBSC) infusion. Intravenously injected PBSCs have been reported to migrate to the Central Nervous System (CNS) and to persist for weeks. We report two cases of pHGBT in which, following PBSC infusion, we observed peculiar brain MRI signal alterations suggestive of clumps of CD34+ cells. A 15-month-old female underwent surgery and chemotherapy for an infratentorial, non-disseminated, Atypical Teratoid Rhabdoid Tumor. Following the second course of high-dose chemotherapy, MRI excluded residual disease, but revealed two contrast-enhancing nodules in the supratentorial ventricular system, with no evidence of diffusion restriction, unlike the primary tumor. Cerebrospinal fluid was collected by means of lumbar puncture and centrifuged: no neoplastic cells were found, while a few cells were positive when immunostained with anti-CD34 antibody. As no disease progression was documented, the patient completed her treatment with focal radiotherapy. Three months after the end of therapy, MRI showed new enhancing nodules with restricted diffusion, in keeping with leptomeningeal spread of disease; these progressively increased in size, despite subsequent lines of treatment, while the above-mentioned ventricular nodules shrank. Similar transient alterations were detected in a 4-year-old boy who had received treatment for high-risk Medulloblastoma, including high-dose chemotherapy. CONCLUSIONS: In the setting of new enhancing brain and spine findings with atypical MRI features, after high-dose chemotherapy to treat pHGBT, the hypothesis of CNS homing of CD34+ hematopoietic stem cells should be considered in the differential diagnosis.

Influence of Pretransplant Anemia on Red Blood Cell Transfusions in Myeloma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation

Background and Objectives: Anemia during peripheral blood stem cells (PBSCs) transplant is considered a bad prognostic marker. The study aimed to determine whether pretransplant anemia influence peritransplant transfusion requirements in myeloma patients. Methods: Myeloma patients planned for PBSC transplant were stratified based on hemoglobin levels at time of mobilization, PBSC collection, and PBSC infusion. Univariate and multivariate analysis was performed to study the predictors for good mobilization, adequate CD34 yield by apheresis, and red blood cell (RBC) transfusion in the peritransplant period. Results: Of 67 patients, the prevalence of anemia at mobilization, PBSC collection, and PBSC infusion was 37%, 58%, and 70%, respectively. Eighty-five percent had good mobilization with peripheral blood CD34 count of 50 cells/μl (8–123) and 81% had adequate CD34 yield with first apheresis. Thirty-two percent patients received peritransplant RBC transfusion with the median of one unit (range: 0–5). Anemia on the day of infusion did influence the RBC transfusions in the peritransplant period (P = 0.03). Conclusion: One third of myeloma patients require RBC transfusion support in the peritransplant period. We identified pretransplant anemia neither influenced mobilization nor PBSC collection but increased the risk for RBC transfusion in the peritransplant period.

Validation and Implementation of the Use of Peripherally Inserted Central Catheter (PICC) for the Administration of Peripheral Blood Stem Cells (PBSC): A Single-Institution Experience

