Optimizing autologous stem cell collections for patients with multiple myeloma receiving G-CSF and Plerixafor: A single center project.

BACKGROUND: Increasing indications for cellular therapy collections have stressed our healthcare system, with autologous collections having a longer than desired wait time until apheresis collection. This quality improvement initiative was undertaken to accommodate more patients within existing resources. STUDY DESIGN AND METHODS: Patients with multiple myeloma who underwent autologous peripheral blood stem cell collection from October 2022 to April 2023 were included. Demographic, mobilization, laboratory, and apheresis data were retrospectively collected from the medical record. RESULTS: This cohort included 120 patients (49.2% male), with a median age of 60 years. All received G-CSF and 95% received pre-emptive Plerixafor approximately 18 hours pre-collection. Most (79%) had collection goals of at least 8 × 106/kg CD34 cells, with 63% over 70 years old having this high collection goal (despite 20 years of institutional data showing <1% over 70 years old have a second transplant). With collection efficiencies of 55.9%, 44% of patients achieved their collection goal in a single day apheresis collection. A platelet count <150 × 103/µL on the day of collection was a predictor for poor mobilization; among 27 patients with a low baseline platelet count, 17 did not achieve the collection goal and 2 failed to collect a transplantable dose. CONCLUSIONS: With minor collection goal adjustments, 15% of all collection appointments could have been avoided over this 6-month period. Other strategies to accommodate more patients include mobilization modifications (Plerixafor timing or substituting a longer acting drug), utilizing platelet counts to predict mobilization, and modifying apheresis collection volumes or schedule templates.

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

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

A comparative review of Aphexda and Mozobil for mobilization prior to stem cell collection.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma leading to prolonged progression free and overall survival. Successful engraftment following hematopoietic stem cell infusion requires adequate stem cell doses. Current mobilization regimens include granulocyte colony-stimulating factor (G-CSF) with or without plerixafor. Motixafortide is a recently approved agent that can be used in combination with G-CSF for mobilization. In the absence of any head-to-head trials comparing the two products, this article aims to outline the similarities and differences of these two agents. Though moxitafortide has a more favorable pharmacokinetic profile in comparison to plerixafor, in clinical trials, the agents demonstrated similar efficacy. In addition, the use of motixafortide in clinical practice may be limited by product cost as well as administration and monitoring requirements.

Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis.

BACKGROUND: Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis. METHODS: We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis). RESULTS: A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P=0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment. CONCLUSIONS: Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838 .).

Synthesis of novel 1,2,4-trioxanes and antimalarial evaluation against multidrug-resistant Plasmodium yoelii nigeriensis.

Malaria epidemics represent one of the life-threatening diseases to low-income lying countries which subsequently affect the economic and social condition of mankind. In continuation in the development of a novel series of 1,2,4-trioxanes 13a1-c1, 13a2-c2, and 13a3-c3 have been prepared and further converted into their hemisuccinate derivatives 14a1-c1, 14a2-c2, and 14a3-c3 respectively. All these new compounds were evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular (im) routes. Hydroxy-functionalized trioxane 13a1 showed 80% protection and its hemisuccinate derivative 14a1 showed 100% protection at a dose of 48 mg/kg × 4 days by both routes, which is twice active than artemisinin by oral route.

Patterns of use, effectiveness and safety of gadolinium contrast agents: a European prospective cross-sectional multicentre observational study.

BACKGROUND: The EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe. METHODS: Prospective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting. RESULTS: 2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious. CONCLUSIONS: This European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

What Is the Correlation Among dGEMRIC, T1p, and T2* Quantitative MRI Cartilage Mapping Techniques in Developmental Hip Dysplasia?

