Infusion-related Adverse Reactions Research Articles

Efficacy and Safety Analysis of Carfilzomib-Containing Regimen in the Treatment of Multiple Myeloma：a Multicenter Real-World Study

Purpose To investigate the efficacy and safety of carfilzomib-containing regimens in the treatment of multiple myeloma（MM） in different lines of treatment. method The clinical data of 55 multiple myeloma patients who received carfilzomib treatment in 10 medical centers in Shandong from January 2022 to March 2023 were retrospectively analyzed , and grouped according to the number of MM treatment lines, they were divided into group A : newly diagnosed multiple myeloma ( NDMM ), group B : patients with first relapse, and group C : patients treated with carfilzomib in the third line or above. Del ( 17p ), t ( 4;14 ), t ( 14;16 ) were defined as high-risk cytogenetic abnormalities result All patients with multiple myeloma were treated with the combined regimen based on carfilzomib, including 24 patients in group A , 9 patients in group B , and 22 patients in group C. Among all patients, there were 27 cases ( 49.1% ) of high-risk cytogenetics, and 13 cases with ECOG score ≥ 3 points ( 23.6% ), 10 cases ( 18.2 ) had eGFR <30 ml/min. The median follow-up time of patients in group A , group B and group C was 8 months, 9 months and 8 months. The overall response rate ( ORR ) was 91.7% , 88.9% and 77.3% for patients in Arms A , B and C who started carfilzomib, respectively . The ≥very good partial response ( VGPR ) rates were 75% and 66.7% for Arm A and B patients , respectively , while the ≥VGPR rate for Arm C patients was 41.0% . The negative rate of minimal residual disease ( MRD , sensitivity: 10 -6 ) in group A was 62.5% ( 15/24 ). Follow - up deadline is March 2023 On the 31st , the median progression-free survival ( PFS ) time and median overall survival ( OS ) time of patients in the three groups were not reached. After the application of carfilzomib, the incidence rate of grade 3-4 adverse events ( AE ) was 32.7% ( 18/55 ). The main hematological adverse reactions were anemia, thrombocytopenia, lymphopenia and neutropenia. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections. in conclusion Carfilzomib-based regimens in the treatment of multiple myeloma have good curative effect and safety, and the first-line and first-time relapse patients have better curative effect.

Efficacy of Systematic Nursing Combined with Lianzhi Xiaoyan Capsule on Clinical Outcome of Emergency Intravenous Infusion in Patients with Acute Gastroenteritis

This study aimed to explore the efficacy of systematic nursing combined with Lianzhi Xiaoyan capsule on clinical efficacy and the incidence of adverse reactions due to emergency intravenous infusion in patients with acute gastroenteritis. The patients were divided into a control group, comprising patients who received conventional Western medicine treatment and routine emergency nursing, and an observation group, comprising patients who received conventional Western medicine treatment and routine emergency nursing combined with Lianzhi Xiaoyan capsules. The total effective rates among patients in the observation group were higher than those among patients in the control group (P < 0.05). The durations of fever, abdominal pain, diarrhea, nausea, and vomiting among patients in the observation group were shorter than those among patients in the control group. High-sensitivity C-reactive protein, interleukin-6, and CD8+ levels among patients in the observation group were lower than those among patients in the control group. The incidences of adverse reactions during intravenous infusion were lower, and patient satisfaction with nursing care was higher among patients in the observation group than among those in the control group. Systematic nursing combined with Lianzhi Xiaoyan capsules has significant clinical efficacy and can reduce emergency intravenous infusion-related adverse reactions in patients with acute gastroenteritis.

A Phase II Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Patients with Multiple Myeloma Progressing on or after One Line of Lenalidomide-Containing Therapy

