Severe Infusion Reactions Research Articles

Infusion reactions in natural killer cell immunotherapy: a retrospective review

Background aimsThe use of natural killer (NK) cells as a cellular immunotherapy has increased over the past decade, specifically in patients with hematologic malignancies. NK cells have been used at the authors’ institution for over 15 years. Most patients have a reaction to NK cell infusion. The authors retrospectively analyzed the reactions associated with NK cell infusions to characterize the types of reactions and investigate why some patients have higher-grade reactions than others. MethodsA retrospective chart review of NK cell infusions was performed at the authors’ institution under nine clinical protocols from 2008 to 2016. An infusion reaction was defined as any symptom from the time of NK cell infusion up to 4 h after infusion completion. The severity of infusion reactions was graded based on Common Terminology Criteria for Adverse Events, version 4. Two major endpoints of interest were (i) infusion reaction with any symptom and (ii) grade ≥3 infusion reaction. Multivariable logistic regression models were used to investigate the association between variables of interest and outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained for each variable. ResultsA total of 130 patients were receiving NK cell infusions at the authors’ institution. The most common reported symptom was chills (n = 110, 85%), which were mostly grade 1 and 2, with only half of patients requiring intervention. There were 118 (91%) patients with infusion reactions, and only 36 (28%) were grade 3. There was one life-threatening grade 4 reaction, and no death was reported due to infusion reaction. Among grade ≥3 reactions, cardiovascular reactions (mainly hypertension) were the most common, and less than half of those with hypertension required intervention. NK cell dose was not associated with any of the grade 3 infusion reactions, whereas monocyte dose was associated with headache (grade ≤3, OR, 2.17, 95% CI, 1.19–3.97) and cardiovascular reaction (grade ≥3, OR, 2.13, 95% CI, 1.13–3.99). Cardiovascular reaction (grade ≥3) was also associated with in vitro IL-2 incubation and storage time. Additionally, there was no association between grade ≥3 infusion reactions and overall response rate (OR, 0.75, 95% CI, 0.29–1.95). ConclusionsThe majority of patients who receive NK cell therapy experience grade 1 or 2 infusion reactions. Some patients experience grade 3 reactions, which are mainly cardiovascular, suggesting that close monitoring within the first 4 h is beneficial. The association of monocytes with NK cell infusion reaction relates to toxicities seen in adoptive T-cell therapy and needs further exploration.

Abstract PS13-51: A phase II study of neoadjuvant weekly carboplatin/paclitaxel followed by dose-dense doxorubicin/cyclophosphamide (DD AC)in patients with triple negative breast cancer (TNBC): Wisconsin oncology network (WON) study

Abstract Background: The CALGB 40603 and BrighTNess studies found that adding high dose carboplatin every 3 weeks to the standard neoadjuvant DD AC - paclitaxel regimen in TNBC increased the pathologic complete response (pCR) rate to 54-58% but with the cost of increased treatment related toxicities resulting in decreased completion of the full course of treatment. Our hypothesis is by changing the high dose carboplatin every 3 weeks to low dose weekly carboplatin, it will retain the same benefit in pathologic response rate and minimize the treatment related toxicities, which in turn permits the full course of neoadjuvant treatment given to patients. Patients and Methods: This multi-center study was conducted through the WON (NCT03301350). Eligible TNBC patients for neoadjuvant chemotherapy received weekly carboplatin (AUC=2) and paclitaxel 80 mg/m2 for 12 doses, followed by dose dense doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks with granulocyte growth factor support for 4 cycles. A one-week break was added before DD AC after the first 22 patients in order to minimize prolonged cytopenia. Primary end point was pCR. Secondary endpoints were frequency of dose modification and treatment related toxicities. Results: Accrual target was 50 with 80% power to detect a 20% difference using a one-sided binomial test at an alpha significance level of 0.025, but study was terminated earlier. Twenty-nine eligible patients consented for the study from November 2017 to February 2020. Median age was 52 year-old (range, 33-80). Twenty-eight patients received the study regimen. Three were removed due to early study termination and one (3.8%) died from grade 5 neutropenic sepsis after the last cycle of DD AC before surgery. Thus, 24 patients were evaluable for the primary outcome and 26 were evaluable for dose modification and toxicity outcomes. Eight patients (33%) achieved pCR and another 4 patients (17%) had minimal (ypT1aN0) residual disease. Of 26 patients, 24 (92%) were able to receive the full course of treatment +/- dose modification. One patient required the discontinuation of weekly carboplatin/paclitaxel completely due to severe infusion reaction and one did not finish the treatment before the study was terminated. Eight patients (31%) required dose delay with 5 of them during the weekly carboplatin/paclitaxel treatment. Seven patients (27%) also required dose reduction with 5 of them during the weekly carboplatin/paclitaxel treatment. Seventeen patients (65%) experienced severe adverse event (grade 3 or 4) with the majority of events (12/17) relating to grade 3-4 neutropenia or neutropenic fever. Conclusion: Although our study showed a lower pCR rate of 33% in compare to the previous CALGB 40603 (54%) and BrighTNess (58%) studies, we demonstrated that the majority of patients (92%) were able to receive the full course of study treatment. This weekly carboplatin with paclitaxel - AC regimen was used in the recent Keynote 522 study as the backbone chemotherapy to combine with check-point inhibitor immunotherapy in TNBC. However, any dosing schedules of carboplatin, weekly or every 3 weeks, add substantially to grade 3 or 4 toxicity of paclitaxel - AC. Aggressive supportive care management is needed when carboplatin is used. Citation Format: Yee Chung Cheng, Ruth O'Regan, Lubna N Chaudhary, Sailaja Kamaraju, Harvey Einhorn, Emmanuel Sampene, Marialane Pigsley, Mark E Burkard, Christopher R Chitambar, Kari B Wisinski. A phase II study of neoadjuvant weekly carboplatin/paclitaxel followed by dose-dense doxorubicin/cyclophosphamide (DD AC)in patients with triple negative breast cancer (TNBC): Wisconsin oncology network (WON) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-51.

