Single-dose Infusion Research Articles

Effects of single-dose ruminal infusions of high or low short-chain fatty acid concentrations and high or low pH on apparent total tract digestibility and hindgut fermentation of pre-weaned dairy calves

While the importance of pH and short-chain fatty acids (SCFA) on rumen development are well-known, their impact on the small and large intestine are unclear. This study investigated how single-dose ruminal infusions with high or low short-chain fatty acid concentrations and high or low pH affect calves' productivity as well as physiological parameters associated with hindgut acidosis at 3-time points in 49 d. Holstein bull calves (n = 32) were individually housed and fed milk replacer (900 g/d) twice daily and calf starter and water ad libitum. At d 10 ± 3 of life, the rumens were fistulated and cannulated. At d 14 of life, calves were grouped by body weight and assigned in a 2 × 2 factorial arrangement of treatments: high or low SCFA concentration (285 vs. 10 mM) and high or low pH (6.2 vs. 5.2), creating 4 treatment groups: high SCFA concentration, high pH (HS-HP); high SCFA concentration, low pH (HS-LP); low SCFA concentration, high pH (LS-HP); and low SCFA concentration, low pH (LS-LP). On d 21, 35, 49, feces were sampled to calculate apparent total-tract digestibility, determinate organic acid concentrations (i.e., SCFA, BCFA and lactic acid), and pH. Afterward, the rumen was evacuated and underwent a single-dose infusion for 4 h with one of 4 treatment buffers. After completion of rumen infusion on d 49, calves were harvested, and the tissue weight and length, and digesta pH of the rumen, cecum, colon, and rectum were recorded along with the digesta pH of duodenum, jejunum, and ileum only at d 49 after dissection. Data were analyzed with main factors as fixed effects and repeated measures for weekly measurements. Treatments did not affect performance parameters such as feed intake, ADG, apparent total-tract digestibility and gut measurements. In the duodenum, jejunum, and ileum, HS-HP had a greater digesta pH than LS-HP, while the hindgut digesta pH was only affected by the SCFA concentration. High SCFA concentration increased the concentration of colonic isovaleric acid and fecal BCFA, while only colonic acetic acid and fecal lactic acid concentrations were affected by treatment. Fecal SCFA and BCFA concentrations increased mainly on d 35. In summary, 4 h of physiological buffer infusion in the rumen does not change apparent total-tract digestibility and gut measurements but does affect hindgut fermentation parameters (i.e., organic acid concentrations and digesta pH). In addition, calves can experience increased risks of hindgut acidosis around 35 d of life.

A first-in-human phase 1, multicenter, open-label study of CB-012, a next-generation CRISPR-edited allogeneic anti-CLL-1 CAR-T cell therapy for adults with relapsed/refractory acute myeloid leukemia (AMpLify).

TPS6586 Background: CAR-T cell therapies have shown significant clinical benefit in treating adults with many hematologic malignancies. In acute myeloid leukemia (AML), a challenge in the development of CAR-T cell therapies has been the limitation of suitable target antigens since many are also expressed on hematopoietic stem cells (HSCs). The target antigen C-type lectin-like molecule-1 (CLL-1) has emerged as an attractive therapeutic target due to its expression on AML mature blasts and leukemic stem cells and its absence on HSCs. CB-012 is an allogeneic CAR-T cell therapy that targets CLL-1. CB-012 is derived from healthy donor T cells by using Cas12a CRISPR hybrid RNA-DNA (chRDNA) technology to introduce 5 genome edits: (1) TRAC gene knockout (KO), which eliminates T cell receptor expression to reduce the risk of graft-versus-host disease, (2) site-directed insertion of a fully human anti-CLL-1 CAR into the TRAC locus, (3) KO of PD-1 to enhance antitumor activity by reducing T cell exhaustion, (4) β2-microgobulin ( B 2M) gene KO, which eliminates HLA class I presentation to mitigate host T cell-mediated rejection, and (5) site-directed insertion of a B2M–HLA-E-peptide fusion into the B 2M locus to reduce NK cell-mediated rejection. In murine xenograft models of AML, CB-012 significantly reduced the tumor burden and increased the survival of mice bearing CLL-1+PD-L1+ tumors. Methods: CB-012 is being evaluated in a multicenter, Phase 1 clinical trial in patients with relapsed/refractory (r/r) AML. A 3+3 dose escalation design is being utilized with the primary objectives to determine the safety and tolerability of CB-012 and the recommended Phase 2 dose (RP2D). An expansion phase will follow dose escalation at the recommended dose(s) for expansion. Additional objectives include preliminary antitumor activity and pharmacokinetics. Key inclusion criteria include nonproliferative disease defined as ≤25% blasts in the bone marrow and peripheral blood, ECOG performance status ≤1, and adequate organ function. After receiving lymphodepletion therapy with cyclophosphamide (750 mg/m2/d) and fludarabine (30 mg/m2/d) administered concurrently for 3 days followed by a 2-day break, patients receive a single-dose infusion of CB-012 and are followed for safety and efficacy. The dose escalation portion of the study is actively enrolling patients. The AMpLify trial is registered at clinicaltrials.gov (NCT06128044). Clinical trial information: NCT06128044 .