Introduction Relapse in patients (pts) with multiple myeloma (MM) is a common occurrence, resulting in a continued need for novel treatment approaches. Isatuximab (Isa), a monoclonal antibody (mAb), combined with pomalidomide (Pom) and dexamethasone (Dex), is indicated for the treatment of pts with relapsed/refractory multiple myeloma who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. The current study aims to evaluate the efficacy and safety of IsaPomDex in pts with MM relapsing for the first time after one line of treatment containing lenalidomide (Len). Methods EAE115 (NCT05298683) is an ongoing, investigator-initiated, phase II, prospective, open-label, multicenter study aiming to enroll 108 pts. Eligible pts are adults with documented MM who have evidence of progressive disease, by the International Myeloma Working Group criteria, on or after treatment with only one prior line of anti-myeloma therapy with lenalidomide (≥2 cycles, alone or in combination) and a proteasome inhibitor. Pts must also have adequate bone marrow and hepatic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with previous anti-myeloma therapy with any anti-CD38 mAb, pomalidomide, or stem cell transplant within 12 weeks before treatment initiation. Pts receive six 28-day cycles of Isa 10 mg/kg (once weekly [QW] by intravenous [IV] infusion on days 1, 8, 15, and 22 in cycle 1 and days 1 and 15 in subsequent cycles), Pom 4 mg (per Os on days 1-21, each cycle), and Dex 40 mg or 20 mg for pts ≥75 years old (per Os or IV on days 1, 8, 15 and 22, each cycle). Fifteen to 60 minutes before Isa infusions, patients receive pre-medications to mitigate potential infusion-related adverse reactions. Following initial 6 cycles, pts achieving at least very good partial response (VGPR) are randomized 1:1 to receive Isa (Q2W or Q4W) plus PomDex, and pts achieving <VGPR continue treatment with Isa (Q2W) plus PomDex. Treatment is given until progressive disease, death, unacceptable adverse events (AEs), lost to follow-up, or consent withdrawal. The study primarily evaluates the overall response rate (ORR; defined as partial response [PR] or better) to IsaPomDex therapy at six months. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty pts had received at least one dose by the cut-off date, of whom 16 (80.0%) were continuing with IsaPomDex treatment; four (20.0%) pts had discontinued due to physician or pt decision or progressive disease or death. At baseline (cycle 1, day 1), pts had a median age of 72.0 years (range: 60.0-85.0), 10 (50.0%) were male, and 13 (65.0%) had ECOG PS 0. Eleven (55.0%) pts were at stage II by the revised International Staging System, 9 (45.0%) pts had lytic bone lesions, 5 (25.0%) pts had high-risk cytogenetics, and 1 (5.0%) pt had soft-tissue plasmacytomas (Table 1). Regarding previous treatment outcomes, 14 (70.0%) pts had achieved ≥VGPR (stringent complete response, 2 [10.0%] pts; complete response, 2 [10.0%] pts; VGPR, 10 [50%] pts). Five (25%) and 1 (5.0%) pts achieved partial and minimal response, respectively. Six (30.0%) pts had received ASCT in the prior line. At a median follow-up of 3.4 (range: 0.6-6.1) months, the median number of IsaPomDex cycles received was 3.0 (range: 1.0-7.0); one (5.0%) pt received six treatment cycles. Of the 18 (90.0%) response evaluable pts (2 pts were ongoing without 2 efficacy assessments) VGPR and PR were achieved by 4/18 (22.2%) and 9/18 (50.0%) pts, respectively. ORR was achieved by 13/18 (72.2%) pts, and the median (range) time from IsaPomDex study dose to first response (≥PR) was 1.0 (range: 0.9-1.3) months. Thirteen (65.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these pts, 10 (50.0%) had a ≥1 grade (gr)≥3 TEAE and 4 (15.0%) had ≥1 gr ≥3 serious TEAE. The most common TEAEs were neutropenia in 9 pts (45.0%), anaemia in 3 pts (15.0%) and fatigue in 3 pts (15.0%). The most common gr ≥3 TEAE was neutropenia in 7 pts (35.0%) (Table 2). Conclusions Second-line treatment with IsaPomDex in pts with MM who have progressed on or after one Len-containing line of treatment appears to be effective, although longer follow-up is needed to assess its efficacy. No new safety signals were observed with the combination.

Preliminary study on the efficacy of rituximab in the treatment of idiopathic membranous nephropathy: A single-centre experience.

To investigate the efficacy of rituximab in the treatment of idiopathic membranous nephropathy (IMN). A total of 77 patients with IMN diagnosed in both our hospital and other hospitals were included in this study; the patients were divided into two groups: a treatment-naïve group (n = 19) and a refractory/relapsed group (n = 58). The clinical data of the patients, including urine examination, blood test, safety evaluation and efficacy evaluation results, were analysed retrospectively. The changes in clinical biochemical indexes and adverse reactions were compared between the two groups before and after treatment, and the clinical efficacy of rituximab (RTX) in the treatment of primary IMN and refractory recurrent membranous nephropathy was evaluated. Of the 77 patients included in this study, the average age was 48 years, and there was a male-to-female ratio of 61:16. There were 19 cases in the initial treatment group and 58 cases in the refractory/relapse group. The 24-hour urine protein quantification, cholesterol, B cell count and M-type phospholipase A2 receptor (PLA2R) results in the 77 patients with IMN after treatment were all lower than those before treatment, and the differences were statistically significant (P < 0.05). Serum albumin was higher than before treatment, and the difference was statistically significant (P < 0.05). The total remission rate in the initial and refractory/relapsed treatment groups was 84.21% and 82.76%, respectively. There was no statistical difference in the total remission rate between the two groups (P > 0.05). During treatment, nine patients (11.69%) experienced infusion-related adverse reactions, which were relieved rapidly after symptomatic treatment. The anti-PLA2R antibody titre of the refractory/relapsed group was significantly negatively correlated with serum creatinine (r = -0.187, P = 0.045) and significantly correlated with 24-hour urine protein (r = -0.490, P < 0.001). There was a positive correlation and a significant negative correlation with serum albumin (r = -0.558, P < 0.001). Regardless of whether RTX is used as an initial therapy or refractory/relapsed membranous nephropathy, most patients with IMN have complete or partial remission after RTX treatment, with mild adverse reactions.

