Severe Infusion-related Reactions Research Articles

Successful use of ofatumumab in two cases of early-onset juvenile SLE with thrombocytopenia caused by a mutation in protein kinase C \u03b4

BackgroundWe previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE.Case presentationAll three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing identified a homozygous missense mutation in PRKCD (p.Gly432Trp), subsequently confirmed by Sanger sequencing to be present in all 3 siblings. All 3 patients were initially treated with rituximab, however 2 of the siblings developed severe infusion-related reactions. For subsequent disease flare in these individuals we therefore used an alternative B cell depleting agent, ofatumumab (300 mg/1.73m2 on day 1; 700 mg/1.73m2 on day 15). This resulted in marked clinical improvement in both patients. To the best of our knowledge, this is the first report describing the successful use of ofatumumab for PKCδ deficiency.ConclusionsPKCδ deficiency causes a monogenic form of SLE which responds well to B cell depletion. Ofatumumab is also likely to have a therapeutic role for sporadic juvenile SLE (jSLE) patients intolerant of rituximab.

Pattern of Cytokine Release in Patients with Chronic Lymphocytic Leukemia Treated with Obinutuzumab and Possible Relationship with Development of Infusion Related Reactions (IRR)

Background: Infusion related reactions (IRR) are commonly seen with administration of biologic therapies but remain relatively poorly understood. Rituximab is thought to induce cell death upon binding to CD20 primarily by complement dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Obinutuzumab (GA101, Gazyva®, Gazyvaro®) is a new generation humanised IgG1 Type II anti-CD20 mAb with contrasting properties to rituximab. The Fc portion has been glycoengineered (afucosylated) to increase binding affinity to Fcgamma receptor 3(FcγRIII). These features result in higher direct cell killing activity, enhanced ADCC and phagocytosis (ADP) and less complement activation compared with rituximab.Early experience with rituximab has shown that release of pro-inflammatory cytokines occurs with initial administration and is higher in patients experiencing IRRs compared to those who are not. We report on the cytokine release in a subset of 38 patients with chronic lymphocytic leukemia (CLL) treated with obinutuzumab monotherapy pooled from the earlier Phase I (GAUSS) trial (NCT00576758) and Phase I/II (GAUGUIN) trial (NCT00517530).Methods: Eligible patients for both studies had relapsed/refractory CLL with no alternative, higher priority therapy available. All patients were treated sequentially with intravenous (IV) obinutuzumab monotherapy and were universally pre-medicated with an oral anti-pyretic (paracetamol/acetaminophen) and an IV anti-histamine 30 minutes prior to starting the infusion. Steroid pre-medication was not mandated in either study.Cytokine serum samples (quantitatively measured using the Becton-Dickinson (BD) Cytometric Bead Array) were taken from each patient prior to each obinutuzumab infusion, mid-way through the infusion, at the end of infusion and 2-5 hours after completion. Samples for complement analysis were also taken at these same time points (C3/C4 analysed using Siemens BNII Nephelometer, C3a/C5a using BD Pharmingen ELISA kit). Peripheral blood samples for immunophenotyping were also taken at baseline, prior to and at the end of each infusion. The development of an IRR with the first infusion was defined as the occurrence of related signs and symptoms within 24 hours of administration of antibody and graded according to the CTCAE guidelines v4.0.Results: Of the 38 patients treated, 35 developed symptoms of IRR (Grade 1/2=25, Grade 3/4=10) with the first infusion accompanied by a rapid decrease in circulating CD19+ B cells, a drop in the measurable natural killer (NK) CD16+56+ cells and an increase of pro-inflammatory cytokines IL6, IL8, TNFα and IFNγ (see figures 1 and 2). There were no meaningful differences between pre-treatment baseline cytokine levels across all subgroups. At the mid-infusion time-point, patients with absolute lymphocyte count (ALC) at baseline ≥50x109/L released higher levels of IL6 (mean IL6(log10) 3.16 vs 2.41), IL-8 (mean IL8(log10)3.57 vs 2.91), TNFα (mean TNFα(log10) 2.59 vs 1.92), IFNγ (mean IFNγ(log10)2.38 vs 1.8) and IL10 (mean IL10(log10) 2.03 vs 1.69) than those with ALC <50x109. Patients who had higher grade IRR (≥grade 3) had higher baseline values for lymphocyte count and β-2microglobulin, lower baseline platelet count and higher Binet stage than those without severe grade IRR, however none of these differences were statistically significant at p≤0.05. . Markers of complement activation, C5a and C3a, did not increase and C3/C4 levels remained stable across all groups. Cytokine release was limited to the first infusion of obinutuzumab only and did not recur with subsequent infusions (Fig . 1).Conclusions: This sub-analysis demonstrates that the first obinutuzumab administration triggers immediate and strong release of cytokines (IL6, IL8, TNFα, IFNγ and IL10) in association with rapid destruction of circulating B cells in patients with CLL. The close temporal relationship between release of pro-inflammatory cytokines (especially IL6 and IL8) and development of IRRs, in addition to the lack of complement activation induced by obinutuzumab, suggest that cytokine release is part of the IRR pathophysiology. Intervention strategies targeting cytokines may therefore be a promising strategy to reduce the incidence and severity of IRRs. [Display omitted] [Display omitted] DisclosuresFreeman:Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart’s) Other. Off Label Use: Presentation may refer to mitigation strategies such as the use of tocilizumab in patients with cytokine release syndrome. Morschhauser:Bayer: Honoraria; Mundipharma: Honoraria; Genentech: Honoraria; Spectrum: Honoraria; Gilead: Honoraria. Sehn:Roche: Research Funding. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Wassner-Fritsch:Roche Pharmaceuticals: Employment. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Salles:Roche Pharmaceuticals: Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria.