The interim analysis of a first-in-human phase 1 trial of ET-901, a CRISPR edited allogeneic immune-cloaked anti-CD19 CAR-T cell therapy in patients with r/r B-NHL.

e19010 Background: Allogeneic CAR T-cell therapy faces challenges like limited persistence and host rejection. Current research has improved its viability by modifying genes like B2M, despite new challenges like NK cell targeting have emerged. Through CRISPR screening, we discovered a novel gene, named GeneX, and its role in enhancing T cell persistence against allogeneic attacks and AICD. GeneX influences glycan composition, affecting immune responses and AICD initiation. Engineered GeneXKO/TCRKO/anti-CD19 CAR T cells (ET-901) resisted allogeneic killing and maintained anti-tumor effects without causing GvHD, marking a significant advancement in CAR T-cell therapy. Methods: ET-901 is being tested in a phase 1 trial for r/r B-NHL at a single center, utilizing a 3+3 dose escalation scheme and planning for expansion at the recommended Phase 2 dose. Participants must have an ECOG status of 0–2, without a history of allo-HSCT or CAR-T therapy. The study's main goals are to assess ET-901's safety and establish the optimal Phase 2 dosage. Patients undergo a 3-day lymphodepletion with fludarabine (30-50 mg/m2/d) and cyclophosphamide (500-1000 mg/m2/d), followed by a single-dose infusion of ET-901 at escalating doses (DL1:1*10e6/kg, DL2:3*10e6/kg, and DL3:10*10e6/kg). Pharmacokinetic monitoring occurs during follow-up. Results: From September 2023, a total of six patients were enrolled in the escalation cohort, including 4 patients with LBCL and 2 with FL. In these patients (3 males), the median age was 53 years (range: 46–55 years), and the median number of prior treatment lines was 5. The median SPD was 7,650 mm2 (range: 2,700-43,400 mm2). Notably, two cases in DL2 exhibited unusual lymphoma infiltration sites: patient No.4 in the forearm muscle and patient No.5 in the spleen. Update to February 2024, we have completed the safety evaluation of Dose Level (DL) 1 and DL2. No DLTs were observed. The most common TRAEs of any grade included leukopenia (6/6), granulocytopenia (6/6), anemia (6/6), thrombocytopenia (6/6), CRS (6/6), infection (2/6), ICANS (2/6), and GvH like reaction (1/6). All patients achieved objective responses, with 2 cases of PR and 4 cases of CR (1 in DL1, 3 in DL2). The peak values of CAR+ cells count and VCN in peripheral blood were 36.0/μl (range: 14.0-48.0/μl, median: day 7), and 9.6e4 copies/μg (range: 7.7e4-1.2e5 copies/μg, median: day 7), respectively. In all patients, a second expansion of CAR-T cells was observed alongside B cell recovery. This confirms that GeneX knockout enables allo CAR-T cells to maintain long-term immune privilege while preserving their biological function. Conclusions: The study demonstrated the safety and feasibility of ET-901 in patients with r/r B-NHL. These findings highlight the potential of ET-901 as an effective therapeutic approach for improving outcomes for these patients. Clinical trial information: NCT06014073 .

The Manufacturer's Recommended Dilution for Intravenous Phenytoin and the Challenge of Preparing Single-Dose Infusions Less Than 250 mg.

The Manufacturer's Recommended Dilution for Intravenous Phenytoin and the Challenge of Preparing Single-Dose Infusions Less Than 250 mg.