The Efficacy and Safety of Daratumumab-Based Regimen in Treatment of Multiple Myeloma Patients with Renal Impairment

To investigate the efficacy and safety of daratumumab in treatment of multiple myeloma (MM) patients with renal impairment (RI). The clinical data of 15 MM patients with RI who received daratumumab-based regimen from January 2021 to March 2022 in three centers were retrospectively analyzed. Patients were treated with daratumumab or daratumumab combined with dexamethasone or daratumumab combined with bortezomib and dexamethasone and the curative effect and survival were analyzed. The median age of 15 patients was 64 (ranged 54-82) years old. Six patients were IgG-MM, 2 were IgA-MM,1 was IgD-MM and 6 were light chain MM. Median estinated glomerular filtration rate (eGFR) was 22.48 ml/(min·1.73 M2). Overall response rate of 11 patients with MM was 91% (≥MR), including 1 case of stringent complete response (sCR), 2 cases of very good partial response (VGPR), 3 cases of partial response (PR) and 4 cases of minor response (MR). The rate of renal response was 60%(9/15), including 4 cases of complete response (CR), 1 case of PR and 4 cases of MR. A median time of optimal renal response was 21 (ranged 7-56) days. With a median follow-up of 3 months, the median progression-free survival and overall survival of all patients were not reached. After treatment with daratumumab-based regimen, grade 1-2 neutropenia was the most common hematological adverse reaction. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections. Daratumumab-based regimens have good short-term efficacy and safety in the treatment of multiple myeloma patients with renal impairment.

Comparison of Post Transplant Outcomes between Refrigerated and Cryopreserved Autologous Hematopoietic Stem Cells in Patients with Multiple Myeloma

Introduction: Approximately 10% of individuals with hematological malignancies are diagnosed with Multiple Myeloma (MM); in addition, the incidence and prevalence of the disease have progressively increased in recent decades. Despite the recent remarkable advances in treatment, autologous hematopoietic stem cell transplantation (ASCT) is still a fundamental part of the therapeutic management of this population. Particularly in developing countries, ASCT is an underused tool. Social and economic issues play an essential role in accessing the procedure. Refrigerated hematopoietic stem cells (R-HSC) can be an attractive alternative to the traditional use of cryopreserved hematopoietic stem cells (C-HSC) since cryopreservation demands highly trained human resources, high-cost supplies, and sophisticated equipment. Aim: In order to compare the applicability, safety, and possible clinical and economic benefits of ASCT with different types of cell storage before infusion, we analyzed the medical records of patients diagnosed with MM who were transplanted using R-HSC or C-HSC. Methods: The study was approved by the local Research Ethics Committee. We analyzed charts of patients diagnosed with MM and submitted to ASCT at Erasto Gaertner Hospital between January 2017 and July 2021. R-HSC: Cells were stored immediately after leukapheresis, without any handling procedure, kept in a standard refrigerator at a temperature between 2-6oC, and infused within 48 hours after collection. C-HSC: Cells were collected by leukapheresis and submitted to cryopreservation within 12 hours after the procedure. As a cryoprotectant, a solution with dimethyl sulfoxide (DMSO) at a final concentration of 5.5% was used. The product's temperature was reduced under a controlled cooling rate and stored in a freezer at -80oC. All patients received a single intravenous dose of melphalan (200-100mg/m2) 24 hours before receiving the cells as conditioning regimen. In the group of patients who received R-HSC, the cells were removed from the refrigerator and immediately infused at a rate of 10 ml/minute. However, in patients who received C-HSC, the cells were removed from the freezer, thawed in a water bath at 37oC, and infused intravenously at a rate of 10 ml/minute. All patients received G-CSF from D+5 until neutrophilic engraftment. Results: We reviewed records of 170 patients. One hundred eight subjects received R-HSC and 62 C-HSC. Demographic characteristics, CD34+ cell dose received, melphalan dose, febrile neutropenia, and early mortality related to the procedure were similar between the two groups. There was a significant statistical difference in favor of the group utilizing R-HSC related to days until neutrophil engraftment (10 vs. 14 days p<0.0001), days until platelet engraftment (12 vs. 15 days p<0.0001), days of hospitalization (13 vs. 16 days p<0.0001) and infusion-related adverse reactions (10.1% vs. 33.8% p=0.003). There were no cases of graft failure in both groups. A reduction of 32.4% in the total cost per transplant was noticed in the R-HSC group. Conclusions: We demonstrated in this analysis that the use of stem cells stored in a standard refrigerator, with a temperature between 2-6oC for up to 48 hours after the collection is a safe and efficient approach. It was capable of simplifying the ASCT, preventing infusion-related adverse reactions, assuring an early neutrophil and platelet engraftment, and reducing hospitalization days. This strategy should be considered especially in resource constrained settings to avoid unnecessary expenses, increase the number of transplant centers, and expand access to the procedure.