BACKGROUND: Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a validated technique for evaluating cartilage health in developmental dysplasia of the hip (DDH), which can be a helpful prognosticator for the response to surgical treatments. dGEMRIC requires intravenous injection of gadolinium contrast, however, which adds time, expense, and possible adverse reactions to the imaging procedure. Newer MRI cartilage mapping techniques such as T1 rho (ρ) and T2* have been performed in the hip without the need for any contrast, although it is unknown whether they are equivalent to dGEMRIC. QUESTION/PURPOSE: In this study, our purpose was to determine the correlation between the relaxation values of three cartilage mapping techniques, dGEMRIC, T1ρ, and T2*, in patients with DDH. METHODS: Fifteen patients with DDH (three male, 12 female; mean age 29 ± 9 years) scheduled for periacetabular osteotomy underwent preoperative dGEMRIC, T1ρ, and T2* MRI at 3T with quantitative cartilage mapping. The outcomes of dGEMRIC, T1ρ, and T2* mapping were calculated for three regions of interest (ROI) to analyze the weightbearing cartilage of the hip: global ROI, anterior and posterior ROI, and further subdivided into medial, intermediate, and lateral to generate six smaller ROIs. The correlation between the respective relaxation time values was evaluated using the Spearman correlation coefficient (rS) for each ROI, categorized as negligible, weak, moderate, strong, or very strong. The relaxation values within the subdivided ROIs were compared for each of the three cartilage mapping techniques using the Kruskal-Wallis test. RESULTS: There was a moderate correlation of T1ρ and T2* relaxation values with dGEMRIC relaxation values. For the global ROI, there was a moderate correlation between dGEMRIC and T2* (moderate; rS = 0.63; p = 0.01). For the anterior ROI, a moderate or strong correlation was found between dGEMRIC and both T1ρ and T2*: dGEMRIC and T1ρ (strong; rS = -0.71; p = 0.003) and dGEMRIC and T2* (moderate; rS = 0.69; p = 0.004). There were no correlations for the posterior ROI. The mean dGEMRIC, T1ρ, and T2* relaxation values were not different between the anterior and posterior ROIs nor between the subdivided six ROIs. CONCLUSION: Quantitative T1ρ and T2* cartilage mapping demonstrated a moderate correlation with dGEMRIC, anteriorly and globally, respectively. However, the clinical relevance of such a correlation remains unclear. Further research investigating the correlation of these two noncontrast techniques with clinical function and outcome scores is needed before broad implementation in the preoperative investigation of DDH. LEVEL OF EVIDENCE: Level II, diagnostic study.

"Azole" as privileged heterocycle for targeting the inducible cyclooxygenase enzyme.

An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.

Contrast-to-Dose Relationship of Gadopiclenol, an MRI Macrocyclic Gadolinium-based Contrast Agent, Compared with Gadoterate, Gadobenate, and Gadobutrol in a Rat Brain Tumor Model.

Background Detection of cerebral lesions at MRI may benefit from a chemically stable and more sensitively detected gadolinium-based contrast agent (GBCA). Gadopiclenol, a macrocyclic GBCA with at least twofold higher relaxivity, is currently undergoing clinical trials in humans. Purpose To determine the relationship between MRI contrast enhancement and the injected dose of gadopiclenol in a glioma rat model compared with those of conventional GBCA at label dose. Materials and Methods Between April and July 2012, 32 rats implanted with C6 glioma received two intravenous injections at a 24-hour interval. The injections were randomly selected among five doses of gadopiclenol (0.025, 0.05, 0.075, 0.1, and 0.2 mmol/kg) and three reference GBCAs (gadoterate meglumine, gadobutrol, and gadobenate dimeglumine) at 0.1 mmol/kg. MRI tumor enhancement was assessed on T1-weighted images before and up to 30 minutes after injection. Two blinded radiologists visually and qualitatively scored contrast enhancement, border delineation, and visualization of tumor morphology. Quantitatively, variations in contrast-to-noise ratio (ΔCNR) between tumor and contralateral parenchyma were calculated at each time point and were compared for each treatment at 5 minutes by using a mixed model after normality test. Results A total of 24 rats underwent the complete protocol (n = 5-7 per group). A linear dose-dependent ΔCNR relationship was observed between 0.025 and 0.1 mmol/kg for gadopiclenol (R 2 = 0.99). No difference in ΔCNR was observed between the three reference GBCAs (P ≥ .55). Gadopiclenol resulted in twofold higher ΔCNR at 0.1 mmol/kg (P < .001 vs gadobutrol and gadoterate, P = .002 vs gadobenate) and similar ΔCNR at 0.05 mmol/kg (P = .56, P > .99, and P = .44 compared with gadobutrol, gadobenate, and gadoterate, respectively). For both readers, 0.05 mmol/kg of gadopiclenol improved contrast enhancement, border delineation, and visualization of tumor morphology (scores > 3 compared with scores between 2 and 3 for the marketed GBCA). Conclusion Gadopiclenol at 0.05 mmol/kg yielded comparable change in contrast-to-noise ratio and morphologic characterization of brain tumors compared with gadobenate, gadoterate, or gadobutrol at 0.1 mmol/kg. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Clinical outcomes of multiple myeloma patients who undergo autologous hematopoietic stem cell transplant with G-CSF or G-CSF and plerixafor mobilized grafts.