Background:Infusion of peripheral blood stem cell (PBSC) in patients undergoing autologous transplantation (ASCT) has been conventionally performed using central venous catheters (CVC) inserted through the subclavian or internal jugular vein. Peripheral inserted central catheters (PICC) are routinely used for infusion of blood products and medication, but its use for PBSC infusion has not been well established. Our study aimed to evaluate the feasibility and safety of using PICC to deliver PBSC for ASCT through an in-vitro lab-based validation process, followed by a clinical review.Methods: •Lab based validationIn vitro infusion of 6 cryopreserved PBSCs was performed, 3 infused PICC whist 3 via CVC. Each product was thawed for the same amount of time and drained by gravity. Pre-infusion and post-infusion total nucleated cell counts (TNC), CD34 counts and CD34 viability of the PBSCs were analysed by flow-cytometry and compared using paired T test. In vitro infusion rates were also compared between PICC and CVC groups. •Clinical Outcome AnalysisThe clinical study included 31 patients (Lymphoma N=21, myeloma N=5, Others, N=4) who underwent ASCT at National University Cancer Institute, Singapore (NCIS) from September 2019 to July 2021. All patients had a 19G BARDS dual lumen PICC inserted in either the brachial or basilic veins and used for PBSC infusion. The PBSC infusion rate, infusion associated complications, time to absolute neutrophil count (ANC) >1, and platelet count engraftment >100K were analysed.Clinical outcomes in the lymphoma cohort, who received BEAM conditioning (N=17) were also compared with a control group, matched for conditioning, cell dose and age, who had PBSC infused via CVC.Results: •In vitro findings:Overall flow rates for infusion through PICC was slower (mean 0.1mls/s vs 0.3mls/s, p < 0.05). However, there were no significant % differences in TNC counts (5% vs 9%, p=0.4), CD34 counts (17% vs 15%, p=0.9) and viability (4% vs 7%, p=0.2) between pre and post infusion samples for PICC and CVC.. •Clinical findings:30 patients (Lymphoma N=21, myeloma N=5, N=4) were included. 15 (50% of patients) had a for ASCT while 15 (50%) had an existing PICC. For patients with an existing PICC, the median duration of catheter in situ was 86 days. New lines were inserted 2-7 days prior to the PBSC infusion. The median age of the patients was 54 (20-71) with 19 males (63%). . There were 5 infusion related complications, 2 in an existing PICC and 3 in new PICCs. 4 were related to slow flow rate and 1 was related to sediments seen in the line. None led to a need for alternative line for infusion. The median time to ANC recovery was 10 (range 9-14), 10 (range 9-11) and 11 days (range 10-12), while the median time to platelet engraftment was 18 (range 10-195), 20 (range 15-55) and 22 (16-85 days) for the lymphoma BEAM conditioning (N=17), lymphoma Carmustine/ Thiotepa conditioning (N=4), and the myeloma (N=5) cohorts respectively.Clinical outcomes in the lymphoma cohort, who also compared with a control group matched for conditioning, cell dose and conditioning. The in-vivo infusion rate was slower in the PICC group, compared to the CVC group (3.1 mls/min vs 4.5mls/min, p<0.05).There was however no differences in engraftment with median time to ANC recovery 10 days (range 9-14) vs 11 days (range 9-13) (p>0.05) and median time to platelet engraftment 18 (range 14-195) vs 19 days (range 14 -57) (p>0.05) in the PICC vs CVC groups respectively.Conclusion:Our in-vitro and clinical findings confirmed that the use of PICC for PBSC infusion is safe and efficacious and reduces the need for CVC insertion. Our findings have led to change in clinical practice with utilization of PICCs for PBSC infusions for ASCT. DisclosuresNo relevant conflicts of interest to declare.

Bortezomib Consolidation after Nonmyeloablative Allogeneic Transplant Is Safe and Leads to a High Incidence of Immunophenotypic Complete Response in High-Risk or Young Myeloma Patients