The results of investigating the efficacy and safety of non-medical switching from the original rituximab to its biosimilar in rheumatoid arthritis patients (AMBIRA study)

Wide usage of biologic disease-modifying anti-rheumatic drugs (DMARDs) biosimilars in clinical practice has greatly increased the availability of biologic therapy for rheumatic patients. Nevertheless, not only economic expediency but efficacy and safety are the key principals of any treatment including biologic DMARDs. Objective . To investigate the efficacy and safety of switching from the original rituximab (MabThera®, “F. Hoffmann-La Roche Ltd.”, Switzerland) to its biosimilar (Acellbia®, “BIOCAD”, Russia) by non-medical reasons in rheumatoid arthritis patients. Subjects and methods . 40 rheumatoid arthritis patients on basic therapy who had taken at least one course of original rituximab (MabThera®) 1000 mg twice in 2 weeks more than 6 months ago were included. They were switched to equal-dose biosimilar (Acellbia®) by non-medical reasons and were observed throughout the year. At 12, 24 weeks and one year after switching dynamics of the next parameters were evaluated: pain level according to visual analogue scale (VAS), tender joint count (TJC), swollen joint count (SJC), acute inflammatory and immunological markers, disease activity score (DAS28) calculated using erythrocyte sedimentation rate (DAS28-ESR) or C-reactive protein (DAS28-CRP), health assessment questionnaire (HAQ) index and safety profile. Results . All the data are presented as median of indicator in the moment of measurement after switching therapy (Meperiod). In 12-week period TJC [(Me]_0=9.50, Me_12=6.0, p< 0.01) and SJC (Me_0=2,0, Me_12=1,0, p<0.01) were decreased with positive dynamics on the 24 and 48 weeks. Also, similar results were observed in the VAS pain level. DAS28 showed significant decreasing during observation: Me0=4.38, Me24=3.55, Meyear=3.49, p<0.01 for DAS28-ESR; and Me0=3.91, Me24=3.15, Meyear=3.03, p<0.01 for DAS28-CRP. Immunological markers were increased or stable during the first months after switching, but then they were significantly decreased: Me0=45.0 U/ml, Meyear=23.0 U/ml, p<0.01 for rheumatoid factor; and Me0=88.0 U/ml, Meyear=50.5 U/ml, p<0.01 for anti-cyclic citrullinated peptide. HAQ index was stabilized during 1 year: Me0=1.00, Meyear=0.75, p<0.01. Severe infusion reactions on Acellbia® were not observed, safety profile was similar to MabThera®. Conclusion . Our investigation revealed that non-medical switching from original rituximab (MabThera®, “F. Hoffmann-La Roche Ltd.”, Switzerland) to its biosimilar (Acellbia®, “BIOCAD”, Russia) has no significant influence on the therapy efficacy and safety.

The Comparison of Results of Autologous Transplantation Using Non-Cryopreserved and Cryopreserved Hematopoietic Stem Cells (HSC)