Impact of Plerixafor (P) mobilized stem cells on immune reconstitution, such as absolute lymphocyte count at day 30 (ALC30), and on long-term outcomes of Multiple Myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) has not been well established. We evaluated total of 469 patients mobilized with G-CSF (G) alone, and 141 patients mobilized with G-CSF plus plerixafor (G+ P). Patients only received plerixafor if they had peripheral blood CD34+ blood count <20/µL on first planned day of collection. Primary endpoint, ALC30, was 1.3 K/µL (range, 0.1-4.5) and 1.2 K/µL (range, 0.1-5.1) for G and G + P, respectively (P =. 61). The median PFS was 2.5 years (95% CI, 2.1-3.2) and 2.8 years (95% CI, 2.0-3.3) for G and G + P, respectively (HR: 1.13; 95% CI, 0.84-1.50; P = .42). The median OS was 6.1 years (95% CI, 4.6-NR) for G group compared to 3.7 years (95% CI, 3.2-NR) for the G + P group (HR: 1.64; 95% CI, 1.12-2.40; P = .01). The median follow-up time for OS was 2.53 years (95% CI, 2.13-2.99) and 1.59 years (95% CI, 1.17-2.02) for G and G+ P group, respectively. In this large retrospective analysis of MM patients mobilized with G-CSF vs G-CSF + P, there was no significant difference in lymphocyte recovery or PFS. There was an overall survival difference in patients who were poor mobilizers and could not be mobilized with G-CSF alone.

Phase 1 study of combinatorial sorafenib, G-CSF, and plerixafor treatment in relapsed/refractory, FLT3-ITD-mutated acute myelogenous leukemia patients.

Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.

Evaluation of mobilization efficacy with an extended interval following plerixafor administration.

Plerixafor is a hematopoietic stem cell mobilizing agent used in combination with granulocyte-colony stimulating factor to improve collection for autologous stem cell transplantation. Despite a recommendation for administration 11 h prior to apheresis per package labeling, logistical challenges lead many institutions to administer plerixafor at an extended interval. The purpose of this study was to determine if plerixafor effectively and efficiently mobilizes CD34+ cells when given at an extended interval prior to apheresis. This was a retrospective evaluation of adult patients who received plerixafor based on an algorithm reserving daily plerixafor only for patients with a pre-apheresis CD34+ count of < 20 cells/µL (pre-apheresis plerixafor) or with a low CD34+ yield after the first apheresis session (rescue plerixafor). The primary outcome was achievement of a disease-specific collection goal of ≥ 6 ×106 CD34+ cells/kg for multiple myeloma and ≥ 4 ×106 CD34+ cells/kg for lymphoma. The mean interval between plerixafor administration and apheresis was 17 h in this study. Despite this extended interval, 64% of patients met their disease-specific collection goal. A minimum collection goal of ≥ 2 ×106 CD34+ cells/kg was achieved by 95% of patients. Mobilization remained efficient with a median of two days to complete collection. Based on this data, plerixafor effectively and efficiently mobilizes CD34+ cells when given at an extended interval prior to apheresis.

A Pilot, Exploratory, Randomized, Phase II Safety Study Evaluating Tumor Cell Mobilization and Apheresis Product Contamination in Patients Treated with Granulocyte Colony-Stimulating Factor Alone or Plus Plerixafor.