▪Introduction: Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for newly diagnosed multiple myeloma (NDMM) patients but is hampered by a high incidence of relapse and chronic graft-versus-host disease (cGVHD). We hypothesized that bortezomib (BTZ) in consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could decrease the incidence of cGVHD while improving quality of response.Method: NDMM patients ≤65 years with high-risk (HR) disease (defined as HR cytogenetics [del17p, t(4;14), t(14;16), t(14;20), del1p or gain 1q], ISS 3 or plasma cell leukemia) or ≤ 50 year regardless of risk status with an 8/8 HLA identical sibling or unrelated donor are eligible to participate in this prospective trial. After triplet BTZ-based induction chemotherapy and ASCT, outpatient NMA alloSCT is performed with either fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 5 days (sibling donor) or fludarabine 30 mg/m2 for 3 days and total body irradiation 2 Gy (unrelated donor) followed by peripheral blood stem cell infusion. Acute GVHD (aGVHD) prophylaxis consists of tacrolimus and mycophenolate mofetil (MMF). BTZ is started on day +120 post-transplant at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow minimal residual disease (MRD) evaluation is performed with highly sensitive (≥10-5) next-generation flow cytometry using 8-color Euroflow protocol before alloSCT, before BTZ, every 3 months for 2 years and at relapse. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated according to modified Glucksberg and NIH criteria, respectively.Results: As of 07/10/2017, 33 NDMM patients (16 males) have been enrolled; median age is 55 (range: 35-64) years. ISS 3 is found in 39%, Durie-Salmon stage 3A or 3B in 85%, HR cytogenetics in 58% (12% del17p, 15% t(4;14), 33% gain 1q21, 9% del1p and 12% with >1 HR cytogenetics). Induction consisted of CyBorD (79%) or VTD (21%) for a median of 4 (range: 4-7) cycles followed by ASCT. Median times from induction to ASCT and from ASCT to alloSCT are 5.7 and 4.4 months, respectively. Sibling donor transplants were performed in 42%. With a median follow-up of 15 months after alloSCT, 23 patients have started BTZ and received 96% of planned doses. No dose reduction was needed for toxicity. Consolidation BTZ improve depth of response, increasing ≥CR rate from 55% to 80% and iCR rate from 17% to 67% (Table 1), regardless of cytogenetic abnormalities. Median progression-free survival (PFS) is not reached; 12-month PFS is 87% (CI: 66-96) (Fig. 1). The cumulative incidence of progression at 12 months is 8%. Median overall survival (OS) is also not reached and 12-month OS is 91% (CI: 68-98). In 23 patients followed ≥6 months, cumulative incidences of grade II-IV and grade III-IV aGVHD are 30% and 15%, respectively. In 18 patients followed ≥12 months, the cumulative incidence of all grade and moderate-severe cGVHD at 12 months are 58% and 40%, respectively, with mostly mouth, skin and liver involvement. There is no clear association between time of occurrence of cGVHD and improvement of response. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a non-relapse mortality at 12 months of only 5%. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ include diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1BK virus) and subclinical EBV reactivations (n=4).Conclusion: Tandem ASCT-NMA alloSCT and BTZ consolidation result in a remarkably high rate of CR or better including iCR. Despite a HR NDMM population, a low relapse rate is observed. BTZ following alloSCT is safe and may contribute to decrease both the incidence of cGVHD or its severity. [Display omitted] DisclosuresSebag:Celgene, Janssen: Consultancy. Cohen:University of Montreal: Patents & Royalties: royalties.

Use of Peripherally Inserted Central Catheter (PICC) for the Infusion of Peripheral Blood Stem Cell Products Is Safe and Effective

Introduction: Cryopreserved peripheral blood stem cell (PBSC) products are thawed at bedside and infused by gravity through a large bore central venous line (CVL). Peripherally inserted central venous catheters (PICC) are routinely used for infusion of blood products and medications but are rarely used to administer hematopoietic progenitor cells (HPC). The rationale for this practice is not well established but the general assumption is that the smaller gauge sizes of the PICC and resultant decreased infusion rates would damage the HPCs. The use of PICC to infuse HPCs can have many benefits, such as patient comfort, cost effectiveness, and reducing potential line-related complications from the insertion of a large bore, and often additional, CVL. These line-related complications include infections, pneumothorax, haematomas, etc. The aim of this prospective observational study is to present the experience of using PICC in lymphoma patients receiving autologous PBSC transplantation in terms of the safety and efficacy. Methodology: From September 2019 to June 2020, a prospective observational study involving 16 patients with lymphoma undergoing autologous PBSC transplantation was conducted in National University Cancer Institute, Singapore (NCIS). The patients were divided into 2 groups - the first group included 9 lymphoma patients who received their autologous PBSC transplant via PICC, while the second/control group included 7 lymphoma patients who received the treatment via a large bore CVL. The types of PICC and CVL inserted for the patients were standardized - 19G dual lumen PICC and 7Fr triple lumen non-tunnelled CVL respectively. All the CVLs were inserted in the right internal jugular vein, while the PICC were inserted in either the brachial or basilic veins. All patients in both groups underwent BEAM conditioning transplantation regime prior to autologous PBSC transplantation. The duration of the catheter-in-situ, catheter-associated complications, PBSC infusion rate, CD34 cell dose, total nucleated cell dose infused, and the time for absolute neutrophil and platelet count engraftment were analysed for the study. Results: The baseline characteristics and results for both groups are shown in Table 1. It is important to highlight that for the first group using PICC, none of them had any adverse event from PBSC transplantation. 44.4% of the patients had only minor issues during the PBSC infusion, mainly due to slower infusion rate and sediments were seen in the tubing of the PICC. These issues were quickly overcome by manual flushing of the PICC with normal saline fluid boluses. Only 1 out of 9 had a mild skin irritation at the insertion site of the PICC. For the second/control group using CVL, 43% of them had both PICC and CVL in-situ at one point of their treatment. These patients underwent an additional procedure for CVL insertion and the CVL was removed within 2 weeks of insertion. Only 1 out of 7 patients had minor issue of severe nausea during the PBSC infusion. There was no adverse event during the PBSC infusion or catheter associated complication. Conclusion: Our study showed that the use of PICC is safe and effective for patients receiving autologous PBSC transplantation, compared to the conventional large bore central venous catheters. Despite having longer PBSC infusion rate for PICC, the time taken for neutrophil and platelet recovery between both groups were comparable and there were no serious complications. Table Disclosures Chng: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria.