Background: Bone marrow (peripheral blood stem cells (PBSCs)) autologous transplantation is the standard care for transplant-eligible patients with multiple myeloma. This treatment option is somewhat limited due to the high consumption of economic resources and the access to Cryobank. We performed a retrospective analysis of multiple myeloma patients who underwent autologous transplantation using non-cryopreserved and сryopreserved grafts at our institution from March 2016 to April 2020. Aim: Compare the results of autologous transplantation using non-cryopreserved and cryopreserved hematopoietic stem cells (HSC). Methods: 78 patients with MM were included in the study (male/female ratio 1.3:1). All patients got the standard immunochemotherapy programs. They had remission (≥partial response) till the auto-HSCT. Patients were divided in two groups depending on the technique of HSC storage: non-CRYO (n=35) and CRYO (n=43). Cryopreservation is a standard method of storage of HSC suspension. In our work we used the native HSC suspension which was saved from +4 °C to +6 °C during 72 - 120 hours. An effectivity and safety were evaluated in such parameters as the number of CD34+ and 7AAD- cells, colony-forming ability (CFA). All of these were made after apheresis and before reinfusion of HSC. Also, we compared the duration of hematopoiesis's recovery, the number of platelet transfusions, the length of hospitalization after auto-HSCT. Additionally, the effectiveness of therapy was assessed according to the IMWG response criteria and the level of residual tumor load before SCT and on day +100. Results : There were no differences in the total number of CD34 + cells x 106/kg, or in the level of 7AAD- cells, or in the total CFA. However, there was a significant difference in the percentage of loss of CD34+ cells from the moment of apheresis to the moment of reinfusion. We suppose it was caused adverse effects by temperature changes in CRYO group. In both groups, there were no severe infusion reactions on day 0. The adverse events (nausea, vomiting, tachycardia, increased total bilirubin and indicator liver enzymes) were absent in the non-CRYO group. But 29/43 (67.4%) patients had such symptoms in the CRYO group on day 0. The results are presented in the comparison table (image 1) of the evaluated parameters. All patients had full recovery of hematopoiesis till discharge from the hospital. Neutrophil recovery was achieved at 11th day (range 9-14) and platelets at 12th day (range 8-19) in the non-CRYO group, and 10th day (range 8-14) and 12th day (range 8 -20) in the CRYO group, respectively. The frequency of achieving a partial response before autoHSCT was 37% (13/35), a very good partial response - 40% (14/35), a complete response - 23% (8/35) in the non-CRYO group and 72% (31/43), 14% (6/43) and 14% (6/43) in the CRIO group, respectively. HSCT was improved the efficiency of treatment as well as the frequency of complete and MRD-negative responses in both groups. Partial response after autoHSCT was achieved in 23% (8/35) patients, very good partial response in 40% (14/35), complete response in 37% (13/35) in the non-CRYO group compared to the CRYO group (47% (20/43), 21% (9/43) and 32% (14/43), respectively). The MRD status was assessed before and after autoHSCT in 48 patients. The frequency of MRD-negative response before autoHSCT was 8.7% (2/23), after transplantation - 21.7% (5/23) in the non-CRYO group and 4% (1/25) and 12% (3/25) in the CRYO group, respectively. AutoHSCT was increased the "depth" of the response in 25 patients. However, there were no significant differences between the same-type categories in the non-CRYO and CRYO groups (p>.05). AutoHSCT led to decrease of tumor load (TL). The average TL value was 0.55% before HSCT and 0.018% after HSCT (p=.036) in the non-CRYO group and 2.05 and 0.37 (p=.003) in the CRYO group, respectively. The mean TL after HSCT in the non-CRYO (0.018%) was smaller than mean TL in the CRYO (0.37%) groups (p <.05). Conclusion: The method of storage of PBSCs without cryopreserved is equal to traditional method controlled freezing with Dimethyl sulfoxide and can be used in hospitals which have no a Cryobank in their composition. Table Disclosures Shuvaev: Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.

Dabrafenib Is a Safe and Effective Therapy in Relapsed/Refractory Classical Hairy Cell Leukemia

BACKGROUND: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder. The BRAF V600E mutation was shown to be the underlying genetic driver for the vast majority of classical HCL (HCLc) cases and treatment with the BRAF inhibitor (BRAFi), vemurafenib, has proven extremely successful. Dabrafenib is an oral BRAFi used in melanoma, often in conjunction with trametinib, a MEK inhibitor. Data exists on the use of dabrafenib combined with trametinib in HCLc but there is no efficacy or safety data on either single agent dabrafenib or dabrafenib combined with rituximab. We present a small series of 7 patients treated with either single agent dabrafenib or combination dabrafenib and rituximab. METHODS: Since 2018 dabrafenib was accessible via a Novartis managed access programme for BRAF V600E mutated HCLc patients who had no alternative treatment options. Six patients received dabrafenib, 2 as single agent due to recent prior ineffective rituximab therapy or severe rituximab infusion reaction and the remaining 4 patients with dabrafenib and rituximab. Dabrafenib was given at 150mg twice daily on a continuous 28 day cycle. Rituximab 375mg/m2 IV was given once every 2 weeks for a total of 8 doses. As there was no availability for re-treatment on cessation of therapy and no other suitable/accessible treatment options, patients with ongoing response and good tolerance were continued on indefinite therapy. One additional patient was treated with frontline dabrafenib and rituximab due to various comorbidities including end stage renal failure limiting other treatment options. RESULTS: Mean age on commencing dabrafenib was 73 (52-87) and in the relapsed patients the median number of prior lines of therapy was 5 (3-13). Four patients had undergone prior splenectomy. Two patients had received prior BRAFi therapy with vemurafenib and 3 had received prior Moxetumomab. Patients received a median of 8 cycles of dabrafenib. 4 patients received all 8 cycles of rituximab with 1 discontinuing rituximab due to adverse drug reaction. Adverse drug reactions to dabrafenib were mostly grade 1-2. The most common reaction was benign keratotic skin lesions occurring in 5/7 patients. Their onset was typically after 4 weeks of treatment, persisting whilst therapy continued. Other notable adverse drug reactions were hair thinning and palmar-plantar erythrodysesthesia both occurring in 3/7 patients. Hair thinning did seem to improve with decreasing the dosage and resolve on cessation of the drug. Palmar-plantar erythrodysesthesia was managed with dose reduction and non-steroidal anti-inflammatory drugs. Response assessment criteria used were from the 2017 hairy cell leukemia foundation consensus guidelines for the diagnosis and management of patients with HCLc. All patients responded to therapy. Hematological response was rapid, most patients achieving hematological CR after 2-3 cycles. Five patients achieved a CR, 2 were MRD+ve, 2 were MRD-ve and 1 was a radiological CR. The remaining 2 patients achieved a hematological response, 1 partial and 1 complete. Six patients had sufficient follow up for assessment with 2/6 having relapsed and 4/6 remaining in remission. Median follow up was 17 months, median DOR and median OS were not reached. The 2 patients in our cohort (patients 1 and 3) receiving prior vemurafenib each received 6 cycles, 1 achieving CR lasting 3 months, the other achieving PR lasting 11 months. Both responded rapidly to dabrafenib, one treated with dabrafenib and rituximab achieved an MRD+ve CR with DOR 21 months. The other received single agent dabrafenib and achieved a hematological response with DOR 15.2 months. Treatment response and survival are shown in table 1 and figure 1. Figures 2-7 show the hematological response at time points within the first year of therapy. DISCUSSION: In this small cohort we have shown that dabrafenib as a single agent or combined with rituximab is a safe and effective therapy in BRAF V600E mutated HCLc, even in those patients with prior time limited duration BRAFi therapy. There was no hematological toxicity noted. The main adverse drug effect was development of skin lesions however none were malignant. The only malignant lesion noted pre dated the commencement of dabrafenib. Dermatological surveillance is therefore recommended. Hematological response was rapid with significant improvement seen as early as 4 weeks from commencing therapy. Disclosures El-Sharkawi: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Other: Conference fees. OffLabel Disclosure: Use of BRAF inhibitor Dabrafenib in BRAF V600E mutation positive classical Hairy Cell Leukemia.