First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

E-Iron: An Asynchronous Telemedicine Referral Platform for Management of Anemic Pregnant Patients and the Expediting of Treatment with Intravenous Iron

Introduction: Intravenous iron (IVI) is a valuable but underused strategy in the management of iron deficiency anemia in pregnancy, a common condition linked to adverse maternal and neonatal outcomes. At our institution and elsewhere, administration of IVI has historically entailed referral to hematology, a frequently slow and labor-intensive process, that commonly results in significant delays, thus undermining the usefulness of this intervention. E-Iron is a specialized e-consult protocol operational at our institution, built into the EPIC EMR, and designed to facilitate ‘electronic’ referral of patients requiring IVI. Using a template-based design, e-IRON assists referring providers with the gathering and electronic submission of key clinical information required to determine eligibility for IVI. Following submission, a hematologist reviews the request within 3 days. If IVI is deemed appropriate, it is promptly scheduled, as is a face-to-face appointment if deemed necessary. Where IVI is not deemed appropriate, guidance as to alternate management is provided. We have previously shown that e-IRON, by dispensing with the need for a face-to-face hematology visit, simplifies the process of referral for IVI across a broad range of indications, and significantly accelerates the administration of IVI when appropriate. Here we report on the characteristics and selected outcomes of a cohort of anemic pregnant women referred to the e-IRON program over an 18-month period. Results: From July 2021 until December 2022, 239 patients were referred. Of these, 18 were excluded from our analysis due to absence of follow up data. The vast majority (84%) of referrals occurred in the 3rd trimester, the median number of days prior to estimated date of delivery being 47, (average 54.7 days) IV iron was approved for 149 patients (67% of total referred). Of these, 132 patients (89%) received infusion, which occurred a median of 13 days (IQR: 9.4 - 17.5) after the e-IRON consult was placed. Reasons for non-administration included “no shows” (60%) and intervening delivery (33%). Treatment consisted of ‘single dose infusion’ in 88% of infused patients, either using iron dextran 1g, - the Georgetown regimen - (68%), or iron carboxymaltose 750 mgs (19%). No significant complications relating to infusions were reported. IVI was not approved where deemed to be without utility (63%), notably, if the patient was not iron deficient, if the request was too close to delivery, or if anemia was mild. In such cases consideration for IVI during admission for delivery was recommended to expedite post-delivery Hb recovery. IVI was not approved if laboratory studies were not current (11%) or if failure of oral iron was not demonstrated (26%). In the latter group of 19 patients a trial of oral iron was recommended, deemed successful in 10, but in whom 7 ultimately proceeded to IVI. A face-to-face hematology consultation was recommended in 7 patients (3%). 36 patients in the cohort (16%) had a history of bariatric surgery. IVI was approved in 89% of this group, versus 63% in patients without this history. Effects of the intervention are shown in Table 1, with a notable decrease in the proportion of anemic women at time of delivery, most marked in the group who received IVI. The improvement in Hb was greater the earlier IVI was administered. Transfusions occurred exclusively in the context of post-partum hemorrhage, and predominantly with surgical delivery (Table 2). Rates in the cohort were higher than in a historical control (12.2% vs 5.2%). This was attributed to selection bias; e-IRON referrals occurring in a higher pregnancy risk cohort. Conclusions: E-IRON represents a successful implementation of an electronic, asynchronous, telemedicine protocol, that facilitates rapid triage and treatment of anemic pregnant patients requiring IVI. We have shown that the earlier infusion is administered, the greater the increment in Hb, which underscores the value of a protocol that minimizes the time interval between referral and infusion. The speed of IVI administration since implementation of e-IRON is unprecedented at our institution. We believe the model is easily replicated, and can be readily implemented in any other health system that utilizes an integrated EMR, providing similar benefit to an at-risk patient demographic, with a common clinical problem that is habitually neglected or undertreated.

A first-in-human phase 1, multicenter, open-label study of CB-011, a next-generation CRISPR-genome edited allogeneic anti-BCMA immune-cloaked CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CAMMOUFLAGE trial).

TPS8063 Background: Autologous CAR-T cell therapies have shown significant benefit in the treatment of adults with relapsed/refractory multiple myeloma (r/r MM). However, these CAR-T cell therapies may have inherent challenges, including functional deficiencies in the patient’s T cells, that could yield an inconsistent or impaired product, as well as require extended time and complexity in manufacturing, thereby limiting patient access and potentially requiring bridging therapy. CB-011 is an allogeneic, off-the-shelf anti-BCMA CAR-T cell therapy derived from healthy donor T cells. A next-generation CRISPR-Cas12a genome-editing technology using CRISPR hybrid RNA-DNA (chRDNA) guides, developed at Caribou to significantly reduce off-target editing, was implemented to generate 4 genome edits in the manufacture of CB-011: (i) the TRAC gene was knocked out to eliminate T cell receptor (TCR) expression and prevent graft versus host disease (GvHD), (ii) the BCMA-specific CAR was site-specifically inserted into the genome at the TRAC locus to eliminate random integration and serves to target the tumor antigen, (iii) the B2M gene was knocked out to eliminate expression of HLA class I molecules to mitigate host T cell cytotoxicity, and (iv) a B2M-HLA-E fusion transgene was site-specifically inserted into the genome at the B2M locus to overcome host NK cell-mediated killing following recognition of “missing self.” This immune cloaking strategy has the potential to allow persistent antitumor activity of the CAR-T cells in the context of antigen engagement. Significant preclinical efficacy in vitro and in vivo supports the clinical evaluation of CB-011. Methods: CB-011 is being evaluated in a multicenter, Phase 1 clinical trial in patients with r/r MM. A 3+3 dose escalation design followed by expansion at the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) is being utilized. Primary objectives are to determine the safety and tolerability of CB-011, and the recommended Phase 2 dose (RP2D). Additional key objectives include preliminary antitumor activity and pharmacokinetics (PK). After concurrently receiving lymphodepletion therapy with cyclophosphamide (300 mg/m2/d) and fludarabine (30 mg/m2/d) for 3 days, patients receive a single dose infusion of CB-011 and are followed for safety and efficacy. Antitumor activity and disease response are measured by International Myeloma Working Group criteria. The CaMMouflage Phase 1 trial is actively enrolling patients and additional information is available on clinicaltrials.gov (NCT05722418). Clinical trial information: NCT05722418 .