HLA-mismatched GPBSC infusion therapy in refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: an observational study from a single center

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory state. Epstein–Barr virus (EBV) infection-associated HLH (EBV-HLH) is one of the most common secondary HLH and suffers a very poor prognosis. Allo-HSCT is often required for refractory EBV-HLH, but some patients still cannot proceed to the next allo-HSCT due to various factors. This study aimed to observe the efficacy of HLA-mismatched granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (GPBSCs) infusion for refractory EBV-HLH.MethodsA retrospective case-control study of refractory EBV-HLH patients with GPBSC infusion from HLA-mismatched donors after chemotherapy (as GPBSC group) and sole chemotherapy (as control group) was performed. Efficacy was evaluated 2 and 4 weeks and all patients were followed-up until March 1, 2018.ResultsThere were 18 cases who accepted infusion between March 2016 and Sep 2017 and 19 were randomly selected from refractory EBV-HLH patients who underwent salvage therapy during the same period for the control group. In GPBSC group, WBC (p = 0.017), Fbg (p = 0.040), and ferritin (p = 0.039) improved significantly after treatment. The overall response rate was 66.7% (CR 22.2%, PR 44.4%). However, there are no significant differences in changes of WBC, HGB, PLT, TG, Fbg, Ferritin, AST, ALT, and T-bil between two groups. Only the Fbg level was recovered better in the GPBSC infusion group (p = 0.003). In the GPBSC group, EBV-DNA decreased significantly after 2 weeks (p = 0.001) and 4 weeks (p = 0.012) after treatment, and the effect of the decrease was significantly better than that of the chemotherapy alone group in 2 weeks but not 4 weeks (p2w = 0.011, p4w = 0.145). The median survival time in the infusion group was 20.4 weeks [95% CI 10.9, 29.9], and the median survival time in the control group was 10.8 weeks [95% CI 0–24.34]. In the short-term, the infusion group’s survival rate was better (2-month 88.89% vs. 52.63%, p = 0.008; 3-month 83.33% vs. 47.09%, p = 0.012), but there was no difference in OS (p = 0.287).ConclusionsInfusing GPBSCs combined with chemotherapy is effective, especially in decreasing EBV-DNA, performs better than chemotherapy alone, and improves short-term survival rate. GPBSC infusion is suggested as a bridging treatment method to allo-HSCT.

Efficacy of photocatalytic air purifiers in reducing dimethyl sulfide malodor following cryopreserved peripheral blood stem cell infusion

Dimethyl sulfoxide (DMSO) is used as a cryoprotectant for peripheral blood stem cells (PBSC) preservation. Dimethyl sulfide (DMS) is a metabolite of DMSO secreted through patients' breath after PBSC infusion. It possesses malodor causing an unpleasant environment. We evaluated the efficacy of a photocatalyst environment purifier, which has the potential to lyse toxic substances, in reducing DMS malodor. High DMS concentration in the air after PBSC infusion rapidly decreased after operating the device. Our results suggest that photocatalytic reaction has the potential to reduce the DMS odor associated with PBSC infusion.

