Infusion-related Side Effects Research Articles

“Click” amphotericin B in prodrug nanoformulations for enhanced systemic fungemia treatment

Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free “Click” drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG5kBA4 has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG5kBA4 demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study

Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Low-Dose Immune Tolerance Induction Therapy for Severe Hemophilia a Inhibitor Patients: Immunosuppressants Improve Outcomes but Are Generally Not Necessary for Inhibitor-Titer below 200 BU/Ml

Background We previously showed that low-dose immune tolerance induction (ITI) incorporating immunosuppressants (IS) for severe hemophilia A patients with inhibitor titer ≥40 Bethesda Units (BU)/mL (LD-ITI-IS 40 regimen) had relatively high success rate with lower cost compared to those on high-dose ITI. Recent evidence suggested that patients with inhibitor titer &amp;lt;200 BU/mL do not need high-dose ITI raising the question that IS may also not be necessary. Objectives To compare the efficacy of LD-ITI incorporating IS only for inhibitor titer ≥200 BU/mL (LD-ITI-IS 200 regimen) with that of LD-ITI-IS 40 regimen. Methods A prospective, single-arm, single-center cohort study on patients receiving LD-ITI-IS 200 beginning 2021, compared to those receiving LD-ITI-IS 40 before 2021. The inclusion criteria were: (i) patients with an established diagnosis of SHA [FVIII clotting activity (FVIII: C) &amp;lt;1% before inhibitor development]; (ii) patients ≤14 years age at the ITI-start; (iii) patients with high-titer inhibitors (≥5BU/mL). All study patients received a LD-ITI with pd-FVIII/VWF (at 50 FVIII IU/kg) every-other-day. IS (rituximab + prednisone) were added for peak inhibitor-tier ≥40 BU/mL in LD-ITI-IS 40 regimen and ≥200 BU/mL in LD-ITI-IS 200 regimen. IS used for each regimen included rituximab 375 mg/m 2/week (maximum 600 mg) for 4 weeks, together with prednisone 2 mg/kg/day (maximum 60 mg) for one month, then tapered over 3 months. For patients receiving rituximab, intravenous immunoglobulin (200 mg/kg/month for 6 months) was administered for infection prophylaxis. Success is defined as negative inhibitor plus FVIII recovery ≥66% of the expected. Partial success is defined as achieving inhibitor elimination but with persistently abnormal FVIII recovery. Results We enrolled 30 patients on LD-ITI-IS 200 and 64 patients on LD-ITI-IS 40, with similar baseline clinical characteristics (Table 1). Given that IS was initiated at a higher peak inhibitor-titer in the LD-ITI-IS 200 regimen, IS in the LD-ITI-IS 200 group was introduced at a significantly lower rate than that in the LD-ITI-IS 40 regimen group (30% vs. 62.5%, p = 0.003). The 2 regimens (LD-ITI-IS 200 vs.LD-ITI-IS 40) had similar success rate (66.7% vs. 79.7%), median time to success (7.4 vs. 10.6 months) (Figure 1), and ABR during ITI (3.7 vs. 2.8). The per kg treatment cost from ITI-start to ITI success in the LD-ITI-IS 200 (US$2167) was significantly lower than that in the LD-ITI-IS 40 (US$3349). Among patients taking IS in the two regimens rituximab infusion-related side effects were similar, being 22.2% (2/9) for the LD-ITI-IS 200 patients and 22.5% (9/40) for the LD-ITI-IS 40 patients. All these side effects could be resolved and subsequently prevented by antihistamine drugs. No severe adverse events occurred. Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS 200 regimen) and 28 IS-using (on LD-ITI-IS 40 regimen) had similar success rate (60% vs. 78.6%) and time to success (9.0 vs. 8.8 months). The per kg treatment cost from ITI-start to ITI partial success in the LD-ITI-IS 200 (US$891) was significantly lower than that in the LD-ITI-IS 40 (US$2819). Between the two protocols, there were 12 patients with peak inhibitor-titer ≥200BU/mL (all using IS, 7 in LD-ITI-IS 200, 5 in LD-ITI-IS 40). Among them, 8 patients (66.7%, 4 on each regimen) achieved success over a median 10.1 months, and none relapsed at median 13.5 months follow-up since achieving success. Between the 2 protocols, there were 44 patients (13 in LD-ITI-IS 200, 31 in LD-ITI-IS 40) with peak inhibitor-titer 5-39 BU/mL. Their overall success rate was 79.5%. Nine of the 44 patients (2 in LD-ITI-IS 200, 7 in the LD-ITI-IS 40) received IS because they failed to have adequate inhibitor titer decline in the first 3 months of ITI. All 9 achieved success at median 11.3 months from ITI-start with no relapsed after a median 22.6 months follow-up since success. Conclusions We have optimized the use of IS in our low-dose ITI protocol for SHA patients with high-titer inhibitors. We showed that more restrictive use of IS only for patients with peak inhibitor-titer ≥200 BU (instead of at a lower titer of ≥40 BU) maintained the same efficacy while decreasing the cost. Decreasing use of IS would decrease its potential side effects including infection risks.