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5mg/kg dose); 3.8 vs 4.5 L/h (1500mg dose) and 2.2 vs 3.1 L/h (25mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Role of single-dose intravenous iron therapy for the treatment of anaemia after orthopaedic trauma: protocol for a pilot randomised controlled trial

IntroductionOrthopaedic trauma and fracture care commonly cause perioperative anaemia and associated functional iron deficiency due to a systemic inflammatory state. Modern, strict transfusion thresholds leave many patients anaemic; managing this...

A universal GlycoDesign for lysosomal replacement enzymes to improve circulation time and biodistribution.

Currently available enzyme replacement therapies for lysosomal storage diseases are limited in their effectiveness due in part to short circulation times and suboptimal biodistribution of the therapeutic enzymes. We previously engineered Chinese hamster ovary (CHO) cells to produce α-galactosidase A (GLA) with various N-glycan structures and demonstrated that elimination of mannose-6-phosphate (M6P) and conversion to homogeneous sialylated N-glycans prolonged circulation time and improved biodistribution of the enzyme following a single-dose infusion into Fabry mice. Here, we confirmed these findings using repeated infusions of the glycoengineered GLA into Fabry mice and further tested whether this glycoengineering approach, Long-Acting-GlycoDesign (LAGD), could be implemented on other lysosomal enzymes. LAGD-engineered CHO cells stably expressing a panel of lysosomal enzymes [aspartylglucosamine (AGA), beta-glucuronidase (GUSB), cathepsin D (CTSD), tripeptidyl peptidase (TPP1), alpha-glucosidase (GAA) or iduronate 2-sulfatase (IDS)] successfully converted all M6P-containing N-glycans to complex sialylated N-glycans. The resulting homogenous glycodesigns enabled glycoprotein profiling by native mass spectrometry. Notably, LAGD extended the plasma half-life of all three enzymes tested (GLA, GUSB, AGA) in wildtype mice. LAGD may be widely applicable to lysosomal replacement enzymes to improve their circulatory stability and therapeutic efficacy.

Comparative Study Between Intravenous Clonidine and Preservative Free Intravenous Lignocaine in Attenuation of Pressor Response to Laryngoscopy and Endotracheal Intubation

Objectives To compare the attenuation of pressor responses by intravenous clonidine and preservative-free lignocaine to laryngoscopy and endotracheal intubation. Materials and Methods A randomized, prospective, comparative, double-blinded study was conducted in 80 adult patients who were randomized into two groups of 40 each, group clonidine (Group C) and group lignocaine (Group L). Group C patients were given 2 µg/kg clonidine in 20 ml of normal saline as a slow infusion over 10 min prior to intubation. Group L patients were given 1.5 mg/kg of preservative-free 2% lignocaine in 20 ml of normal saline as a single-dose infusion over 3 min prior to intubation. Baseline vital and hemodynamic parameters were monitored during the perioperative period at 1-, 5-, and 10-min post-intubation. Results The attenuation of heart rate (HR) after intubation was much better with clonidine than lignocaine as there is statistically significant difference in the mean HR between the two groups at 1, 5, and 10 min after intubation with the HR significantly lesser in the Group C than the Group L at all times after intubation. Both clonidine and lignocaine were effective in attenuating systolic blood pressure response after intubation, but clonidine was more effective than lignocaine as systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in the Group C remained much lower than the Group L and the difference between the two groups was statistically significant at all times after intubation. Conclusion Premedicating with a single slow infusion of 2 µg/kg i.v. clonidine has been proven to be effective in maintaining perioperative hemodynamic stability at 1, 5, and 10 min post-intubation than lignocaine.