Peripheral Blood Stem Cell Therapy Does Not Improve Outcomes of Femoral Head Osteonecrosis With Cap‐Shaped Separated Cartilage Defect

A combination treatment with porous tantalum rod implantation and intra-arterial infusion of peripheral blood stem cells (PBSCs) provides a promise for treating early and intermediate stages of osteonecrosis of the femoral head (ONFH). However, its clinical indications and application restrictions remain unclear. This study aims to determine the clinical, histological, and radiological outcomes of a combination treatment using mechanical support and a targeted intra-arterial infusion of PBSCs for painful ONFH with a cap-shaped separation (CSS) cartilage defect. Compared with the standard pain management (control group), this combination treatment did not improve the Harris Hip Score (HHS) at 36 months. Micro-CT and histologic analyses showed severe focal destruction in all CSS-ONFH femoral heads in both the combination and control groups. Femoral heads showed a higher percentage of bone lesions in the combination treatment group than in the control group. There was no significant difference in osteoclast number in the subchondral bone areas between the two groups. A high level of expression of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, was detected in blood vessels around the subchondral bone in both groups. The RANKL/OPG (receptor activator of the nuclear factor-kB ligand/osteoprotegerin) ratio was also similar between the control and combination treatment groups. Our results indicate that this combination treatment is not an effective method for the treatment of patients with painful CSS-ONFH. Moreover, this combination treatment did not inhibit inflammatory osteoclastogenesis in patients with more advanced disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:269-276, 2020.

Mitoxantrone-melphalan conditioning regimen for autologous stem cell transplantation in relapsed/refractory lymphoma

Background/aimHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin’s lymphoma (HL) or non-Hodgkin’s lymphoma (NHL). In this study, we report the outcome of the mitoxantrone-melphalan conditioning regimen for lymphoma.Materials and methodsThe study group included 53 patients who were relapsed/refractory HL (n = 14) and NHL (n = 39) and received mitoxantrone and melphalan followed by ASCT. The transplant regimen consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by peripheral blood stem cell infusion (PBSC).ResultsPrior to high-dose chemotherapy, 37.7% of the patients were in complete remission (CR) and 45.3% were in partial remission (PR), and 17% had stable or progressive disease. After high-dose chemotherapy and PBSC, 44 out of 51 patients achieved CR (86.2%). CR was achieved in 24 out of 33 patients (72.7%) who were transplanted in a marginally active phase of the disease. At a median followup of 25.4 months (1.8–131.3 months) after ASCT, 13 patients relapsed/progressed and 8 patients died. The estimated 2-year overall survival (OS) was 81.9%, and event-free survival (EFS) was 59.3%.ConclusionHigh-dose chemotherapy followed by ASCT is an effective conditioning regimen in relapsed/refractory lymphoma patients who are undergoing ASCT.

Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT <31 years (p = 0.010) and prior platelet transfusion <86 U (p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.

Allogeneic Hematopoietic Cell Transplantation in the Outpatient Setting.

Conditioning with fludarabine and low-dose total-body irradiation before allogeneic hematopoietic cell transplantation (HCT) enabled treating older or medically infirm patients with advanced hematologic malignancies in the outpatient setting. Between December 1997 and June 2017, 1037 patients with hematologic malignancies received peripheral blood stem cell (PBSC) grafts from HLA-matched or 1 HLA antigen/allele-mismatched related or unrelated donors. Median age was 58 (range, 18 to 80) years. Serious comorbidities with Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) scores ≥3 were present in 52% of patients. We found that 47% of patients were either never hospitalized or only had an overnight hospital stay for infusion of late-arriving PBSCs while 53% were admitted for a median of 6 days. Main reasons for admission were infection, fever, graft-versus-host disease, and regimen-related toxicity. Two thirds of admissions occurred within 3 weeks of HCT. The 5-year risk of nonrelapse mortality (NRM) was 26% among hospitalized patients and 13% among nonhospitalized patients. Significant risk factors for hospitalization included unrelated transplants, 1 HLA antigen-mismatched transplant, high HCT-CI scores, and diagnosis of nonmyeloma malignancies. Significant risk factors for NRM were hospitalization, older age, unrelated transplants, and high HCT-CI scores. Ambulatory allogeneic HCT is feasible and safe.

Correction: Allogeneic hematopoietic stem cell transplantation for relapsed acute myeloid leukemia in ETO positive with reduced-intensity conditioning.