Amphotericin B and monoacyl-phosphatidylcholine form a stable amorphous complex

Amphotericin B (AmB) is a “life-saving” medicine for the treatment of invasive fungal infections and visceral leishmaniasis. To date, all marketed AmB formulations require parenteral administration, which causes high rates of acute infusion-related side effects and dose-dependent nephrotoxicity. The development of an oral AmB formulation will entail numerous advantages including increased patient compliance, eliminated infusion-related toxicities and reduced nephrotoxicity. Unfortunately, the gastrointestinal absorption of AmB is negligible due to its extremely low solubility in both aqueous and lipid solvents, and its poor gastrointestinal permeability. Drug-phospholipid complexation is an emerging strategy for oral delivery of poorly soluble drugs. In this study, monoacyl-phosphatidylcholine (MAPC) was complexed with AmB forming an AmB-MAPC complex (APC), to enhance the dissolution rate and aqueous solubility of AmB, in order to enable oral delivery of AmB. X-ray powder diffraction demonstrated that AmB was transformed to its amorphous form following complexation with MAPC, i.e. in the APC. Fourier-transform infrared spectroscopy suggested molecular interactions between AmB and MAPC. Dynamic light scattering indicated formation of colloidal structures after aqueous dispersion of APC; Cryogenic transmission electron microscopy showed that APC formed small round, “rod-like” and “worm-like” micellar structures and Small-angle neutron scattering provided three-dimensional micellar structures formed by APC upon aqueous dispersion, which indicated that AmB was inserted into the micellar mono-layer membrane formed by MAPC. Additionally, APC showed an increased dissolution rate and a higher amount of AmB solubilized in fasted state simulated intestinal fluid, compared to AmB/MAPC physical mixtures and crystalline AmB. In conclusion, an APC exhibiting amorphous properties was developed, the APC showed improved dissolution rate and increased apparent aqueous solubility compared to AmB, indicating that the application of APC could be a promising strategy to enable the oral delivery of AmB.

Autologous Stem Cell Transplantation (ASCT) for Refractory Juvenile-Onset Systemic Sclerosis (jSSc) Is Safe and Well Tolerated and Improves Clinical and Patient-Reported Outcomes