Increased rates of cetuximab reactions in tick prevalent regions and a proposed protocol for risk mitigation.

Cetuximab is an anti-epidermal growth factor receptor mouse-human chimeric monoclonal antibody used to treat advanced colorectal cancers. Initial data suggest that severe infusion reactions occurred in 4.5%, many on first exposure. The majority of those with anaphylactic reactions possess predeveloped IgE antibodies to galactose-alpha-1,3-galactose. It is thought that the vector for preexposure to alpha-gal is antigen inoculation via tick bites. This retrospective study reviews the experience of two community cancer centers in high tick exposure areas in Sydney with cetuximab anaphylaxis and proposes a protocol to avoid this. Severe cetuximab infusion reactions occurring in the Northern Cancer Institute Frenchs Forest and St Leonards clinics, Sydney, from May 2014 to February 2019 were recorded. Area of residence was then compared to areas of known high tick prevalence. A total of 87 patients received cetuximab in this period. Six patients (6.9%) experienced at least a grade 3 reaction, three females, age range 41-72 years (median 57.5 years). All were receiving cetuximab for metastatic colorectal cancer and their anaphylaxis occurred with the first infusion in all cases. These cases support the existing theory of increased rates of cetuximab anaphylaxis in areas of high tick prevalence. Given this, we recommend the following protocol for patients being considered for cetuximab therapy: known mammalian meat allergy as an absolute contraindication; all patients receiving cetuximab should have RAST (ImmunoCAP® ) testing for alpha-gal specific-IgE-specific antibodies before first infusion and those who test positive to be considered alternate therapy.

Assessment of Confirmed Clinical Hypersensitivity to Rituximab in Patients Affected with B-Cell Neoplasia.

Rituximab hypersensitivity reactions are rare but are one of the main causes of rituximab elimination from antilymphoma immunochemotherapy treatments. While the clinical picture may be indistinguishable from other infusion-related reactions, hypersensitivity reactions (HSR) do not disappear and instead become more intense with subsequent administrations. Objective. To describe the use of the 12-step protocol for desensitization to intravenous rituximab in clinical practice and the complementary study of a possible IgE-mediated HSR in the context of B-cell lymphoma treatment. Methods. A 12-step rituximab desensitization protocol was performed prospectively within clinical practice in 10 patients with a history of severe infusion reactions or in patients who had a repeated reaction at subsequent doses despite taking more intense preventive measures. Skin prick tests were performed at the time of reaction and at a later time to eliminate false negatives due to possible drug interference. Results. Overall, with the desensitization protocol, 70% of patients were able to complete the scheduled immunochemotherapy. Two patients had to discontinue the therapy due to clinical persistence and the third due to lymphoma progression. Intradermal tests with 0.1% rituximab were positive in only 20% of cases, demonstrating a mechanism of hypersensitivity. Conclusions. The 12-step desensitization protocol is very effective and assumable within healthcare practice. There is a need to determine the mechanism underlying the infusion reaction in a large proportion of cases due to the risk of future drug exposure.