[This corrects the article DOI: 10.18632/oncotarget.22612.].

Plerixafor in poor mobilizers with non-Hodgkin\u2019s lymphoma: a multi-center time-motion analysis

High-dose chemotherapy alongside peripheral blood stem cell (PBSC) infusion has become the standard of care in different hematologic malignancies. The goal of PBSC mobilization is to allow collection of sufficient CD34+ cells to proceed to transplantation. The current mobilization regimen with granulocyte colony-stimulating factor (G-CSF), alone or in combination with chemotherapy, still fails in 10–25% of patients. Plerixafor is able to rescue most of these patients from mobilization failure. In this study, we investigated the impact of plerixafor on the cost and time spent on apheresis in patients who were considered poor mobilizers, with <20 × 106/µl peripheral CD34+ cells after mobilization but prior to apheresis. Patient hospital records from ten centers in three European countries were reviewed and compared during two time periods, namely prior and after plerixafor introduction to the market. During the plerixafor period, patients spent less time on apheresis (350 vs. 461 min). Poor mobilizers given plerixafor collected more CD34+ cells during the first apheresis session, leading to a decrease in the average number of apheresis sessions needed. The total apheresis yield was unaffected. This analysis shows that the use of plerixafor lessens the time–effort associated with the management of poor mobilizers and reduces apheresis costs.

A Phase I Trial of 90Y-BC8-DOTA (Anti-CD45) Monoclonal Antibody in Combination with Fludarabine and TBI As Conditioning for Allogeneic Peripheral Blood Stem Cell Transplant to Treat High Risk Multiple Myeloma

Introduction: Novel agents and autologous stem cell transplant (auto-SCT) have resulted in a survival benefit among patients with multiple myeloma (MM), but almost all ultimately relapse. Allogeneic transplant (allo-SCT) provides a tumor-free graft and graft-versus-myeloma (GVM) effect, but myeloablative conditioning regimens are associated with high rates of treatment-related mortality (TRM). In contrast, reduced intensity allo-SCT conditioning regimens are associated with lower TRM, but patients receiving these regimens tend to have a higher risk of relapse. Radioimmunotherapy (RIT) offers the potential to deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When incorporated into reduced intensity allo-SCT, RIT may improve responses without the associated toxicity historically associated with myeloablative conditioning. We studied 90Yttrium conjugated to an IgG1 murine anti-CD45 monoclonal antibody (MAb) (BC8), in conjunction with a reduced intensity-conditioning regimen prior to allogeneic SCT. We used CD45 as a target due to its ubiquitous expression in hematopoietic stem cells. We used the high-energy (2.8 MeVmax) beta-emitter, 90Y to facilitate a bystander crossfire effect and eliminate malignant plasma cells.Methods: This is a single-arm, open label, dose-escalation, phase I trial designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with fludarabine (flu) and low dose total body irradiation (TBI) followed by HLA‐matched, related or unrelated allo-SCT for patients with high risk MM. Inclusion required patients to have at least one high risk MM-associated disease characteristic at diagnosis (del13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), del 17 by FISH, beta-2 microglobulin >3.5 mcg/mL, LDH >1.5 times upper limit of normal, plasma cell leukemia or progressive disease following primary therapy), and/or disease progression after auto-SCT. To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium-BC8-DOTA followed by gamma camera imaging and bone marrow biopsy. On pre-transplant day -12, patients received 90Y-BC8-DOTA at a dose calculated from the trace-labeled 111Indium-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to growth factor mobilized donor peripheral blood stem cell infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine initiated on day 0 and day -3, respectively. The MTD was defined as the dose of 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT.Results: A total of 15 patients were enrolled. Patient characteristics and outcomes are summarized in Table 1. One patient was withdrawn from the study prior to receiving the therapy dose after testing positive for human anti-mouse antibodies. The remaining 14 patients went on to receive 90Y-BC8-DOTA (0.5 mg/kg antibody) at escalating 90Y dose levels of 6 to 32 Gy to the liver, which is the normal critical organ. Six patients (43%) experienced grade 3-4 toxicity, predominantly GI and metabolic/electrolyte disturbances. No DLTs were observed. Because no DLTs were seen, the MTD could not be estimated. All patients achieved platelet and neutrophil engraftment, and 13 patients (93%) were >95% donor in the CD3, CD33 and CD56 compartments at day +28. Estimates of overall and progression-free survival at 2 years were 77% and 78%, respectively (Figure 1). Eleven patients who completed the study regimen are alive at 2.6 months to 4.1 years. Of these, 6 patients are in complete remission, 2 have persistent disease, and 3 have relapsed at 4 months, 6 months, and 3 years post-transplant. Three patients died: 2 due to progressive disease and 1 due to respiratory failure in the setting of liver GVHD.Conclusion: The inclusion of 90Y-BC8-DOTA into a reduced intensity allo-SCT conditioning regimen is feasible and no dose-limiting toxicities have been observed. The efficacy of this regimen is promising compared with historical control rates of conventional allo-SCT for MM and should be explored in a phase II trial. [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Gopal:Seattle Genetics: Consultancy, Research Funding. Becker:GlycoMimetics, Inc.: Research Funding. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees.