Introduction: jSSc is a rare autoimmune disease that leads to inflammation, fibrosis, and dysfunction of multiple organ systems which can cause skin sclerosis, interstitial lung disease (ILD), myositis, fasciitis, gastrointestinal and vascular disease. Severe SSc is often refractory to immunomodulatory medications including newer targeted agents. ASCT has demonstrated success in adults with SSc, but experience and data in pediatric patients is limited. Methods: We report our first four consecutive adolescent and young adult ASCT patients. All patients were referred to our scleroderma center at UPMC Children's Hospital of Pittsburgh where they were evaluated by our multidisciplinary team. Baseline patient characteristics are summarized in Table 1. Patients met criteria for ASCT by severity of lung or skin disease, or both. The first 3 patients had severe ILD or musculoskeletal chest wall weakness resulting in pulmonary function tests (PFTs) below traditional cut offs for adult SSc ASCT trials. All four patients had refractory disease and had previously received 3-8 immunomodulatory medications. Autologous stem cells were mobilized with cyclophosphamide and filgrastim and collected via pheresis. Following this, conditioning chemoradiation was administered per an IRB-approved individual treatment plan (Patients 1-3) or on our clinical trial NCT03630211 (Patient 4) with rituximab, anti-thymocyte globulin (ATG), TBI 600 cGy with lung and kidney shielding, and cyclophosphamide or thiotepa +/- alemtuzumab. A CD34+ selected cryopreserved autologous peripheral blood stem cell graft was infused on day 0. Antimicrobial prophylaxis was given per institutional standard and PCRs for EBV, CMV and adenovirus were closely monitored. Steroids were weaned off by 5 weeks post-ASCT. Results: The median cell dose was 5.9 e6 CD34/kg. All patients engrafted, with median neutrophil engraftment on day 11 (range 11-15), and median platelet engraftment (>50K) on day 18.5 (range 16-20). There were infusion-related side effects with equine ATG, but none with rabbit ATG. There were no cases of sinusoidal obstructive syndrome, thrombotic microangiopathy or clinically significant bleeding. No patients required a PCA for pain and received minimal (median=3) doses of narcotics. Patients were discharged from the hospital a median of 19 days after transplant (range 17-21). Only one patient was readmitted, and had a negative 48 hour infectious rule out. Two patients acquired COVID-19 infections at 5 and 19.5 months post-ASCT; both remained outpatient with quick improvement after treatment with best available therapy. There were no viral reactivations, bacterial or fungal infections. There has been no evidence of organ toxicity and there are objective improvements in clinical parameters as well as patient reported outcomes (PROs) over the follow-up visits (Table 2). All patients demonstrated an improvement in their skin involvement, as measured by the modified Rodnan Skin Score (mRSS). There was an improvement in clinical symptoms and exam findings of Raynaud's. The lower esophageal sphincter became less hypotensive; objective measures and symptoms of gastroesophageal reflux were much improved. Despite severely reduced values of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) prior to ASCT, all subjects regained pre-ASCT values. All patients demonstrated an improvement in their PROs and report improvement in fatigue, pain, and the ability to participate in activities of daily living. All patients are off immunomodulatory medications. Tandem serial skin biopsies of the forearm support decreased collagen burden and disappearance of a myofibroblasts population with single cell RNA sequencing (n=3, timepoints 0, 6, 12 mos; data not shown), which correlates with an improvement in the skin score. Conclusions: In refractory jSSc patients, ASCT is well tolerated, even in patients with severe disease who would otherwise not be eligible for clinical trials based on exclusion criteria that were developed for adults with SSc. ASCT can serve as a hard reset to the immune system for patients with this refractory autoimmune disease, with improvements in clinical parameters that reflect disease modification involving the skin, musculoskeletal, vascular, and gastrointestinal systems. Further clinical research treating patients with this rare disease is of great need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P043 Amphotericin B in pediatrics: analysis by age stratification suggests a greater chance of adverse events from 13-month of age onward

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMBackgroundDeoxycholate amphotericin B (D-AMB) remains an antifungal of great therapeutic value in pediatrics. It is generally accepted that its use in neonates is safer than in older children. However, childhood presents different periods of development which deserves to be evaluated more precisely. Our goal was to assess the usage profile of D-AMB in stratified pediatric age groups, adapted according to the National Institute of Child Health and Human Development (NICHD) classification.MethodsWe conducted a retrospective cross-sectional observational study at a Brazilian tertiary children's hospital. Nonparametric tests were applied, such as the chi-square test to compare proportions and Fisher's exact test to assess the association between categorical variables or in contingency tables.ResultsA total of 127 medical records were stratified as preterm neonatal (birth <37 weeks postmenstrual age), term neonatal (birth 27 days), infants (28 days-12 months), toddler (13 months-2 years), early childhood (3-5 years), middle childhood (6-11 years) and early adolescence (12-18 years). Very few acute infusion-related side effects were observed during administration of D-AMB in pediatrics. We found an unfavorable impact of D-AMB from 13 months onward, suggesting this group as a turning point for a greater chance of adverse events, and not soon after the neonatal period as is conventionally known (Fig. 1).ConclusionsClinical or observational studies based on age stratification are essential to precisely elucidate whether drugs with toxicity potential can be used safely in the pediatric population. Searching for a turning point has been shown to contribute to the accuracy of the study, while providing more substantial information on the impact of D-AMB on different pediatric age groups.

Infusion-related side-effects during convection enhanced delivery for brainstem-diffuse midline glioma/diffuse intrinsic pontine glioma