A First-in-Human Phase 1, Multicenter, Open-Label Study of CB-010, a Next-Generation CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy with a PD-1 Knockout, in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma (ANTLER Study)

Background: Autologous CAR-T cell therapies have shown significant benefit in the treatment of adults with relapsed/refractory B cell non-Hodgkin lymphoma (r/r B-NHL). However, these CAR-T cell therapies have inherent challenges including functional deficiencies in the patient's T cells that could yield an inconsistent or impaired product. In addition, the extended time and complexity in manufacturing the product can limit patient access and potentially require bridging therapy. CB-010 is an allogeneic, off-the-shelf anti-CD19 CAR-T cell therapy derived from healthy donor T cells; it is the lead program in Caribou's allogeneic CAR-T cell therapy platform. Patients (pts) receiving CB-010 do not require leukapheresis or bridging therapy. A next-generation CRISPR-Cas9 genome-editing technology developed at Caribou, which uses Cas9 and CRISPR hybrid RNA-DNA (chRDNA) guides to significantly reduce off-target editing, was implemented to generate 3 genome edits in the manufacture of CB-010: (i) knockout of the TRAC gene to eliminate TCR expression to reduce the risk of graft-versus-host disease (GvHD), (ii)site-specific insertion of a CD19-specific CAR into the TRAC locus, and (iii) knockout of the gene encoding PD-1, designed to limit premature CAR-T cell exhaustion and enhance antitumor activity. Statistically significant preclinical survival benefit across B-NHL subtypes and longer-duration efficacy in vivo compared to similar CAR-T cells without a PD-1 knockout support the clinical evaluation of CB-010. Methods and Study Design: CB-010 is being investigated in a multicenter, Phase 1 clinical trial in pts with r/r B-NHL. A 3+3 dose escalation design followed by expansion at the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) is being utilized. Primary objectives are to determine the safety and tolerability of CB-010 and the RP2D. Additional key objectives include preliminary antitumor activity and pharmacokinetics (PK). After serially receiving lymphodepletion therapy with cyclophosphamide (60mg/kg/day for 2 days) and fludarabine (25mg/m2/day for 5 days), pts receive a single dose infusion of CB-010 and are followed for safety and efficacy. Initial antitumor activity, as well as time to progression, overall survival, and disease response as measured by Cheson criteria will be evaluated. The study is actively enrolling patients. Cohort 1 at an initial single dose of 40 million CAR-T cells has been completed successfully with 6 patients. Dose escalation of CB-010 is ongoing, and patients are being enrolled in cohort 2 to receive a single dose of 80 million CAR-T cells. The ANTLER Phase 1 trial is registered on clinicaltrials.gov (NCT04637763).

A single low-dose rituximab infusion in severe chronic refractory myasthenia gravis in resource-limited settings

The benefits of multi-dose rituximab cycles in patients with refractory anti-muscle-specific kinase antibody myasthenia gravis (MuSK+MG) are well reported, although less consistently in anti-acetylcholine receptor antibody MG (AChR+MG). Responsivity data to single low-dose rituximab infusions for refractory autoimmune myasthenia, are limited. Here, observational outcomes using MG grading scores and prednisone doses, before and after at least six months of a single-dose infusion of rituximab, were audited in previously treatment-refractory MG patients in a resource-limited setting. Seventeen moderately-severe to severely symptomatic MG patients received single low-dose rituximab infusions (median 500-600 mg) after a median MG duration of 6 years; 13 individuals responded including 5/5 MuSK+MG, 7/10 AChR+MG and 1/2 double seronegative MG. Three (60%) MuSK+MG and three (30%) AChR+MG achieved persistent asymptomatic status. Although more MuSK+MG vs AChR+MG cases stopped prednisone (80% vs 20%, respectively), the prednisone doses in the AChR+MG group was significantly reduced ≥30% (p = 0.008) due to improved MG composite scores (p = 0.016) and with durable benefit (median 12 months). There were no differences between responders and non-responders in MG duration and age at infusion. These results suggest that a single low-dose rituximab infusion is worth trying in refractory MG, including AChR+MG patients, as some patients showed good and durable responses. These results are particularly relevant to resource-limited settings.