MO004THE SAFETY PROFILE OF REPEAT RITUXIMAB TREATMENT IN ANCA-ASSOCIATED VASCULITIS - A 10 YEAR SINGLE CENTRE STUDY

Abstract Background and Aims Rituximab is a proven effective induction and remission-maintenance treatment in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Studies have identified hypogammaglobulinemia, infection, and late-onset neutropenia as potential adverse events. There is limited data on long-term outcomes following extended periods of B-cell depletion therapy with rituximab in AAV cohorts. We conducted a retrospective study to examine the safety profile of repeated rituximab treatment in AAV. Method All patients with AAV treated with rituximab between 1st January 2008 and 31st December 2018 were identified through local dispensary database. Patients were stratified into low (≤4g), medium (>4g to ≤8g) and high (>8g) dose groups according to the cumulative rituximab dose received until 1st October 2019. Baseline characteristics and events including death, opportunistic and severe infections (defined as infections required hospitalization and/or intravenous antibiotic administration), neutropenia (neutrophil count ≤1.5x109/L), hypogammaglobulinemia (IgG level≤5.0), infusion reactions and malignancy diagnosed post-rituximab treatment were examined and compared between the groups. Results 364 patients (49% male, 52 year old mean age) received rituximab for treatment of active disease or remission maintenance. 49%(n=175) had repeat rituximab treatments (267/513 treatment courses for relapsing disease and 247/513 for remission maintenance). There were 262 (72%), 70(19%) and 32(9%) patients in low-, medium- and high-dose groups respectively. The median cumulative rituximab dose for each group was 2g, 6g and 12g (p<0.001). Low-dose group patients were older (59 and 40 years, p<0.001) and more likely to have renal-limited disease compared to high-dose groups (19%vs4%; p<0.05). Conversely, there were more ear-nose-throat (ENT) /ocular limited (41% and 13%; p<0.05) and antiproteinase 3 (PR3)-ANCA positive disease (56% vs 38%, p<0.05) in high-dose compared to low-dose group. The overall median duration of follow up was 72 months (QR: 28-135months)(Table1). Outcomes (Table2): Infections: no difference in serious or opportunistic infection rate between groups (1.2 vs 0.1 vs 0.1infections/patient/year; p=0.18). 77% of opportunistic infections across all groups were related to herpesvirus (e.g. Cytomegalovirus/Herpes Zoster/Herpes Simplex) reactivation. Hypogammaglobulinemia: incidence was comparable between groups (9.7% vs 10% vs 9%, p=0.91). Overall median time to event was 5 months from first rituximab. Neutropenia: 101 patients had recorded neutropenia after rituximab (Low-dose: 32%; medium-dose 16% and High-dose: 22%, p<0.05). All were related to concurrent immunosuppressants (e.g. Azathioprine, cyclophosphamide or mycophenolate) or infection. Events resolved after withdrawal or reduction of concurrent immunosuppressant or treatment of underlying infection. Cancer: No difference in malignancy rate between groups (6% vs 14% vs 3%, p=0.22). 39 malignancies reported in 32 patients post rituximab treatment. The two commonest reported cancers were skin (36%) and breast cancer (21%) Deaths: 58 patients died during the study period. Mortality rate in the low and medium-dose groups were comparable (82% survival at 30 month after last rituximab). Conversely, there were no deaths in the high-dose group. Conclusion In this large, single-centre cohort of patients with AAV, we did not observe an increased incidence of adverse events with increasing cumulative rituximab exposure. This likely reflects physician bias in patient selection for repeat treatment and suggests that in selected patients, extended periods of rituximab treatment might be safe. The superior survival seen in high-dose group was likely related to higher proportion of ENT/ocular limited vasculitis.

Serious adverse events in children with juvenile idiopathic arthritis and other rheumatic diseases on tocilizumab – a real-world experience

ObjectivesTo assess the incidence rate and type of serious adverse events (SAE) in children with rheumatic inflammatory diseases treated with the interleukin 6 blocker tocilizumab (TCZ). MethodsA retrospective review of all consecutive patients diagnosed with an inflammatory rheumatic disease and receiving at least one dose of TCZ was performed in two French tertiary pediatric rheumatology centers between 01/2007 and 06/2019. SAE were defined as a life-threatening event and/or an event requiring hospital admission, leading to permanent disability or treatment discontinuation. ResultsOne hundred four children (64 female) were included. Most children suffered from systemic (n = 43) or polyarticular-course juvenile idiopathic arthritis (n = 43). Median age at TCZ start was 8.9 years (IQR 4.7 – 12.1), most children had received prednisone (81%), and/or a biologic agent (84%) prior to TCZ. Median TCZ treatment duration was 1.6 years (IQR 0.5 – 2.7), total TCZ exposure 215 patient years. Thirty-three SAE were observed in 26 (25%) children (SAE 15.3/100 patient years), mostly infections and infusion reactions. Children with SAE were significantly younger at disease onset (p = 0.034) and TCZ initiation (p = 0.016). Children experiencing infusion reactions were more likely to have systemic JIA or another autoinflammatory disease (p = 0.021), they all had active disease. At last follow up, 61 (59%) children remained on TCZ. ConclusionIn this cohort, SAE and most commonly serious infections were observed in a quarter of children. Severe infusion reactions were associated with persistently active autoinflammatory disease. Ongoing careful monitoring of TCZ-treated patients, especially young children with marked systemic inflammation is required.

The Healthcare Professionals' Perspective on Impact and Actions Taken Following Severe Infusion Reaction Events in Oncology Centers in Europe.