IntroductionSide-effects during convection enhanced delivery (CED) are poorly understood. We intended to determine the frequency of side-effects during brain stem infusion and determine risk factors for side-effects persisting longer than 24 h.MethodsChildren with a radiological diagnosis of brain stem diffuse midline glioma/Diffuse Intrinsic Pontine Glioma were treated on compassionate grounds with awake infusion of carboplatin and sodium valproate into the brain stem using the 4-catheter (2 trans-cerebellar 2 trans-frontal) chronic, intermittent Renishaw Drug Delivery System. We used change in the Pontine Neurological Observation Score (PONScore), a standardised neurological assessment tool, to identify side-effects during infusion. Recovery was determined by retrospective chart review.Results55 infusions were performed in 8 children (3–11 years). Mean PONScore increased during infusion from 3.3 to 5.7 (p-value > 0.001). One hundred and fifty-seven infusion-related side-effects were identified including headache (33/157) and limb weakness (49/157). Fifty-four side-effects persisted > 24 h. Side-effects that had occurred during a previous infusion and those that occurred during infusion via trans-cerebellar catheters were more likely to be persistent with OR 2.333 (95% CI 1.094–4.976; p-value = 0.028) and 2.155 (1.029–4.513; p-value = 0.042) respectively. If infusion was stopped or titrated at onset rather than continued, the side-effect was less likely to persist > 24 h, OR 0.473 (95% CI 0.177–0.948; p-value = 0.037). Most side-effects developed within the first three millilitre of infusion.ConclusionsSide-effects during brainstem infusion are common, can be transient or persist longer than 24 h. Neurological injury during infusion may be time dependent and accumulative rather than volume dependent.

Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial.

Introduction Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials. Methods This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group (n = 5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group (n = 4) received SMT plus 5 infusions of 1 × 106 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t-test and Mann–Whitney U test for quantitative variables. The Kaplan–Meier estimator was used to build survival curves. In this study, we followed the intention-to-treat analysis, with a significance of 5%. Results Nine patients with a mean Child–Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. The average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. The survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0). Conclusion BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3.

Chimeric Anti CD-20 Monoclonal Antibody-Rituximab in Refractory Childhood Idiopathic Thrombocytopenic Purpura: An Indian Experience.

The treatment of chronic idiopathic thrombocytopenic purpura (ITP) continues to be a challange. A significant proportion of patients continue to be symptomatic despite all available means of therapy. Recently Rituximab, a chimeric anti CD-20 monoclonal antibody has been shown to be an effective mode of therapy in such patients with an overall response rate of appx 50 %.We studied the efficacy and side effects of this therapeutic modality in 10 children (6 girls) with chronic ITP. The patients belonged to pediatric age group (median age: 9 years, range 4–18 years) with 4 children less than 10 years of age. All the patients were screened for systemic illnesses and different secondary causes leading to thrombocytopenia. They all had been treated with standard therapies using conventional and high dose steroids, ciclosporin cyclophosphamide, vincristine, periodic use of high dose IVIG and splenectomy in 6 patients, but had continued to be symptomatic with recurrent mucocutaneous bleeds and markedly low platelet counts (< 20x 109/L). All patients received intravenous Rituximab at a dose of 375 mg/M2 as weekly dose for 4 consecutive weeks. The infusion related side effects were a few (n= 3) and minor. They included urticarial rash (1) and fever(2) that responded to antipyretics. None of these were severe enough to interrupt the treatment. A complete response was defined as a platelet count > 100 x 109/L, partial response (PR) as count > 50x109/L and a minor response as a count < 50x109/L but without the need of continued treatment. Patients showing no significant rise in platelet count were marked as showing no response. Of the 10 evaluable children, 9 (90%) showed overall response; 4 (40%) showed complete response and 4 (40 %) showed partial response. Two (20%) patients showed minor responses. Patients have been under follow up for last 3 years. The patients with CR and PR have been in remission for longer periods (as much as 150 weeks ).The side effects due to the therapy have been few and very mild. Besides infusional reactions in 3 patients (Transient fever in 2 and mild rash in 1) there were no significant toxicities. No correlation could be found between clinical/laboratory parameters with the responsiveness or the duration of response except that patients showing a higher degree of response continued to be in remission for a longer period as compared to the ones with lesser degree of response. The high percentage of response in our patients as compared to the ones in other studies could be due to the fact that our patients belonged to a younger age group. Probably children show a better response.In conclusion, Rituximab offers a safe and convenient modality of treatment in symptomatic children with refractory ITP. Its use is certainly cost effective even in a developing country in view of the good degree of a sustained response in these refractory patients wherein all modalities of treatment have failed.