Immunotherapy in indolent Non-Hodgkin's Lymphoma

Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3rd generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.

A novel rituximab administration protocol to minimize infusion-related adverse reactions in patients with B-cell lymphoma.

Background Infusion-related reactions (IRRs) during rituximab administration are occasionally severe and remain problematic in oncology practice. Aim To establish a safer, risk-stratified rituximab protocol for patients with B-cell lymphoma. Method We stratified patients into low-, moderate-, and high-risk groups according to the number of risk factors for IRRs, specifically, low-grade histology and bulky tumors (>10cm): Then, the administrating schedule of rituximab (375mg/m2, diluted in 1mg/mL concentration) was individualized. For the first rituximab cycle, the low- and moderate-risk groups underwent conventional infusion #1 (25-200mg/h, ~4.3h), and the high-risk group underwent long infusion (25-100mg/h, 6.8h). Patients in the low-, moderate-, and high-risk groups without IRRs in the first cycle underwent short infusion (100-400mg/h, 2.3h), conventional infusion #2 (100-200mg/h, 3.5h), and conventional infusion #1, respectively. Patients with IRRs in the first cycle received a second rituximab cycle with the same schedule as the first cycle. The procedure for the third cycle was at the attending physician's discretion. Results Among 81 patients, the overall incidence of IRRs was 28%. IRR incidences in the low- (n = 39), moderate- (n = 35), and high-risk groups (n = 7) were 31%, 20%, and 57%, respectively. All IRRs were grade ≤2. The overall conversion rate to short infusion in the third cycle was 54%, without any IRRs. Conclusions Our step-by-step rituximab protocol demonstrated a fewer incidence of severe IRRs among B-cell lymphoma patients receiving rituximab.

A Novel Protocol for Rituximab Administration with Reduced Incidence of Severe Infusion-Related Adverse Reactions in Patients with B-Cell Non-Hodgkin Lymphoma