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.

Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study.

BackgroundAs recommended in the current prescribing information, rituximab infusions in patients with rheumatoid arthritis (RA) take 4.25 hours for the first infusion and 3.25 hours for subsequent infusions, which is a burden on patients and the health care system. We therefore evaluated the safety of infusing rituximab at a faster rate for an infusion period of 2 hours in patients with RA.MethodsPatients with an inadequate response to anti-TNF who were rituximab-naive or -experienced received 2 courses of rituximab: Infusion 1 (Day 1) was administered over the standard 4.25 hours, and Infusions 2 (Day 15), 3 (Day 168) and 4 (Day 182) were administered over a faster 2-hour period. The primary endpoint was incidence of infusion-related reactions (IRRs) associated with Infusion 2.ResultsOf the 351 patients enrolled, 87% and 13% were rituximab-naive and -experienced, respectively. The incidence (95% CI) of IRRs associated with Infusion 1 was 16.2% (12.5%, 20.5%) and consistent with weighted historical incidence of 20.7% (19.4%, 22.1%). The incidence (95% CI) of IRRs associated with Infusions 2, 3, and 4 compared with respective weighted historical incidences at the standard infusion rate was 6.5% (4.1%, 9.7%) vs 8.1% (7.2%, 9.1%); 5.9% (3.5%, 9.3%) vs 11.5% (10.3%, 12.8%); and 0.7 (0.1%, 2.6%) vs 5.0% (4.2%, 6.0%), respectively. All IRRs were grade 1 or 2, except for 3 grade 3 IRRs associated with Infusion 1 and 2 grade 3 IRRs associated with Infusion 2. Four patients experienced a total of 5 grade 3 IRRs; 3 of these patients continued on to received subsequent infusions at the faster rate. There were no serious IRRs.ConclusionThis study demonstrated that rituximab can be administered at the faster infusion rate at the second and subsequent infusions without increasing the rate or severity of IRRs.

Successful rechallenge of cetuximab following severe infusion-related reactions: a case report.

Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is associated with a risk of infusion reactions, similar to other infusional agents. Although avoiding a rechallenge with cetuximab following a severe infusion reaction is preferable, this may not be an option if few other reasonable alternatives exist. We report herein a successful case of cetuximab rechallenge, carried out by extending infusion times and using saline dilution in a patient who had severe infusion reactions twice and who required continuation of treatment. Cetuximab reintroduction with saline dilution and a slower infusion rate in an intensive care setting allowed safe continuation of therapy.