DOP74 Initial Clearance of infliximab is a predictor for the time of formation of anti-drug antibodies

Abstract Background Treating patients with biologics like infliximab (IFX), may cause the formation of antidrug antibodies (ADA). ADA are associated with faster drug clearance, reduced treatment efficacy and increased risk of infusion-related side effects. The aim of this study is to identify possible predictors for ADA-formation. Methods A time to first detection of ADA model was developed by using data from a Phase 3 clinical trial of biosimilar CT-P13 and originator infliximab comparing efficacy and safety in moderately to severely active Crohn’s disease (CD). We analyzed data from 220 patients initiating IFX. Seven subjects with ADA present at baseline were discarded. The following baseline covariates were evaluated in this analysis: age, weight, first estimated drug clearance, disease duration, dose, sex and concomitant immune-modulators. Continuous covariates were divided into lower quartile, inter-quartile range, and upper quartile bins. Kaplan-Meier survivor estimates were plotted by bin. The data was then modeled parametrically with NONMEM by constructing a full model which was further refined using the Wald’s Approximation Method algorithm. Hazard ratios and probability of ADA at time points of interest were calculated for significant covariates. Results Initial IFX clearance, concomitant immunomodulators and IFX dose were identified as being statistically significant predictors of the time to first ADA. The model suggested that the hazard of ADA increases by 61% for every increase on 0.1 L/day in clearance, it decreases by 41% with concomitant administration of immunomodulators and decreases by 29% for every increase in dose of 100 mg. Thus, for a patient with initial IFX clearance of 0.2 L/day, no immunomodulators and a dose of 328 mg, the average time to first ADA is 374 days (range 221–451). If clearance is 0.4 L/day under the same conditions, then ADA onset is 144.5 days (range 90–216). Increasing the starting dose to 428 mg would improve the time to onset to 203 days (range 110–337). Again, under the same conditions, adding immunomodulator would increase the time to onset to 354 days (range 214–451). Conclusion We have identified initial infliximab clearance as an independent predictor for onset of ADA in CD patients. Our results suggest that early assessment of clearance should guide treatment optimization with IFX in patients with CD, including the addition of concomitant immunosuppressants or increasing the dose during induction.

COMPARISON OF ALEMTUZUMAB AND ANTI-THYMOCYTE GLOBULIN TREATMENT FOR ACUTE KIDNEY ALLOGRAFT REJECTION

Rabbit anti-thymocyte globulin (rATG) is currently the treatment of choice for glucocorticoid-resistant, recurrent, or severe acute allograft rejection (AR). However, rATG is associated with severe infusion-related side effects. Alemtuzumab is incidentally given to kidney transplant recipients as treatment for AR. In the current study, the outcomes of patients treated with alemtuzumab for AR were compared with that of patients treated with rATG for AR. The patient-, allograft-, and infection-free survival and adverse events of 116 alemtuzumab-treated patients were compared with those of 108 patients treated with rATG for AR. Propensity scores were used to control for differences between the two groups. Patient- and allograft survival of patients treated with either alemtuzumab or rATG were not different [hazard ratio (HR) 1.14, 95%-confidence interval (CI) 0.48-2.69, p = 0.77, and HR 0.82, 95%-CI 0.45-1.5, p = 0.52, respectively). Infection-free survival after alemtuzumab treatment was superior compared with that of rATG-treated patients (HR 0.41, 95%-CI 0.25-0.68, p < 0.002). Infusion-related adverse events occurred less frequently after alemtuzumab treatment. Alemtuzumab therapy may therefore be an alternative therapy for glucocorticoid-resistant, recurrent, or severe acute kidney transplant rejection.

Hydroxyethyl starch is an alternative washing solution for peripheral bloodstem cells products

Cryopreservation of hematopoietic stem cells (HSC) involves slow rate cooling in the presence of a cryoprotectant (DMSO) to avoid the damaging effects of intracellular ice formation. The infusion of DMSO with the thawed product has been related to adverse events. Reduction of DMSO content by washing the HSCs after thawing has been suggested as a method to avoid infusion-related side-effects. Albumin-dextran washing methods have proved useful in thawing HSC products. Dextran40 shortages prompted us to search for suitable alternatives. We report the results of a comparative study of the use of hydroxyethyl starch (HES) as an alternative to dextran40 for washing thawed HSCs products. A total of 10 HSC bags cryopreserved with 10 % DMSO were used. We conducted a paired study; one of the bags was thawed and washed with our standard washing solution (Dextran 40) and the paired bag with HES solution with a final HES and Human Serum Albumin (HSA) concentration of 2.4 % and 4.2 % respectively. Each final product was tested immediately after washing (sample 0’) and after 90 min (sample 90’) for total nucleated cells (TNC) recovery, acridine orange viability, viable CD34+ enumeration, and clonogenicity. No significant difference was found for any of the cell counts, viability tests, cell recovery, or potency. We can state that the washing solution based on 2.4 % HES and 4.2 % HSA is equivalent to that used in our routine practice. Therefore, we could use the solution with HES, paying special attention to the renal function of the recipient.

Intravenous immunoglobulin for presumed viral myocarditis in children and adults.

Intravenous immunoglobulin for presumed viral myocarditis in children and adults.