Introduction: Rituximab is widely used as the standard treatment for most types of B-cell non-Hodgkin lymphomas (B-NHL). However, infusion-related reactions (IRRs), such as fever, chills, nausea, rashes, rigors, or hypotension, are a significant burden to patients and oncology practitioners. Thus, we developed a novel protocol on the rituximab administration to avoid severe IRRs during a short-time infusion in the outpatient chemotherapy center of Nihon University Itabashi Hospital.Methods: This observational study aimed to establish an effective dosing schedule for safely administering rituximab within a short time for patients with various B-NHL types. Rituximab was diluted to a concentration of 1 mg/mL and intravenously administered to patients at a dose of 375 mg/m 2. Before the rituximab administration, prophylactic premedications were given per guidelines. We stratified patients into low (n = 0), moderate (n = 1), or high risk (n = 2) groups according to the observed number of risk factors for IRRs identified in our previous study, i.e., indolent histology and presence of bulky disease (>10cm) (Hayama et al. 2017, PMID: 28144804). In the low- and moderate-risk groups, the infusion rate of rituximab was set at 25 mg/h (first 1h), 100 mg/h (next 1h), and a maximum of 200 mg/h thereafter (conventional infusion #1, approx. 4.3h). In the high-risk group, the infusion rate of rituximab was set at 25 mg/h (first 1h) and a maximum of 100 mg/h thereafter (long infusion, approx. 6.8h). The second infusion of rituximab was dependent on the occurrence of IRRs in the first cycle. If a patient in the low-risk group did not have IRRs in the first cycle, the infusion rate of rituximab in the second cycle was then started at 100 mg/h for the first 30min and increased by 100 mg/h every 30min to a maximum of 400 mg/h thereafter (short infusion, approx. 2.3h). Also, for a patient in the moderate-risk group without any grade of IRRs in the first cycle, the infusion rates of second rituximab was set at 100 mg/h (first 1h) and a maximum of 200 mg/h thereafter (conventional infusion #2, approx. 3.5h). Finally, a patient in the high-risk group without IRRs in the first cycle received the second rituximab as per the conventional infusion #1. If patients experienced any grades of IRR in the first cycle, the next rituximab was administered on the same schedule as the first cycle. The infusion procedure for the third cycle was at the discretion of attending physicians (Figure). The primary endpoint was the incidence of IRRs during the first and second doses of rituximab in each risk group. The secondary endpoints were; overall incidence of IRRs in the first and second doses of rituximab; infusion rates of rituximab at the IRRs; conversion rate of the short infusion at the third cycle in each group; overall conversion rate of the short infusion at the third cycle.Results: A total of 81 B-NHL patients treated with rituximab in 2018 and 2019 at Nihon University Itabashi Hospital was evaluated. The incidence of IRRs during the first and second cycles in each risk group was 31%, 20%, and 57% in the low- (n = 39), moderate- (n = 35), and high-risk (n = 7) groups, respectively, with no significant difference among the three risk groups (p = 0.1407). The overall incidence of IRRs was 28% without grade 3 or higher severity. The IRRs occurred most frequently at the infusion rate of 100 mg/h (n = 16). Conversion rates to the short infusion at the third cycle of rituximab were 82%, 29%, and 29%, in the low-, moderate-, and high-risk groups, respectively, with a significant imbalance between the groups (p <0.0001). The overall conversion rate of the short infusion in the third cycle was 54%, without any grades of IRRs (Table).Conclusions: Our step-by-step infusion protocol of rituximab provided a safe and comfortable drug administration for both patients and oncology practitioners. In addition, the protocol can reduce unexpected, severe adverse reactions to rituximab that typically require hospital admission and medical expenses (UMIN-CTR, UMIN000032309). [Display omitted] DisclosuresMiura: Chugai: Honoraria; Kyowa Kirin: Honoraria. Hatta: Pfizer Japan Inc.: Honoraria; Novartis KK: Honoraria; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical.: Honoraria.

Rituximab Desensitization in Liver Transplant Recipients With Preformed Donor-specific HLA Antibodies: A Japanese Nationwide Survey.

Background.The significance of preformed donor-specific anti-HLA antibodies (DSAs) in liver transplant recipients is controversial. Moreover, there has been no established desensitization protocol for DSA-positive recipients.Methods.A Japanese nationwide survey was performed to investigate the clinical practice among preformed DSA-positive patients with special reference to rituximab desensitization.Results.There was a total of 47 cases, including 2 pediatric cases, in which rituximab (287 ± 159 mg [319 (50–916)/m2]) was administered to desensitize preformed DSA. The decision for the indication of rituximab desensitization was based on a single-antigen assay in the majority of cases (83%, 39/47), and the most frequent protocol was rituximab monotherapy (n = 12) followed by quadruple treatment with rituximab tacrolimus, mycophenolate mofetil, and plasmapheresis (n = 11). The overall 1-, 3-, and 5-y graft and patient survival rates among adult patients were 85%, 83%, 83%, and 81%, 77%, 74%, respectively, while neither graft loss nor death was observed in the 2 pediatric cases. The 1-, 3-, and 12-mo cumulative incidence of antibody-mediated rejection (AMR) was 11%, 13%, and 13%, respectively. The incidence of AMR was significantly higher in the lower rituximab dose group than in the higher rituximab dose group (cutoff 300 mg/m2, 4% versus 24%, P = 0.041). The rate of infusion-related adverse drug reactions (ADRs) was 4.4%, and all ADRs were mild and self-limiting. A total of 99 ADRs among 27 patients were reported, none of which were severe adverse events associated with rituximab.Conclusions.The rituximab induction was well tolerated among DSA-positive liver transplant recipients with a satisfactory outcome. A rituximab dose >300 mg/m2 was observed to achieve less incidence of the development of AMR.

Subvisible Particles in Solutions of Remicade in Intravenous Saline Activate Immune System Pathways in In Vitro Human Cell Systems.