Because of the potential risk of tumor cell mobilization with granulocyte colony-stimulating factor (G-CSF), it is crucial to evaluate any potential effect of plerixafor treatment in the presence of G-CSF on multiple myeloma (MM) cell mobilization. This was an open-label, multicenter, randomized, exploratory, safety study (NCT01753453) that investigated the extent of MM cell mobilization after treatment with G-CSF + plerixafor in patients who were deemed poor mobilizers of hematopoietic stem cells. The primary efficacy outcome was the number of MM cells in peripheral blood and apheresis product after G-CSF + plerixafor treatment versus G-CSF alone. Key secondary efficacy outcomes included overall survival and disease status up to 2 years after the first G-CSF dose. Twenty patients were randomized and received at least 1 dose of study treatment. There were no patients with MM cells in peripheral blood up to day 8 G-CSF administration in either treatment group. Up to day 8 no patient in the G-CSF + plerixafor arm and only 1 patient in the G-CSF arm mobilized at least 4.5 × 105 MM cells in the apheresis product. Nine of 10 patients from each treatment arm proceeded to transplantation. MM cells were detected in 5 patients from each treatment arm before and after transplantation. Adverse events observed in the G-CSF + plerixafor arm were consistent with the known safety profile of plerixafor. No MM cells were detected in peripheral blood of either treatment group up to day 8 of mobilization. Only 1 patient in the G-CSF alone group mobilized at least 4.5 × 105 MM tumor cells in apheresis product up to day 8. However, 50% of patients in both treatment arms had detectable amounts of MM cells in their peripheral blood pre- and post-transplantation. There were no new safety concerns with plerixafor.

Etoposide + Granulocyte Colony-Stimulating Factor and Optional Plerixafor in Patients Who Failed Chemomobilization with or without Plerixafor.

We conducted a retrospective study of 62 patients undergoing etoposide (2 g/m2) + granulocyte colony-stimulating factor (G-CSF; 10 patients also received additional plerixafor) as a salvage stem cell mobilization regimen after previous unsuccessful chemomobilization with or without plerixafor. The median peak CD34+ values after etoposide + G-CSF ± plerixafor was 54.07 CD34+/µL compared with 9.6 CD34+/µL after previous mobilization attempts (P < .001). The median yield was 6.33 × 106 CD34+ cells/kg per 2 apheresis. Etoposide + G-CSF ± plerixafor mobilization regimen resulted in 91.53% successful mobilizations and 89.83% of patients proceeding to autologous stem cell transplantation. All 7 patients who had previously failed plerixafor-based mobilization attempts were successfully mobilized with etoposide + G-CSF ± plerixafor and proceeded to autologous stem cell transplantation. The most common grades 3 to 4 adverse events of etoposide + G-CSF ± plerixafor were febrile neutropenia (69.35%), mucositis (51.62%), and bacteremia (20.97%). No fatal outcomes were observed. Rates of 12-month overall survival and progression-free survival were 88.71% and 70.97%, respectively. Etoposide + G-CSF ± plerixafor is an effective regimen for salvage stem cell mobilization also in patients who failed plerixafor, with most patients undergoing autologous stem cell transplantation. The adverse event rate may warrant a decrease in the dose of etoposide.

CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice.

Antibody-secreting cells (ASCs), including short-lived plasmablasts and long-lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine-12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C-X-C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1-/- mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti-OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long-term (five-month) CXCR4 blockade with AMD3100 after effective short-term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4-CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival.

Acute Adverse Events Following Gadolinium-based Contrast Agent Administration: A Single-Center Retrospective Study of 281 945 Injections.