Rituximab in the treatment of multiple sclerosis in the Hospital District of Southwest Finland

BackgroundThere are already numerous B-cell depleting monoclonal anti-CD20 antibodies which have been used to reduce the inflammatory burden associated with multiple sclerosis (MS). We describe here our experience of treating MS-patients with B-cell depleting rituximab. Patients and methodsAll MS-patients (n = 72) who had received rituximab treatment for at least six months by January 2019 were identified from the patient charts at the Turku University Hospital. Information about MS disease subtype, disease severity, MR-imaging outcomes and B-cell counts were collected from the charts. ResultsRituximab was well received and well tolerated by the patients. There were no serious infusion-related side effects. The most serious adverse event that led to treatment discontinuation was neutropenia. After rituximab initiation the annual number of relapses was decreased in the relapsing remitting and secondary progressive MS groups and the mean number of gadolinium-enhancing lesions was decreased in relapsing remitting MS. Our study confirms the usability of rituximab treatment for MS in the Finnish health care environment. ConclusionsOff-label rituximab-treatment can be successfully used to reduce MS disease burden for the benefit of MS patients.

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy.

Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

Hyper-Sialylated IgG M254, an Innovative Therapeutic Candidate, Evaluated in Healthy Volunteers and in Patients with Immune Thrombocytopenia Purpura: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics

Hyper-Sialylated IgG M254, an Innovative Therapeutic Candidate, Evaluated in Healthy Volunteers and in Patients with Immune Thrombocytopenia Purpura: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics

Comparative Analysis of Alpha-Beta T-Cell and B-Cell Depleted (abTCD) HLA-Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT) Versus Abtcd Haplo-HSCT with T-Cell Add-Back of Rivogenlecleucel Cell [Donor T Cells Transduced with the Inducible Caspase 9 (iC9) Gene Safety Switch] in Children with High-Risk Acute Leukemia (AL) in Remission

Background: For children with AL candidate to receive an allograft and lacking a suitable HLA-matched donor, HLA-haplo-HSCT after abTCD may represent a valid alternative. Due to delayed recovery of adaptive T-cell immunity with abTCD-haplo-HSCT alone, we conducted a phase I/II trial testing the safety and efficacy of post-transplant infusion of a titrated number of donor-derived T cells transduced with the iC9 gene (rivogenlecleucel; ClinicalTrials.gov id: NCT02065869) in children with malignant and non-malignant diseases. Here, we report on the cohort of 70 patients with AL treated in Italy with abTCD-haplo-HSCT+rivogenlecleucel, comparing the results with those of 88 patients given abTCD-haplo-HSCT alone and previously published by our group (Blood 2018; 132:2594-2607). Patients and methods: Patients (age &amp;lt; 18 years) were transplanted between 2010 and 2018. Patient and disease characteristics are shown in Table 1. Median age at HSCT was 6 years (range 0.3-18), and median follow-up was 71 and 31 months for abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. Compared to the control group, abTCD-haplo-HSCT+rivogenlecleucel recipients were transplanted more recently and from a younger donor, and received a higher number of CD34+ cells (Table 1). Diagnosis did not differ between the 2 groups, acute lymphoblastic leukemia (ALL) being the most frequent diagnosis. All patients were transplanted in morphological complete remission (CR1 and CR2) and received myeloablative preparation. Graft composition is reported in Table 1; notably all patients received &amp;gt;10x106 CD34+cells/Kg and &amp;lt;1x105 alpha-beta+ T-cells/Kg. Patients did not receive any pharmacological post-transplant graft-versus-host disease (GvHD) prophylaxis. Results: Graft failure occurred in 2% of patients in each group. Median time to neutrophil and platelet engraftment was 14 (6-23) and 11 (5-56) days, with no differences between groups (p=0.28). Rivogenlecleucel were infused at a median time of 21 days (range 11-59). Treatment was well tolerated; no infusion-related side effects were recorded. Cumulative incidence (CI) of 100-day grade II-IV acute GvHD was 18.9% vs 15.9% (p=0.77) and CI of 1-year chronic GvHD was 6.9% vs 5.7% (p=0.56) in abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. The 4-year non-relapse-mortality (NRM) was significantly lower in abTCD-haplo-HSCT+rivogenlecleucel (1.4% vs 8%, p=0.05) (Figure 1). There was no statistically significant difference in the 4-year CI of relapse (RI) (17% vs. 25%, p=0.30), respectively. Disease recurrence was the most common causes of death in both groups, viral and fungal infections being the most frequent non-relapse fatalities. The 4-year overall survival (OS) and leukemia-free survival (LFS) was 70% vs 87%, p=0.01 (Figure 2) and 67% vs 82%, p=0.05, for abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. There was no difference in 4-year CI of CMV reactivation between the 2 groups (p=0.68), median time to CMV reactivation being 29 and 30 days (p=0.29), respectively. Once infused, rivogenlecleucel expanded (mainly in the CD8+ subset), reaching a peak at 9 months after infusion. At 6-months, median CD3+, CD3/CD4, CD3/CD8, CD3-/CD56 and CD20/CD19 count/microL were 820, 265, 225, 141, 171, for abTCD-haplo-HSCT and 898, 294, 288, 214, and 161 for abTCD-haplo-HSCT+rivogenlecleucel, (p=ns, p=ns, p=0.02, p=0.03, p=ns), respectively. The advantage in the recovery of CD3/CD8 and CD3-/CD56 after abTCD-haplo-HSCT+rivogenlecleucel persisted at 1 year (p=0.01, p=0.03, respectively). In multivariable analysis, abTCD-haplo-HSCT+rivogenlecleucel was associated with better OS (HR 0.27, p=0.003) and LFS (HR 0.40, p=0.001); there was also a trend for lower relapse risk (HR 0.50, p=0.098). Age below the median value at HSCT (HR 2.62, p=0.01), CR1 at HSCT (HR 0.35, p=0.03) and use of irradiation in the conditioning regimen (HR 0.32, p=0.02) were other factors correlating with OS and LFS. Conclusions: These data confirm that the infusion of donor-derived rivogenlecleucel is safe and well tolerated. Rivogenlecleucel cells infusion contributed to enhance recovery of cytotoxic T and NK cells, improving patients NRM and OS/LFS. Rivogenlecleucel (with the possibility of inducing apoptosis of donor T cells) may facilitate the cellular therapy approaches aimed at optimizing immune recovery after HSCT. Disclosures Merli: Amgen: Honoraria; Bellicum: Consultancy; Novartis: Honoraria; Sobi: Consultancy. Algeri:Bluebird bio: Consultancy, Honoraria; Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria. Woodard:Bellicum Pharmaceuticals, Inc: Employment, Other: Stock, Stock options. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy.