Among patients that receive Remicade® therapy, more than 20% have adverse infusion related reactions and approximately 50% have immunogenic responses.1-3 Upon characterization of initial Remicade®-IV solution we observed a high concentration of subvisible particles that could inadvertently be delivered to patients. This solution was processed through the IV infusion system, mimicking the typical clinical administration setup - either with or without an in-line filter connected to the IV line. The samples generated thereafter were tested using various in vitro assays for activation of the innate immune system via cytokine release in whole blood and in peripheral blood mononuclear cell (PBMC) cultures, and activation of the Toll like receptors (TLRs). Activation of the adaptive immune system was evaluated by monitoring upregulation of surface receptors on dendritic cells (DCs) and CD4+ T cell proliferation in response to IV solution of Remicade®. Our results indicate that subvisible particles in Remicade®-saline solution have a significant role in activation of the immune system but there are extrinsic factors potentially contributed by the in-line filters or other process parameters that also contribute to immune system activation.

The efficacy and safety of daratumumab in relapsed and refractory multiple myeloma

目的探讨达雷妥尤单抗治疗复发/难治多发性骨髓瘤（RRMM）的疗效与安全性。方法回顾性分析2017年9月至2020年3月上海长征医院接受达雷妥尤单抗治疗的46例RRMM患者的临床资料。结果所有RRMM患者均采用以达雷妥尤单抗为基础的方案进行治疗，其中Dd（达雷妥尤单抗+地塞米松）方案组8例，DRd（达雷妥尤单抗+来那度胺+地塞米松）方案组35例，DVd（达雷妥尤单抗+硼替佐米+地塞米松）方案组3例。中位随访9.6个月，可评估疗效患者44例，总缓解率（ORR）75%[完全缓解（CR）率18.2%]。对硼替佐米、来那度胺及两者均耐药患者的ORR分别为70.6%（CR率17.6%）、69.2%（CR率11.5%）和63.6%（CR率13.6%），三组间差异无统计学意义。DRd组、DVd组和Dd组的ORR分别为85.3%、66.7%和28.6%（P＝0.007）。46例患者的中位无进展生存（PFS）时间为8.9个月，中位总生存（OS）时间未达到，1年OS率74%。DRd组中位PFS时间及OS时间较Dd组长（PFS时间：14.4个月对2.0个月；OS时间：未达到对5.2个月）。应用达雷妥尤单抗后，3级以上血液学不良反应以中性粒细胞减少最为常见，非血液学不良反应主要为输液相关不良反应和感染。预后分析显示伴髓外病灶患者的PFS时间和OS时间较不伴髓外病灶患者缩短（PFS时间：5.7个月对14.4个月，P＝0.033；OS时间：6.3个月对未达到，P＝0.029）；ECOG评分3～4分患者的OS时间较ECOG评分1～2分患者缩短（5.9个月对未达到，P＝0.004）。结论以达雷妥尤单抗为基础的方案治疗RRMM具有较好的疗效及安全性。

Risk factors for infusion-related reactions following Ocrelizumab infusion in a community setting: Development of an electronic medical record-based explanatory model

Background: In 2017, ocrelizumab became the first FDA approved disease modifying therapy (DMT) for primary progressive multiple sclerosis (MS). Although effective, adverse infusion-related reactions (IRR), such as erythema, pruritus, hives, and throat irritation, were frequently reported.Objective: To develop an explanatory model of factors associated with increased odds of IRR development to further enhance clinical decision-making when administering ocrelizumab in a community setting.Methods: A retrospective chart review was performed (n = 422) by extracting patient demographic factors and co-occurring conditions and symptoms from electronic medical records. Bivariate analyses were conducted to examine which demographic and clinical characteristics were associated with IRR development, and variables with a p-value of <.10 were then entered into a logistic regression to create the explanatory model.Results: Being female (odds ratio [OR]: 2.60), Hispanic/Latinx (OR: 3.98), and having a history of a co-occurring tremor (OR: 3.78) were risk factors for increased odds of having an IRR.Conclusions: These findings may be helpful in guiding clinical practice routines and improving patient expectations regarding the likelihood of IRR development based on their individual demographics and co-occurring conditions and symptoms.