PurposeThe study aim was to describe the management strategies used for severe infusion-related reactions (SIRs) and understand the impact of such events in oncology day hospitals in France, Germany, Spain, and the UK.MethodsThe study was based on qualitative telephone interviews and quantitative self-completion questionnaires and asked healthcare professionals about the impact of SIRs and consequent actions taken.ResultsThe procedures to prevent and manage SIRs were similar across countries and settings. In all countries, they were part of a larger risk-assessment and adverse events-prevention process. Preventive measures included patient history, risk assessment, pre-medication, and close monitoring of high-risk patients. The management procedures comprised stopping the infusion, triggering of the emergency chain, administering corticosteroids ± antihistamines, and hospitalization if necessary. The recalled SIRs had important consequences to affected patients, healthcare providers, and hospital organizational plans. All affected patients needed to be monitored closely for a prolonged time, thus blocking hospital beds. 44% of patients needed to be hospitalized, 17% needed resuscitation, and one patient died of cardiac arrest immediately after the start of the infusion. Importantly, 82% of patients were not re-challenged with the presumedly SIR-causing regimen or re-challenged in a later line.ConclusionSIRs are unpredictable in nature, may have an extremely rapid onset, and are potentially fatal. Such events have a profound impact on the affected and surrounding patients, the care team and the organizational plan of the day-hospitals. Specific tools to reliably identify high-risk patients and predict the occurrence of events are needed.Electronic supplementary materialThe online version of this article (10.1007/s40801-020-00185-9) contains supplementary material, which is available to authorized users.

Impact and management of severe infusion reactions in cancer centres

Impact and management of severe infusion reactions in cancer centres

Analysis of adverse effects of infliximab treatment in 486 patients with Crohn′s disease

Objective To assess the safety of infliximab(IFX) treatment in patients with Crohn′s disease(CD). Methods From January 2009 to May 2018, at inflammatory bowel disease (IBD) center of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 486 CD patients received the treatment of IFX were enrolled and their clinical data were collected. Univariate and multivariate regression of binary logistic were performed for statistical analysis. Results The median follow-up duration was 31.1 months (12.0 months to 40.0 months). The median duration of IFX therapy was 13.0 months (7.0 months to 21.0 months). Among 486 patients, 98 (20.16%) patients reported adverse effects, and 12 (2.47%) patients discontinued the therapy because of adverse effects. Acute infusion reaction was the most common adverse effect in CD patients who received IFX treatment accounting for 41.84%(41/98)of all the adverse effects, and the incidence was 8.44%. Thirty-nine patients had mild and moderate infusion reaction, and all improved after symptomatic treatment (eight patients discontinued IFX therapy because of recurrent infusion reaction). Two patients developed severe infusion reaction as allergic shock, and both relieved after emergency rescue. Four patients developed late-phase allergic reactions. Among 486 patients, 39 (8.02%) patients had infections, including infections of Clostridium difficile, cytomegalovirus, herpeszoster virus, Mycobacterium tuberculosis, and other opportunistic pathogens. There was no cases of infection related death. Thirty-six patients continued with IFX treatment after infection controlled. Among 486 patients, 14(2.88%) patients had severe infection, and all the cases improved after anti-infection treatment. Twenty-seven CD patients with hepatitis B virus (HBV) infection received anti-viral treatments, no active HBV infection was observed. Colon adenocarcinoma was found in one patient under colonoscopy at 22 months after discontinuation of IFX therapy. There were six patients with the history of benign tumors, and no evidence of recurrence, progress or malignancy during treatment. In terms of other rare adverse effects in 486 patients, there were eight (1.64%) patients with liver function injury, two (0.41%) patients with anemia, one (0.21%) patient with peripheral neuropathy, and four (0.82%) patients with skin lesion. Prolonged duration of IFX therapy, without combination of immune-suppressors and with increased baseline body mass index (BMI) were the risk factors of acute infusion reactions. Prolonged duration of IFX therapy and with low baseline albumin level were the risk factors of infections. Conclusions IFX is generally safe as the treatment for CD patients, and its adverse effects can be clinically controlled. Screening before therapy and monitoring during therapy may reduce the risks of adverse effects. Key words: Crohn disease; Infection; Neoplasms; Infliximab; Adverse effects; Infusion reaction

Effectiveness and safety of belimumab in patients with systemic lupus erythematosus in a real-world setting

Objective: To investigate the effectiveness and safety of belimumab in patients with active systemic lupus erythematosus (SLE) in a real-life setting.Methods: All SLE patients treated with belimumab in the Department of Autoimmune Diseases of the Hospital Clinic of Barcelona were retrospectively analysed. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, clinical SLEDAI-2K, levels of anti-double-stranded DNA (anti-dsDNA) antibody, complement components C3 and C4, and 50% haemolytic complement activity (CH50) were recorded at baseline and at 6, 12, and 24 months. Adverse events were also collected.Results: Twenty-three patients (100% women) were enrolled in the study. The most frequent manifestations that led to belimumab use were arthritis (91%) and skin involvement (39%). Both SLEDAI-2K and clinical SLEDAI-2K improved over time at all time-points (p < 0.005). Complement levels increased and the values of anti-dsDNA antibody decreased during treatment. The mean dose of prednisone could be tapered at all time-points and achieved maximum and significant reduction at 24 months (10.4 ± 4.8 mg/day to 4.8 ± 2.1 mg/day; p < 0.0005). Belimumab was well tolerated and only six patients (26%) experienced adverse events, all of which were classified as infections (one urinary tract infection without bacterial detection in urine culture and five viral infections). No deaths, severe infusion reactions, or hypersensitivity reactions were noted.Conclusion: In our patients with SLE, belimumab decreased disease activity and allowed tapering of the daily glucocorticoid dose with a good safety profile.