Relma-cel (JWCAR029) in relapsed and refractory B-cell non-Hodgkin lymphoma: A two-year survival update of a phase I study.

e19555 Background: B-cell non-Hodgkin lymphoma (B-NHL) has a very poor prognosis. Relma-cel (JWCAR029) is a CD19-targeted chimeric antigen receptor T (CAR-T) cell suspension. In a phase I trial performed in November 2017 in Beijing Cancer Hospital, China, JWCAR029 was used to treat relapsed/refractory B-NHL (R/R B-NHL) in adult patients, showing a high response rate and persistent response. This report aimed to update 2-year survival data generated in the above trial. Methods: This was an open-label, dose-escalating phase I study (JWCAR029-001, NCT03344367) involving patients with R/R B-NHL. The patients received a 3-day treatment with the conditioning chemotherapy regimen, consisting of fludarabine (25 mg/m2/day) and cyclophosphamide (250 mg/m2/day). Then, they received a single dose of intravenous JWCAR029 (25×106, 50×106, 100×106, or 150×106 CAR T cells). Two-year PFS and OS after JWCAR029 treatment were evaluated. The data were updated till the cut-off date of January 18, 2021. Results: A total of 23 patients with R/R B-NHL were enrolled, of whom 22 completed single-dose JWCAR029 cell infusion. All patients completed the 2-year follow-up, with a median time of 24.2 (95%CI 24.0-24.3) months. Based on the efficacy analysis set comprising 20 patients, the best ORR and CRR were 85.00% and 70.00%, respectively. In subgroup analysis, 1-year ORR and CRR in patients administered 100×106 cells were both 3/5 (60%); they were both 5/8 (62.5%) in those administered 150×106 cells. The 1-year and 2-year PFS rates (11 patients censored) were both 55.0%. Median PFS was not reached (95%CI 3.0 months-NA). The 1-year and 2-year PFS rates in patients administered 100×106 cells were both 60.0%; these values were both 62.5% in individuals treated with 150×106 cells. The 1-year and 2-year OS rates (3 patients censored) were both 68.6%. Median OS was not reached (95%CI 10.4 months-NA). The 1-year and 2-year OS rates in patients administered 100×106 cells were both 60.0%; these values were both 75.0% in those treated with 150×106 cells. A total of 6 patients (30%) died. No grade 3 and above CRS or NT were found. Conclusions: JWCAR029 was approved in China in September 2021 after the RELIANCE study (NCT04089215) reported its excellent efficacy and tolerable toxicity in the treatment of relapsed/refractory B-cell lymphoma. This report indicated that R/R B-NHL cases could benefit from JWCAR029. R/R B-NHL cases administered JWCAR029 at 100×106 or 150×106 cells had a promising response rate, with durable PFS and sustained OS benefits after 12 months. The effectiveness and safety of JWCAR029 need to be confirmed in the real-world setting. Clinical trial information: NCT03344367.

Comparative study between omega 3 fatty acid infusion versus octreotide in management of acute pancreatitis

Background: Acute pancreatitis is one of the commonest diseases. While some use octreotide infusion, some rely only on fluid therapy and symptomatic treatment. Ongoing research has commented about omega (ω) 3 fatty acid (FA) infusions being the future of acute pancreatitis treatment as it is cheap and has lesser side effects.Methods: This prospective comparative study was done in patients with acute pancreatitis. Patients were divided into two groups, with group A receiving ω-3 FA single-dose infusion of 60 ml/hour over 4-5 hours and the other group B were subjected to injection of octreotide 100 mcg IV 8th hourly for 5 days with IV fluids. The groups were compared based on improvement in biochemical markers, BISAP score and hospital stay.Results: 132 patients were divided into 2 groups, on day 3 serum amylase levels in the ω-3 FA group were 268.54±65.84, and the octreotide group was 299.18±94.31 (p value=0.032). Day 3 serum lipase levels in the ω-3 FA group were 137.07±62.19, and the octreotide group was 172.07±72.46 (p value=0.002). Day 3 BISAP score in the ω-3 FA group was 1.21±0.41, and the octreotide group was 1.39±0.49 (p value=0.023). The duration of hospital stay in the ω-3 FA group was 8.03±1.09 days and in the octreotide group was 11.83±1.04 days (p&lt;0.0001).Conclusions: Patients receiving ω-3 FA reported lower amylase-lipase levels along with a lower BISAP score. Hence looking for a cheaper and safer alternative, ω-3 FA infusion could reduce the problem on the patient and hospitalization concomitant expenses.

Inter-individual variability in pharmacokinetics and clinical features in pediatric patients with severe hemophilia A

IntroductionAs the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population. Materials and methodsPediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles. ResultSixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t1/2 (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t1/2) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = −0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20–30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10–20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed. ConclusionThis study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A.