Background Acute allergic-like and physiologic reactions occur following administration of gadolinium-based contrast agents (GBCAs) for MRI examinations. Because these reactions are uncommon, it is challenging to compare reaction rates between GBCAs and to determine risk factors. Purpose To compare reaction rates between the four GBCAs gadodiamide, gadobutrol, gadobenate dimeglumine, and gadoterate meglumine, and to determine potential risk factors for reactions. Materials and Methods This retrospective study identified all intravenous GBCA injections for MRI examinations performed at a single institution from June 1, 2009, to May 9, 2017. Reactions were identified by reviewing records from the MRI technologist, MRI nursing staff, radiologist, emergency department, and provider. Reactions were classified as allergic-like or physiologic and as mild, moderate, or severe by using American College of Radiology criteria. GBCA reaction rates and other potential risk factors were examined by using multivariable regression models with generalized estimating equations. Results Analysis included a total of 158 100 patients (median age, 55 years [interquartile range, 40-67 years], 51% women) who received a total of 281 945 GBCA injections (140 645 gadodiamide, 94 109 gadobutrol, 39 138 gadobenate, and 8053 gadoterate). At multivariate analysis, gadobenate or gadobutrol had higher rates of allergic-like reactions compared with gadodiamide (gadobenate: odds ratio [OR], 3.9 [95% confidence interval {CI}: 3.0, 5.1]; P < .001; gadobutrol: OR, 2.3 [95% CI: 1.8, 2.9]; P < .001) or gadoterate (gadobenate: OR, 4.8 [95% CI: 1.0, 23]; P = .049; gadobutrol: OR, 2.8 [95% CI: 0.6, 14]; P = .20). Physiologic reactions were more frequently observed with gadoterate (OR, 7.7 [95% CI: 2.3, 25; P = .001), gadobenate (OR, 1.8 [95% CI: 1.3, 2.5; P < .001), and gadobutrol (OR, 1.6 [95% CI: 1.3, 2.1; P < .001) administration compared with gadodiamide. Six severe allergic-like reactions (three gadobutrol, three gadobenate) occurred requiring hospitalization. Patient age (P values .025 to < .001), sex (P < .001), location (P = .006), and MRI type (P = .003 and P = .006) were associated with acute reactions. Conclusion Gadobenate and gadobutrol are associated with higher rates of allergic-like reactions compared with gadodiamide or gadoterate, and gadoterate, gadobenate, and gadobutrol are associated with higher rates of physiologic reactions compared with gadodiamide. Patient sex, age, location, and MRI type correlate with acute reaction rates. © RSNA, 2019 Online supplemental material is available for this article.

Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft.

A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors, but fails to mobilize 33% of normal allogeneic sibling donors in 1 apheresis. We hypothesized that changing the route of administration of plerixafor from SC to IV may overcome the low stem cell yields and allow collection in 1 day. A phase 1 trial followed by a phase 2 efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0.32 mg/kg. The primary outcome of reducing the failure to collect ≥2 × 106 CD34+/kg recipient weight in 1 apheresis collection to ≤10% was not reached. The failure rate was 34%. Studies evaluating the stem cell phenotype and gene expression revealed a novel plasmacytoid dendritic cell precursor preferentially mobilized by plerixafor with high interferon-α producing ability. The observed cytomegalovirus (CMV) viremia rate for patients at risk was low (15%), as were the rates of acute grade 2-4 graft-versus-host disease (GVHD) (21%). Day 100 treatment related mortality was low (3%). In conclusion, plerixafor results in rapid stem cell mobilization regardless of route of administration and resulted in novel cellular composition of the graft and favorable recipient outcomes. These trials were registered at clinicaltrials.gov as #NCT00241358 and #NCT00914849.

Effects of Gadodiamide and Gadoteric Acid on Rat Kidneys: A Comparative Study.

BACKGROUND: Gadolinium-based contrast agents are complex chelates to provide contrast in NRI. However, recent studies have highlighted the deposition of free Gd+3 ion in various tissues. PURPOSE: To evaluate the histopathological and immunohistochemical changes on rat kidney tissue following both macrocyclic (gadoteric acid) and linear (gadodiamide) agents under the hypothesis that gadolinium-based contrast agents (GBCA) lead to toxic, free Gd+3 accumulation in tissues. STUDY TYPE: The local Animal Care Committee approved the prospective animal study. ANIMAL MODEL: Thirty-two healthy Sprague-Dawley male rats were administered 2 mmol/kg gadodiamide and gadoteric acid for the first 4 days for 5 weeks. Group 1 received no drug (control, n = 8) and Group 2 (n = 8) was administered 0.1 ml/kg saline. Group 3 was administered 0.1 mmol/kg gadodiamide and Group 4 (n = 8) was administered 2 mmol/kg gadoteric acid. ASSESSMENT: Biochemical, histopathological, and immunohistochemical changes in testis kidney tissue were evaluated at the end of 10 weeks. STATISTICAL TESTS: Differences between groups were analyzed using the nonparametric Kruskal-Wallis test followed by one-way analysis of variance and the Tamhane test, also followed by Turkey's HSD test. RESULTS: Gadolinium increased serum urea, Ca+2 , and Caspase-3 positive tubular cell number. Larger Bowman capsules shrank proximal and distal tubules were revealed in the gadodiamide and gadoteric acid groups compared to the control group (P < 0.05). Histopathologic examination showed significantly more interstitial fibrosis, amyloid deposits, and vasocongestion in the gadodiamide group than the gadoteric acid and control groups, while the gadoteric acid group demonstrated significantly more leukocytic infiltration with atrophied proximal and distal tubules than the gadodiamide and control groups (P < 0.05). DATA CONCLUSION: GBCA administration causes significant histopathologic changes in kidney tissue. This study advocates additional investigation to assess the in vivo safety of GBCAs. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:382-389.