P094 Henoch–Schonlein purpura and inflammatory bowel disease

BACKGROUND: Approximately 7.5% of children with inflammatory bowel disease (IBD) develop cutaneous extra-intestinal manifestations, with erythema nodosum, pyoderma gangrenosum, and psoriasis being the most common. Although rare, cases of cutaneous small-vessel vasculitis in children with IBD have been reported. CASE: An 8 Y/M with ileo-colonic Crohn disease presented with 3 days of bilateral lower extremity swelling and 1 day of tender palpable rash on the right arm, chest and dorsal surface of the right foot. Crohn disease was diagnosed at age 5 years and was on mesalamine for treatment at the time of presentation. A year ago he had been on infliximab infusions, but had to stop the treatment after a severe infusion reaction. On exam, patient was uncomfortable, unable to bear weight, afebrile, and without abdominal pain or tenderness to palpation. He had limited range of motion of right foot secondary to pain. No joint swelling was noted. He had a palpable purpuric rash on his right arm, chest and dorsal surface of the right foot. Urinalysis was positive for trace protein and ketones. His ANA titers were positive and rheumatoid factor was negative. A clinical diagnosis of Henoch-Schonlein purpura (HSP) was made based on the typical rash and urinalysis. He was treated symptomatically with acetaminophen and did well subsequently DISCUSSION: HSP occurs in approximately 10–22 persons/100,000 each year. More than 90% of patients are children younger than 10 years, with a peak incidence at 6 years of age. HSP is the most common vasculitis in children and has a slight predominance in males. The clinical features of HSP are a consequence of widespread leukocytoclastic vasculitis owing to immunoglobulin A deposition in vessel walls. In 15% to 20% of patients, the gastrointestinal symptoms precede the diagnostic rash by a number of days. In such patients, IBD is a diagnostic consideration, even though the coexistence of HSP and IBD is quite uncommon. In this report, we describe a child with Crohn disease who developed HSP 3 years after diagnosis. HSP can be seen as a complication of infliximab or adalimumab therapy, but our patient was not on biologic therapy at the time HSP diagnosis.

Variable clinical features and genotype-phenotype correlations in 18 patients with late-onset Pompe disease.

Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer. Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

PS1515 PREMEDICATION WITH MONTELUKAST AND RUPATADINE DECREASES INFUSION TIME, RATE AND SEVERITY OF REACTIONS AND OVERALL COST OF RITUXIMAB ADMINISTRATION

Background:Rituximab is associated with frequent infusion reactions, which carry significant burden to both patients and health care practitioners. Standard pre‐medications (SP) do not prevent reactions sufficiently. Montelukast (M) and Rupatadine (R) are used for treatment of urticarial, allergic rhinitis, and may impact Rituximab infusionAims:We assessed impact of addition of R, M and their combination (R+M) on Rituximab infusion/rate, rate/severity of reactions and administration costMethods:Adult patients with lymphoproliferative disorders treated at our cancer center between Jan 2018 to Jan 2019 were evaluated with Rituximab‐containing regiments. Since the majority of reactions occur during the first infusion, our study was limited to the initial Rituximab treatment. Patients received either SP with diphenhydramine/acetaminophen and additional R, M or R+M combination. Comparative analysis of infusion time/rate, severity of infusion reactions, number of rescue medications and cost of Rituximab infusions among groups was performed using one‐way ANOVA with Tukey post‐hoc or chi‐square. The study was approved by our institutional ethics boardResults:Patients received either: 1) standard premedications (SP); 2) SP + Rupatadine (R) 10 mg; 3) SP + Montelukast (M) 10 mg; or 4) both (SP+R+M). Patient characteristics and therapy are shown in Table 1. Compared to SP, the R, M and R+M groups had greater improvement in Rituximab delivery. Mean infusion time was 305 [range 235–441] min. in SP, 254 [105–390] in M, 265 [193–350] in R and 238 [196–342] in R+M groups, (p = 0.0001). Infusion reactions occurred in 92% in SP vs. 38, 45, 31% in M, R and R+M groups (p = 0.0001). Median reaction grade was 2 in SP, 1 (M), 0 (R and R+M). Median number of rescue medications was 3 [0–10] in SP vs 0 [0–7] in M, R and R+M groups. Cost of rescue medications (US$) was 41 [0–63] (SP), 11 [0–50] (M), 17 [0–63] (R), 7 [0–58] (R+M) groups (p &lt; 0.0001). Mean nursing cost (US$) per patient infusion was calculated as 269 [207–388] in SP vs 222 [92–343] (M), 233 [170–308] (R), 209 [174–301] (R+M) group.RCHOP, Rituximab/Cyclophosphamide/Doxorubicin/ Oncovin/Prednisone; BR, Bendamustine/Rituximab; FCR, Fludarabine/Cyclophosphamide/RituximabimageSummary/Conclusion:Addition of R, M and particularly R+M combination significantly improved Rituximab delivery, decreased the rate and severity of infusion reactions, and lowered the cost of Rituximab administration

Effect of montelukast and rupatadine on rituximab infusion time, rate, severity of reactions, and cost of administration.