MON-001 EFFICACY OF RITUXIMAB IN ADULT ONSET NEPHROTIC SYNDROME PATIENTS

About 40% of idiopathic nephrotic syndrome (INS) show steroid dependence and 10 to 15% are steroid resistant. Therapeutic options for such patients remain limited. Rituximab is a murine- human chimeric anti CD20 monoclonal antibody used for depletion of B cells. Rituximab was first reported to have efficacy in childhood nephrotics. Ever since numerous reports and case series have suggested efficacy in steroid-dependent INS. Data from previous studies suggested that 2-4 doses of Rituximab is required for achieving remission. Prospective observational study. Patients between ages of 14 - 65 years. Biopsy proven Minimal change disease (MCD), Focal segmental glomerulosclerosis (FSGS) or Membranous nephropathy. (MGN) Patients with steroid dependent/Frequent Relapsing nephrotic syndrome(SDNS/FRNS). Patients with steroid resistant nephrotic syndrome. Patients with secondary Nephrotic Syndrome were excluded SIngle dose of Inj Rituximab was given (375 mg/m2 to a max of 500mg) and followed up for 6 months. Infusion related adverse reactions was noted Monitoring of CD19 levels was done on D2-5 and then monthly basis. Proteinuria was tested on a monthly basiis. Steroids were tapered in all patients after achieving remission. Other immunosuppression which was used in SRNS or SDNS as steroid sparing were stopped. Patients who developed relapses after receiving a dose of Rituximab: Dose and duration of prednisolone as in primary therapy of nephrotic syndrome was given.A repeat doses of rituximab was planned for unresponsive patients. The primary outcomes were changes in proteinuria and CD19 Levels following Rituximab. Secondary outcomes were study of any adverse reactions. 30 patients were included.22 were males and 8 were females. 24 patients were SDNS and 6 patients were SRNS. FSGS was the commonest histopathlogy (33%). The mean value at baseline proteinuria was 3494 mg/24 hrs (SD± 1738.84). All patients achieved remission after a single dose of Inj Rituximab, median time of complete remission was 30 days (P: 0.001). 1 patient had mild infusion related reaction which improved with slowing of infusion rate. Some minor infectious complications were observed. These included Tinea corporis in 1 patient in month 1, Pharyngitis in 1 patient in month 2 and month 3 each, while 1 patiient developed Rhinitis in month 3 and 2 patients in month 5. 1 patiient had an episode of watery diarrhea in month 4. CD19 levels were suppressed to <1% in all patients after a single dose. The levels of 12 patients recovered to > 1% after month 3 but 6 out of them remained in remission. 6 patients relapsed during the follow up period of 6 months. All of them were given a course of steroids (1 mg/kg). 4 of them were now steroid sensitive and achieved remission. 1 out of 2 remaining patients didnot consent for a repeat dose of Rituximab and was maintained on a lower dose of steroids to achieve remission, the other 1 patient received a repeat dose of Inj Rituximab following which achieved partial remission. Rituximab is effective in attaining a complete/partial remission in our study population.

Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I.

Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane Review published in 2013 and previously updated in 2015. To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase.Date of most recent search: 30 January 2019. Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo. Two authors independently screened the identified studies. The authors then appraised and extracted data. The quality of the evidence was assessed using GRADE. One study (45 participants) met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in people with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) (low-quality evidence) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance) (low-quality evidence). The levels of urinary glycoaminoglycans were also significantly reduced (low-quality evidence). In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all participants in the treatment group with no apparent clinical effect and titres were reducing by the end of the study (very low-quality evidence). Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation (low-quality evidence). As assessed by questionnaires,changes in a 'Disability Index' after treatment were small and did not differ between groups (low-quality evidence). There were no deaths in either group (low-quality evidence). The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive, with few participants and of low quality. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those individuals diagnosed under 2.5 years of age. We do not anticipate any further trials to be undertaken and therefore do not plan to update this review.

Assisted Administration of Subcutaneous Rituximab to the Patient's Home. Significant Reduction of Indirect Costs Incurred By Care Recipients and Unpaid Caregivers Together with a Total Adherence to the Treatment Schedule and Same Safety

▪Dec 2018, 7 consecutive patients, ( CLL n = 1; FL n = 3; DLBCL n= 1 AEA n=1,ITP n=1), were enrolled in the study. Median age of the patients was 68 years (range, 28-87). The pharmacoeconomic analysis included assessment of direct costs ( hospital inpatient, physician inpatient, physician outpatient, emergency department nursing home care, specialists' and other health professionals' care, diagnostic tests, prescription drugs and drug sundries, and medical supplies),indirect costs incurred by care recipients and unpaid caregivers, including time, productivity and travel cost.Results Rituximab subcutaneous formulation was administered at a fixed dose of 1400 mg with a frequency related to the type and the phase of the treated disease. Before starting MabThera subcutaneous injections, all patients received beforehand, a full dose of Rituximab by intravenous infusion. Premedication with an anti-pyretic an antihistaminic and prednisone , was given orally in the evening before and the morning of the subcutaneous administration the infusion was carried out by the staff of the home care unit together with a doctor. All the procedure was controlled by the hospital specialist through a smart-phone. Median age of the patients was 58 years (range, 32-83). Median number of courses delivered to each patient was 6 (range, 4- 12) .Adherence to treatment was 100%.No Infusion related adverse reactions have been observed.ConclusionIn our experience, despite the high percentage of elderly patients of whom 36% living in rural area, it was possible to give treatment to all patients with high adherence and satisfaction. There has been a reduction in direct medical costs due to less use of hospitalization, a reduction of indirect costs by 70% due to the lower number of working days lost and a drastic reduction of travel costs, with the same safety of administration. DisclosuresNo relevant conflicts of interest to declare.