Reduced-dose plerixafor as a mobilization strategy in autologous hematopoietic cell transplantation: a proof of concept study.

BACKGROUND: Autologous stem cell transplantation (ASCT) is an effective treatment for patients with relapsing myeloma or lymphoma, diseases associated with unsuccessful peripheral blood stem cell (PBSC) collection. Plerixafor is a potent mobilizing agent, allowing more CD34+ cells to be obtained; however, the main obstacle for its use is its high cost. Our aim was to demonstrate that of the use of reduced doses of plerixafor (RD-plerixafor) can be sufficient to collect at least 2 × 106 /Kg CD34+ PBSC in patients with multiple myeloma (MM) or lymphoma undergoing ASCT. STUDY DESIGN AND METHODS: Twenty patients were mobilized with filgrastim (10 µg/kg/4 days) plus a single dose of plerixafor 0.12 mg/kg in Day 4. Apheresis collection was performed on Day 5. One vial of plerixafor was used for two patients. Clinicaltrials.gov NCT03244930. RESULTS: Cell mobilization and collection was successful in 85% of patients (≥2 × 106 CD34+ cells per kilogram). The median collected CD34+ cell count was 4.62 × 106 /kg (range, 1.27-24.5). A 4.1-fold-increase in the median CD34+ PBSC pre-count was observed (from 10.4/µl to 42.4/µl) after RD-plerixafor administration. Seven patients had mild to moderate adverse events. CONCLUSION: RD-plerixafor is an effective, safe, and affordable strategy to ensure adequate PBSC mobilization in patients with MM or lymphoma who undergo ASCT.

The feasibility and efficacy of subcutaneous plerixafor for mobilization of peripheral blood stem cells in allogeneic HLA-identical sibling donors: results of the HOVON-107 study.

BACKGROUND: Plerixafor (PFX) mobilizes CD34+ cells into circulation by disrupting the CXCR4 binding of the hematopoietic stem cell in its bone marrow niche. STUDY DESIGN AND METHODS: in the prospective HOVON-107 study (www.hovon.nl) 23 allogeneic HLA-identical sibling donors received one or two subcutaneous (sc) injections of plerixafor 0.320 mg/kg.The primary endpoint, was defined as feasibility to mobilize a minimum of 2.0 x106 CD34+ cells/kg recipient weight obtained by leukopheresis in at least 90% of the donors. RESULTS: median 3.3 x 106 CD34+ cells/kg (1.9-6.5) were collected after 1 (n=12) or 2 (n=10) sc injections of PFX. Side effects occurred in 15/23 (65%) donors: most were grade 1-2; in 5 donors grade 3 and all resolved. All grafts were directly transplanted. Compared to 10 grafts obtained with G-CSF the number of CD34+ cells was 2.4 fold lower but the percentage of phenotypically most immature CD34+ subset was higher (31% vs 15%). The total number of CD3+ cells in the graft seemed higher after PFX-mobilization, but CD4/CD 8 ratios, and frequencies of Th2, Th17 and regulatory T-cells or NK cells were comparable. All patients engrafted and no increase in incidence or severity of acute or chronic graft versus host disease was observed. CONCLUSION: stem cell mobilization with sc PFX 0.320 mg/kg in allogeneic sibling donors is feasible with limited toxicity for donors. 14 allogeneic donors were mobilized with PFX 0.320 mg intravenously according to the same protocol. Due to the limited numbers, these results are in the supplementary section.