Long-Term Safety in a Phase 1 Study of Siltuximab (CNTO 328), an Anti-Interleukin-6 Monoclonal Antibody, in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease,

Long-Term Safety in a Phase 1 Study of Siltuximab (CNTO 328), an Anti-Interleukin-6 Monoclonal Antibody, in Patients with B-Cell Non-Hodgkin's Lymphoma, Multiple Myeloma, or Castleman's Disease,

Rapid Development of Infusion-Related Severe Hypotension During Rituximab Therapy

To report an incident of rapid development of profound hypotension, differing from the time described in previous reports, during the infusion of rituximab chemotherapy in a patient without prior exposure to the drug. An 84-year-old white male with Rai stage IV chronic lymphocytic leukemia was prescribed rituximab 375 mg/m(2) by intravenous infusion. Rituximab 50 mg/h was initiated after premedication with acetaminophen, diphenhydramine, dexamethasone, and ondansetron 3 days into his hospital course. Five minutes after the infusion had begun, he experienced a significant decrease in blood pressure to 76/45 mm Hg, and the infusion was stopped. After 30 minutes, the blood pressure returned to normal. Rechallenge with rituximab 25 mg/h was attempted, but the blood pressure again declined and the patient experienced chills and rigors. The infusion was discontinued, and the symptoms resolved 1 hour later. Infusion-related adverse reactions associated with rituximab are reported at a higher rate than with other monoclonal antibodies. Hypotension with rituximab has been reported to occur 30 minutes to 2 hours after initiation of the infusion. In contrast, severe hypotension in our patient occurred within 5 minutes after the infusion was started in a patient with no previous exposure to the drug. While many studies hypothesize that cytokine release from lymphocytes and tumor cell agglutination might contribute to severe infusion-related reactions with rituximab, the mechanism of action is not yet known. Use of the Naranjo probability scale indicated that the hypotension was probably associated with rituximab administration. Awareness of the rapidity of this adverse effect in patients who have not received prior treatment with monoclonal antibodies is important during chemotherapy treatment.

411: Rituximab Monitoring in Hematopoietic Stem Cell Transplant: How much is Necessary?

Background: Rituximab, an uncongugated monoclonal antibody that reacts with the CD20 molecule present on most malignant B-cells, is standard treatment for patients with lymphoma. Most rituximab infusions are well tolerated with a mild infusion related symptom complex (fever, chills/rigors) usually occurring within 1 hour after initiation. Severe infusion related reactions (IRR), such as bronchospasm and hypotension, occur infrequently; most often within 2 hours after initiating the first dose. Reactions are caused by cytokine release associated with high numbers of circulating tumor cells. Incidence of IRRs decreases markedly with subsequent infusions. At a university based comprehensive cancer center, controlled trials using rituximab for treatment of NHL are underway in hematopoietic stem cell transplant patients to determine optimal dosing and scheduling. Patients participating in these trials are heavily pretreated with rituximab, and are in partial or complete remission before admission for transplant. Based on phase I and II trials, frequent vital sign (VS) monitoring and concurrent administration of normal saline are recommended. Current organizational clinical practice standards require between 10–16 sets of VS over 5–6 hours for average rituximab infusions; interfering with patient comfort and requiring significant nursing time. Purpose: To determine the frequency and risk of IRRs in patients admitted for transplant and an optimal vital sign monitoring schedule. Method: A nurse initiated, IRB-approved, retrospective review of 200 medical records was conducted. Data analysis is in progress to determine IRR frequency, identify patients at high risk for reactions, and determine an appropriate VS schedule. Results: Study findings will be reported.

Pathogenic study of anti-CD20 infusion-related severe refractory shock in diffuse large B-cell lymphoma

Although rituximab is an effective and safe therapy for B-cell lymphoid malignancies, a few cases of severe infusion-related reactions have been reported. Severe refractory distributive shock is an infrequent side-effect of treatment with rituximab and, to our knowledge, there are no reports describing its pathogenesis in a case of fatal outcome in detail. We present for the first time a case of fatal rituximab infusion-related refractory distributive shock in a patient with CD5+ diffuse large B-cell lymphoma (DLBCL) and analyse the pathogenic mechanisms involved. We have compared measurements obtained from the patient that experienced lethal refractory shock with the four subsequent DLBCL patients treated with rituximab, either at diagnosis or upon relapse, at our center. Serum cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70] and complement components C3 and C4 were analysed, both pretreatment, and 3 h and 9 h after the onset of infusion. When compared with the control subjects, the potential risk factors for rituximab toxicity displayed by the patient that suffered refractory shock included C4 hypercomplementemia, IFN-γ and IL-10 hypercytokinemia, as well as a high tumor burden. The refractory shock was distributive with most cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6 and IL-8) peaking 3 h after infusion and coinciding with the onset of the shock. Furthermore, the concentrations of IL-10 were persistently elevated. In conclusion, the cytokine pattern was similar to that observed in patients with rapid onset septic shock and serum cytokines reached levels markedly higher than previously described in other cases of severe rituximab infusion-related toxicity.