The impact of preapheresis white blood cell count on autologous peripheral blood stem cell collection efficiency and HSC infusion side effect rate.

Autologous peripheral blood hematopoietic stem cell (PBSC) collection efficiency (CE) is reportedly affected by the patient's blood properties; however, studies to identify factors correlated with CE have shown inconsistent results. Additionally, variables such as stem cell graft granulocyte content and patient age, sex, and underlying disease, may be associated with hematopietic stem cell (HSC) infusion-related adverse reactions. In this study, we evaluated the correlation of preleukapheresis PB granulocyte count and PBSC harvest variables with CD34+ collection yield and efficiency, and thawed HSC infusion side effect occurrence. We evaluated data from 361 patients who had undergone autologous PBSC transplant. Large volume leukapheresis was the method for PBSC collection. Complete Blood Count and CD34+ cell enumeration were performed in the preapheresis PB and the apheresis product sample. The PBSC grafts were submitted to non-controlled rate freezing after addition of 5% DMSO plus 6% hidroxyethylstarch as a cryoprotectant solution. The cryopreserved graft was thawed in a 37°C water bath and then infused without further manipulation. The CD34+ yield was associated with preapheresis PB CD34+ count and immature granulocyte count. The PBSC CE was negatively correlated with preapheresis white blood cell (WBC), immature granulocyte and granulocyte count. The leukapheresis product total nucleated cell (TNC) and granulocyte content was correlated with the thawed graft infusion side effect occurrence. This study has shown that preapheresis PB WBC and granulocyte counts were associated with leukapheresis CE. Additionally, the leukapheresis product TNC and granulocyte content was correlated with thawed graft infusion side effect occurrence.

Метаанализ клинической эффективности и безопасности препарата иммуноглобулина для внутривенного введения Октагам 10%®

Polyclonal intravenous immunoglobulin G (IVIG) has been used for 50 years and has become a gold standard for treatment of primary and secondary immunodeficiencies, immune thrombocytopenia and others IVIG preparations are not identical. We performed a metanalysis of clinical trials of Octagam 10%® (Octapharma Pharmazeutika Prod.Ges.m.b.H., Vienna, Austria). Metanalysis demonstrated IVIG to be effective in reducing number of infections in primary and secondary immunodeficiencies, good clinical and laboratory response in immune thrombocytopenia, and also effectiveness in such conditions as Guillen-Barre syndrome, multifocal motor polyneuropathy, Myasthenia gravis, multiple sclerosis, dermatomyositis, polymyositis and others. The number of adverse infusion-related reactions were not different from average for this group of preparations even with highest infusion speed. In conclusion registered in Russia IVIG preparation Octagam 10%® demonstrated to be safe and effective.

Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I.

Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane review published in 2013. To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase.Date of most recent search: 05 October 2015. Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo. Two authors independently screened the identified studies. The authors then appraised and extracted data. One study of 45 patients met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in patients with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance). The levels of urinary glycoaminoglycans were also significantly reduced. In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all patients in the treatment group with no apparent clinical effect and titres were reducing by the end of the study. Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation. The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive and of good quality, although there were few participants. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those patients diagnosed under 2.5 years of age.

Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: Results from a Swedish national observational study

There have been concerns about serious infusion-related adverse drug reactions (ADR) with rituximab in chronic lymphocytic leukemia (CLL). We therefore conducted an observational trial in which CLL patients planned for rituximab-containing therapy were eligible. Ninety-six patients from 19 centers were enrolled. The most common regimen was rituximab, fludarabine and cyclophosphamide. Fifty-six patients experienced ADR during rituximab infusion. Reactions≥grade 3 occurred in five patients and no cases of tumor lysis syndrome were recorded.Despite a high number of circulating tumor cells few severe ADR were noted. Thus, rituximab-containing regimens can be considered safe for CLL patients in general practice.