6500 Background: Rituximab is associated with frequent infusion reactions which carry significant burden to patients and health care practitioners. Standard pre-medications (SP) do not prevent reactions sufficiently. Rupatidine (R) and Montelukast (M) are used for symptomatic treatment of urticaria and allergic rhinitis. We assessed addition of R, M and their combination on Rituximab infusion, rate, severity of reactions and cost of administration. Methods: Adult patients with lymphoproliferative disorders treated at our cancer center between Jan 2018 to Jan 2019 were evaluated with Rituximab-containing regiments. Since the majority of reactions occur during the first infusion, our study was limited to the initial Rituximab treatment. Patients received either SP with diphenhydramine/acetaminophen and additional R, M or R+M combination. Comparative analysis of infusion time/rate, severity of infusion reactions, number of rescue medications and cost of Rituximab infusions among groups was performed using one-way ANOVA with Tukey post-hoc or chi-square. The study was approved by our institutional IRB. Results: Patients received either: 1) SP; 2) SP + Rupatadine (R) 10 mg; 3) SP + Montelukast (M) 10 mg; or 4) both (SP+R+M). Patient demographics are shown in the table. Compared to SP, the R, M and R+M groups had greater improvement in Rituximab delivery. Mean infusion time was 306 [range 235-441] min. in SP, 254 [105-390] in M, 265 [193-350] in R and 248 [196-342] in R+M groups, (p=0.0001). Infusion reactions occurred in 92% in SP vs. 38, 45, 33% in M, R and R+M groups (p=0.0001). Median reaction grade was 2 in SP, 1 (M), 0 (R and R+M). Median number of rescue medications was 3 [0-10] in SP vs 0 [0-7] in M, R and R+M groups. Cost of rescue medications (US$) was 38 [0-63] (SP), 11 [0-50] (M), 17 [0-63] (R), 12 [0-58] (R+M) groups (p&lt;0.0001). Mean nursing cost (US$) per patient infusion was calculated as 269 [207-388] in SP vs 222 [92-343] (M), 233 [170-308] (R), 218 [174-301] (R+M) group. Conclusions: Addition of R, M and particularly R+M significantly improved Rituximab delivery, lowered the rate and severity of infusion reactions, and lowered the cost of Rituximab administration. [Table: see text]

Immunogenicity of Innovative and Biosimilar Monoclonal Antibodies.

The development of hybridoma technology for producing monoclonal antibodies (mAbs) by Kohler and Milstein (1975) counts as one of the major medical breakthroughs, opening up endless possibilities for research, diagnosis and for treatment of a whole variety of diseases. Therapeutic mAbs were introduced three decades ago. The first generation of therapeutic mAbs of murine origin showed high immunogenicity, which limited efficacy and was associated with severe infusion reactions. Subsequently chimeric, humanized, and fully human antibodies were introduced as therapeutics, these mAbs were considerably less immunogenic. Unexpectedly humanized mAbs generally show similar immunogenicity as chimeric antibodies; based on sequence homology chimeric mAbs are sometimes more “human” than humanized mAbs. With the introduction of the regulatory concept of similar biological medicines (biosimilars) a key concern is the similarity in terms of immunogenicity of these biosimilars with their originators. This review focuses briefly on the mechanisms of induction of immunogenicity by biopharmaceuticals, mAbs in particular, in relation to the target of the immune system.

A Case of Cetuximab-induced Severe Infusion Reaction in a Patient with Oral Cancer

A Case of Cetuximab-induced Severe Infusion Reaction in a Patient with Oral Cancer

Effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting in patients with Crohn’s disease or ulcerative colitis

Objective: To assess the effectiveness and safety of biosimilar infliximab (CT-P13) in a real-life setting in adults with moderate-to-severe active Crohn’s disease (CD) or ulcerative colitis (UC).Methods: This multi-centre, observational cohort study was conducted at medical centres in Romania, Czech Republic, and Bulgaria. Effectiveness was measured using the Crohn’s Disease Activity Index (CDAI) for CD or partial Clinical Activity Index (pCAI) for UC. Quality-of-life (QoL) was measured using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Safety was assessed according to treatment withdrawals and adverse events (AEs) monitoring. Analyses were performed in the safety population and were reported based on the observed case (OC) or last observation carried forward (LOCF) method.Results: Altogether, 85 patients with CD (n = 38) or UC (n = 47) received biosimilar infliximab for up to 30 weeks. Most patients (n = 68; 80.0%) had no prior exposure to infliximab. At the end of treatment, 65.8% (95% CI = 49.8–78.9) of CD patients and 55.3% (95% CI = 41.2–68.6) of UC patients showed a clinical response, and 47.4% (95% CI = 32.5–62.7) and 48.9% (95% CI = 35.3–62.8), respectively, were in remission. Statistically significant (p < 0.0001) improvements from baseline were observed in CDAI and pCAI scores (both LOCF). In the combined CD and UC population, SIBDQ was significantly improved (p < 0.0001) from baseline to end of treatment (OC). Two AEs (moderately severe infusion reactions) were judged by investigators to be definitely related to treatment, one of which led to treatment withdrawal.Conclusion: Results align with those of previous studies demonstrating the effectiveness and safety of biosimilar infliximab in CD and UC.