Validating and implementing the use of an infusion pump for the administration of thawed hematopoietic progenitor cells-a single-institution experience.

Direct thaw and administration of previously cryopreserved peripheral blood stem cell products is a commonly used practice and should be performed rapidly to reduce cellular damage caused by dimethyl sulfoxide exposure. Cells are typically thawed at the bedside and infused by gravity through a high-flow-rate central venous catheter. An existing nontunneled catheter is occasionally used instead and often results in a slower infusion rate. To ensure expedient and consistent infusions, we validated and implemented the use of an infusion pump for thawed peripheral blood stem cells. Validation was performed in two phases: in vitro simulation and in vivo clinical assessment. Total nucleated cell recovery and viability plus progenitor cell viability and potency were compared in vitro between two cryopreserved peripheral blood stem cell units that were either passed through a preset infusion pump or drained by gravity. The infusion rate, adverse events, and engraftment times were retrospectively compared between patients who received infusions by infusion pump (n = 35) and by gravity (n = 38). No significant differences were observed in vitro between the infusion methods for all measured variables. Overall infusion rates were similar in vivo for both groups but were significantly lower for patients who had nontunneled catheters that delivered the infusion by gravity. The time to neutrophil and platelet engraftment was similar for both groups. This is the first study to assess the use of an infusion pump for stem cell transplant. The use of an infusion pump for peripheral blood stem cell infusion is safe, provides a reliable and consistent infusion method, and can mitigate the effect of the type of venous access line used.

Allogeneic hematopoietic stem cell transplantation for relapsed acute myeloid leukemia in ETO positive with reduced-intensity conditioning.

ObjectiveThis research is conducted under the intention of exploring the efficacy and safety of reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed ETO positive acute myeloid leukemia (AML).Materials and MethodsTreatment of 15 cases referring to recurrent ETO positive acute myeloid leukemia in an army hospital from January 2010 to January 2013 through allo-HSCT with reduced-intensity conditioning. All participants belonged to the recurrent or refractory type, including 10 males and 5 females, aging from 16 to 48 years old, with the average age of 32.5 years old. Before transplantation, 6 cases were remission while 9 were not, 10 cases were HLA-identical matching and 5 cases were HLA-haploidentical. Donors received G-CSF to mobilize and used peripheral blood stem cell transplantation. Patients received a combination of Fludarabine, Busulfex and cytarabine as conditioning regimen. Preventive donor peripheral blood stem cell infusion was used 3 months after transplantation in order to observe toxicity, graft versus host disease(GVHD) and disease-free survival.ResultsAll patients reached hematopoietic reconstitution, the average time were 15.5d and 16.8d respectively with neutrophils > 0.5 × 109/L and platelets > 20 × 109/L. Engraftment was confirmed by the evidence of 100% donor hematopoiesis and T lymphocyte subsets counts increased significantly before and after transplantation. Univariate analysis showed that the levels of CD3+, CD4+, CD8+, CD19+ significantly increased after transplantation (P < 0.05) . Until June 2016 after the duration of 27.5 months, 8 cases presented the presence of GVHD, one died of complication, another 4 died of relapse and the other three remained disease-free survival, the DFS rate of 2-year was 66.7%, with the longest DFS up to 54 months. Considering of the transplantation cases with remission into relief groups (6 cases), and not ease group (9 cases), 2 years of disease-free survival rates were 66.7% and 66.7%. The survival curves of the two groups are demonstrated with no significant statistical significance (P > 0.05).ConclusionsReduced-intensity allogeneic hematopoietic stem cell transplantation remains effective for relapsed AML with ETO positive, with safe and effective features and can be used as the method for relapsed AML with ETO positive.

Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide

Objective/backgroundNoninfection-related fever can occur after peripheral blood stem cell infusion in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. The objective of this study was to analyze the incidence of fever and characterize some clinical features of affected patients. MethodsA retrospective case-series study with 40 patients who received haploidentical hematopoietic stem cell transplantation was carried out. ResultsThirty-three patients (82.5%) developed fever; no baseline characteristic was associated with its development. Median time to fever onset was 25.5h (range, 9.5–100h) and median peak temperature was 39.0°C (range, 38.1–40.5°C). Not a single patient developed hemodynamic or respiratory compromise that required admission to the intensive care unit. Fever was not explained by infection in any case. Ninety-one percent of the febrile episodes resolved within 96h of cyclophosphamide administration. No significant difference in overall survival, event-free survival, or graft versus host disease-free/relapse-free survival was found in the group of febrile individuals after peripheral blood stem cell infusion. ConclusionFever after peripheral blood stem cell infusion in this clinical setting was common; it usually subsides with cyclophosphamide administration. The development of fever was not associated with an adverse prognosis.

A Study of Human Leukocyte Antigen Mismatched Cellular Therapy (Stem Cell Microtransplantation) in High-Risk Myelodysplastic Syndrome or Transformed Acute Myelogenous Leukemia

The treatment outcomes of myelodysplastic syndrome (MDS) and transformed acute myelogenous leukemia (tAML) remain very unsatisfactory. We designed a combination of human leukocyte antigen (HLA)-mismatched hematopoietic stem cell microtransplantation (MST) with chemotherapy for patients with MDS and tAML and evaluated its effects and toxicity. Patients were between 13 and 79 years old. Patients with MDS (n=21) were given HLA-mismatched MST combined with decitabine and cytarabine; patients with tAML (n=22) were given HLA-mismatched MST combined with decitabine and cytarabine, and also mitoxantrone. Patients in complete remission (CR) also received MST plus decitabine and medium-dose cytarabine chemotherapy without graft-versus-host disease (GVHD) prophylaxis. The overall response rate of the patients with MDS was significantly higher than that of those with tAML (81% vs. 50%; p=.03). The CR rates were 52.4% and 36.4% in the two groups, respectively. There was no difference in the cytogenetic CR rate between the MDS and tAML groups (85.7% vs. 70%, respectively; p=.7). The 24-month overall survival of the patients with MDS was significantly higher than that of the patients with tAML (84.7% and 34.1%, respectively; p=.003). The median recovery times of neutrophils and platelets were, respectively, 14 and 17 days in the patients with MDS, and 16 and 19 days in those with tAML. The treatment-related mortality rates were 4.8% and 18.2%, respectively, in the MDS and tAML groups (p=.34). No GVHD was observed in any patient. Microtransplantation combined with decitabine and chemotherapy may provide a novel, effective, and safe treatment for high-risk MDS and tAML. Microtransplantation (MST) refers to regular chemotherapy combined with granulocyte colony-stimulating factor-mobilized peripheral blood stem cell infusion of human leukocyte antigen-mismatched donor cells without using immunosuppressive agents. It aims to support hematopoietic recovery and perform graft-versus-leukemia (GVL) effects but differs from traditional allogeneic stem cell transplantation because the rate of donor cell chimerism is low and there is and no graft-versus-host disease (GVHD) risk. Thus, a trial was designed to evaluate the safety and efficacy of MST in patients with myelodysplastic syndrome and those with transformed acute myelogenous leukemia. Higher complete remission and cytogenetic complete response rates were observed, and the treatment improved disease progress-free survival, sped hematopoietic recovery, and avoided GVHD.