Study of Hemodynamic Effects of Preoperative Single-Bolus Dexmedetomidine in Elective Laparoscopic Surgeries

Objective: To observe the hemodynamic effects of a single bolus dose of dexmedetomidine in patients undergoing elective laparoscopic surgeries. Methods: A total of 60 adult patients were randomized into two groups of 30 each. Group D patients were given 1 µg/kg dexmedetomidine in 50 mL of saline as a single-dose infusion over 10 min before induction. Group S patients were given a 50-mL 0.9% NS slow infusion over 10 min. Groups D and S patients were premedicated 10 min prior to surgery. Baseline vital and hemodynamic parameters were monitored during the perioperative period. Conclusion: Premedicating with a single bolus of 1 µg/kg IV dexmedetomidine has been proven safe and effective in maintaining perioperative hemodynamic stability, although few developed bradycardia and hypotension, which were managed without any adverse outcome. Furthermore, dexmedetomidine effectively reduced the incidence of shivering.

Del Nido versus HTK cardioplegia for myocardial protection during adult complex valve surgery: a retrospective study

BackgroundHistidine-tryptophan-ketoglutarate (HTK) and del Nido (DN) cardioplegia are intracellular-type and extracellular-type solution respectively, both can provide a long period of myocardial protection with single-dose infusion, but studies comparing the two are rare for adult cardiac surgery. This study aims to evaluate whether DN is suitable for cardioplegia in complex and high-risk valve surgery with long-term cardiac ischemia when compared with HTK.MethodsThe perioperative records of adult patients infused with DN/HTK as a cardioplegic solution who underwent complex valve surgery with an expected myocardial ischaemic duration longer than 90 min between Oct 2018 and Oct 2019 were analysed retrospectively.ResultsOf the 160 patients who received DN/HTK and underwent complex valve surgery, we propensity matched 73 pairs. Both groups achieved satisfactory cardiac arrest effects, and no significant difference was found in their cTnI and CK-MB levels within 12 to 72 h postoperatively. The DN group had a higher rate of return to spontaneous rhythm (0.88 v 0.52, P < 0.001), a lower frequency of postoperative severe arrythmias (12% v 26%, P = 0.036), a higher postoperative stroke volume (65 v 59 ml, P = 0.011) and a higher cardiac output (6.0 v 4.9 L/min, P = 0.007) as evaluated by echocardiography, fewer transfusions and shorter ICU stays (both P < 0.05). The two groups had similar inotrope usage and similar incidences of low cardiac output, morbidities and mortality. Subgroup analysis showed that when the aortic clamping time was greater than 120 min, the advantages of DN were weakened.ConclusionsDN can be safely applied to complex valve surgery, and it has a similar myocardial protection effect as HTK. Further prospective studies are required to verify these retrospective findings.Trial registration retrospectively registered.

Allogeneic, CD34 +, Umbilical Cordblood-Derived NK Cell Adoptive Immunotherapy for the Treatment of Acute Myeloid Leukemia Patients with Measurable Residual Disease