2701 Not Your Usual Gastritis: A Case Report of Pembrolizumab-Induced Lymphocytic Gastritis

INTRODUCTION: Pembrolizumab induces immune checkpoint inhibition of programmed cell death protein-1 (PD-1 inhibitors) in various malignancies. Toxicities have been described, including but not limited to, inflammatory reaction in any system, and infusion related side effects. We report a rare case of symptomatic lymphocytic gastritis after pembrolizumab treatment of vocal cord squamous cell carcinoma. CASE DESCRIPTION/METHODS: 70 year old female with history of right true vocal cord squamous cell carcinoma status post excision and chemoradiation with cisplatin. Recurrence in 1 year to the anterior vocal cord prompted treatment with pembrolizumab. Patient suffered complete esophageal occlusion requiring multiple EGDs with dilatation, gastric tube placement, morphine and transcutaneous fentanyl analgesia. During pembrolizumab treatment she developed new onset nausea and vomiting, intolerance to feeding regimen for 3 weeks, and a 10 pound weight loss in 1 week but no change in bowel movements, melena, abdominal pain, or fever. Physical exam was significant for cachectic female, LUQ G-tube in situ with no erythema/discharge, no abdominal tenderness, rigidity, or organomegaly, normal bowel sounds, and normal rectal exam. Lab work up was not significant. EGD was performed showing diffuse erythematous mucosa in the entire examined stomach. Biopsy showed lymphocytic gastritis negative for metaplasia, dysplasia, or neoplasia with no H-Pylori or other infectious organisms. Patient was started on prednisone 60mg daily with slow taper, metoclopramide, ondansetron PRN, and pembrolizumab was stopped. GI symptoms improved significantly with resolution of emesis. DISCUSSION: Lymphocytic gastritis (LG) is a rare subtype linked with H-pylori infection, celiac, lymphoma, and medication side effect. Patient might be asymptomatic or exhibit dyspepsia, nausea, vomiting or weight loss. Work up includes EGD; however, endoscopic appearance can be nonspecific as patients might have erythema, erosions, nodules or normal appearing mucosa. Diagnosis is made when biopsies show intraepithelial lymphocytes with more than 25 in 100 epithelial cells. Recommended treatment is based on etiology and included removing the offending agent, H-pylori eradication and/or gluten free diet. Steroids are not usually considered in the treatment of LG, but they are proposed as first line therapy in treatment of PD-1 inhibitor related side effects (enteritis, colitis, etc). Our patient had good response to steroids as her LG was induced by PD-1 inhibitor.

Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion.

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of αβ T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The αβ T-cell depleted cell products were characterized by flow cytometry. The median log depletion of αβ T-cells was −4.3 and the median yield of γδ T-cells was 73.5%. The median CD34+ cell dose was 4.4 × 106/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of αβ T-cell depleted products as stem cell boosters with encouraging results.

Anti-CD123 Targeted Therapy with Talacotuzumab in Advanced MDS and AML after Failing Hypomethylating Agents - Final Results of the Samba Trial

IntroductionRecently, progress has been made in the treatment of patients with higher risk myelodysplastic syndromes (HR MDS) and acute myeloid leukemia (AML). Nevertheless, patients failing hypomethylating agents (HMA) have a dismal prognosis and very limited treatment options. Targeting CD123 on leukemic stem cells (LSC) is one promising approach in MDS and AML. Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells (NKs).AimThe SAMBA trial, a phase II study of the German and French MDS study groups within the EMSCO network assessed the overall hematological response rate after 3 months of single agent TAL treatment in AML or HR MDS patients failing hypomethylating agents (HMAs).MethodsTAL was given IV at a dose of 9 mg/kg once every two weeks for a total of 6 infusions, responders received up to 20 additional infusions. After the first 3 months, overall hematological response rate (either CR, PR, marrow-CR, HI, SD) was evaluated by bone marrow biopsy. The study was accompanied by an immune monitoring via flow cytometric analysis to investigate the distribution of T- and NK cells in peripheral blood (PB) and bone marrow (BM) at the time of screening and during therapy in comparison with healthy, age-matched controls.Results24 patients (19 AML and 5 HR MDS) with a median age of 77 (range 71-90) years, who either failed to achieve complete- (CR), partial response (PR), hematological improvement (HI) or relapsed after HMA therapy were included in the study. After TAL administration, 14 patients could be assessed for response after 4 infusions and 10 patients after 6 infusions. The overall response rate (ORR) was 20.8% including 1 complete remission (CRi), 1 patient with hematologic improvement (HI-E) and additionally 3 patients with disease stabilization. The median duration of response in these patients was 3 months (range 3-14 months). Two patients are still on treatment, one patient despite losing objective response (14 months) and one patient with disease stabilization (13 months). The median overall survival for the entire cohort of patients was 3.2 months (range 0.4-11.2 months). In 10 patients (41.6%), therapy with TAL resulted in grade 3/4 infusion related side effects (pneumonia, n=1; infusion-related reaction, n=8; septic shock, n=1).Before treatment initiation, patients had lower levels of CD56dim NK-cells in PB (82% vs. 89% of NK-cells; p=0.069) expressing significantly more inhibiting NK-cell receptors like KIR2DL2 (8.8% vs. 3.2% of NK-cells; p<0.001) and less activating NK-cells receptors like NKG2D (95% vs. 99% of NK-cells; p<0.01) compared to healthy controls. Moreover, expression of PD-1 on lymphocytes and monocytes as well as their matching ligands PD-L1 and PD-L2 on blasts and monocytes in PB was significantly higher in patients compared to healthy controls (p<0.01), another evidence for an exhausted T-cell immune status in our patients prior to treatment initiation.We could not detect any difference in NK-cell levels in responding patients compared to non-responders. Interestingly, pre-treatment expression (MFI and percentage) of CD123 on immature myeloid derived suppressor cells (iMDSC) was higher in responders than in non-responders (p<0.01). Anti-CD123 targeted therapy with TAL resulted in a decreased CD123+ MFI (4239 vs. 2910; p<0.01) on iMDSCs as well as lower levels of iMDSCs in PB and BM (p<0.05).Responding patients displayed a 10-fold reduction of CD123 MFI after 3 months of treatment (2565 vs. 236; p=0.06), indicating that the CD123 molecule on immature MDSCs is targeted effectively by TAL.ConclusionSingle agent TAL has limited efficacy in patients with advanced myeloid malignancies failing HMA. Expression of CD123 on immature MDSCs might serve as a biomarker of response for future anti-CD123 targeted approaches. [Display omitted] DisclosuresGötze:Celgene: Honoraria, Research Funding; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017. Krönke:Celgene: Honoraria. Middeke:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ades:JAZZ: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; silent pharma: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Platzbecker:Celgene: Research Funding.