Although the majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR), most of them relapse due to measurable residual disease (MRD), leading to poorer prognosis. The elimination of MRD before morphological relapse in patients who achieved CR is therefore an important therapeutic strategy to achieve improved long term outcomes in AML.A promising approach is targeting MRD via natural killer (NK) cell adoptive immunotherapy. NK cells can be used without HLA matching (allogeneic), enabling the transfer of high numbers of immune effector cells, which were not exposed to cytotoxic chemotherapy. A phase I dose-escalation trial in ten elderly subjects with AML in morphologic CR after induction chemotherapy showed that a single infusion of an allogeneic NK cell product generated from umbilical cord blood-derived CD34 + cells, following cyclophosphamide/fludarabine (Cy/Flu) pre-conditioning, was safe and well tolerated, with some patients (2 of 4) achieving MRD negativity (Dolstra et al. 2017).Currently, our dose escalation and expansion trial with the “off-the shelf”, cryopreserved, allogeneic NK cell product GTA002 (NCT04632316) is ongoing in adults with AML who are in morphologic CR (including CRi) with MRD and who are not proceeding to allogeneic hematopoietic stem cell transplantation.Two patients have been dosed with a single GTA002 infusion of approximately 5 x 10 8 viable NK cells and completed 6- and 3-month follow-up, respectively. Patient #1 is a 73-year-old male, with AML with recurrent genetic abnormalities (including NPM1mut and FLT3-ITD), who initially received azacitidine and gilteritinib, leading to stable disease. Upon progression, the patient received further treatment with decitabine, followed by 3 cycles of azacitidine/venetoclax (aza/ven), which led to CRi with MRD persistence (confirmed by centralized multiparameter flow cytometry (MFC) on bone marrow (BM)). The patient then received cyclophosphamide (Cy) and fludarabine (Flu) as preconditioning regimen from day -6 to day -3 (Cy: 900 mg/m 2; Flu:15 mg/m 2/day; Flu adjusted for renal impairment), followed by a single intravenous infusion of GTA002 on day 0. The patient experienced a serious adverse event (SAE) on day 5 (grade 3 febrile neutropenia) deemed related to Cy/Flu, which fully resolved on day 16. MRD results by MFC on BM showed that patient #1 converted to MRD negativity (<0.1%) on day 0, which was sustained at 1, 2, 3 and 6 months. Interestingly, NPM1 MRD was detectable by next generation sequencing (MRD-NGS) up to month 1 in peripheral blood (PB), but was cleared by month 2, 3 and 6 in PB (<0.01%VAF). In line with the PB results, NPM1 MRD was detectable in BM at month 1 and was cleared at months 3 and 6.Patient #2 is a 78 year old male with a history of MDS with pancytopenia and IDH2, SRSF2 and PTPN11 mutations that evolved into AML with myelodysplasia-related changes. The patient achieved CR after receiving aza/ven, with MRD positivity after 3 cycles, leading to clinical trial inclusion. He was preconditioned with an adjusted dose of Cy/Flu (Cy 300 and Flu 30 mg/m 2/day from day -5 to day -3), with no SAEs reported. Analysis of BM by MFC showed MRD positivity at screening and on day 0, which turned to MRD negativity at month 1, turning positive again at month 2 and 3. Follow up in PB and BM by MRD-NGS showed that the IDH2 and SRSF2 clones persisted after preconditioning and GTA002 infusion, but the PTPN11 clone became undetectable in PB by Day 0 and in BM by month 2 and month 3.Taken together, these cases describe clearance of MRD by MFC and NGS in AML with a single dose infusion of allogeneic, CD34+ cord blood derived NK cells in one patient and clearance of the PTPN11 mutated clone in another one, reconfirming the excitement to further investigate this treatment strategy for disease control. The delayed clearance of MRD could suggest an ongoing immunotherapeutic effect that will be further investigated. DisclosuresHeuser: Karyopharm: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Bayer AG: Honoraria, Research Funding; BMS/Celgene: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; BergenBio: Research Funding; Astellas: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Tolremo: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Thol: Abbvie: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Pfizer: Honoraria; BMS/Celgene: Honoraria, Research Funding. Schwarzer: Bantam Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pinkernell: Medigene AG: Ended employment in the past 24 months; Glycostem Therapeutics: Current Employment. Ganser: Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Celgene: Honoraria.

RAPIDIRON: Reducing Anaemia in Pregnancy in India\u2014a 3-arm, randomized-controlled trial comparing the effectiveness of oral iron with single-dose intravenous iron in the treatment of iron deficiency anaemia in pregnant women and reducing low birth weight deliveries

BackgroundAnaemia is a worldwide problem and iron deficiency is the most common cause. In pregnancy, anaemia increases the risk of adverse maternal, foetal and neonatal outcomes.India’s anaemia rate is among the highest in the world with India’s National Family Health Survey indicating over 50% of pregnant women were affected by anaemia.India’s Anaemia Mukt Bharat-Intensified National Iron Plus Initiative aims to reduce the prevalence of anaemia among reproductive-age women, adolescents and children by 3% per year and facilitate the achievement of a Global World Health Assembly 2025 objective to achieve a 50% reduction of anaemia among women of reproductive age.However, preliminary results of the NFHS-5 survey completed in 2020 indicate that anaemia rates are increasing in some states and these targets are unlikely to be achieved. With oral iron being the first-line treatment for iron deficiency anaemia (IDA) in pregnancy, these results are likely to be impacted by the side effects, poor adherence to tablet ingestion and low therapeutic impact of oral iron. These reports suggest a new approach to treating IDA, specifically the importance of single-dose intravenous iron infusions, may be the key to India effectively reaching its targets for anaemia reduction.MethodsThis 3-arm, randomized controlled trial is powered to report two primary outcomes. The first is to assess whether a single dose of two different intravenous formulations administered early in the second trimester of pregnancy to women with moderate IDA will result in a higher percentage of participants achieving a normal for pregnancy Hb concentration at 30–34 weeks’ gestation or just prior to delivery when compared to participants taking standard doses of oral iron. The second is a clinical outcome of low birth weight (LBW) (< 2500 g), with a hypothesis that the risk of LBW delivery will be lower in the intravenous iron arms when compared to the oral iron arm.DiscussionThe RAPIDIRON trial will provide evidence to determine if a single-dose intravenous iron infusion is more effective and economically feasible in reducing IDA in pregnancy than the current standard of care.Trial registrationClinical Trials Registry – India CTRI/2020/09/027730. Registered on 10 September 2020, http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=46801&EncHid=&userName=anemia%20in%20pregnancy