Acute adverse reactions of rapid Rituximab infusion among adult patients with Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: A systematic review

Review question/objective The objective of the proposed systematic review is to critically analyse currently available research studies and present the best available evidence related to the safety of rapid Rituximab infusion among patients with NHL and CLL. The specific review questions are: What is the frequency of acute adverse reactions from rapid Rituximab infusion? How severe are the acute adverse reactions from rapid Rituximab infusion? What is the treatment for patients who develop acute adverse reactions from rapid Rituximab infusion What is the mortality rate of patients who develop acute adverse reactions from rapid Rituximab infusion? What are the type and amounts of the premedication given before rapid Rituximab infusion? Background Rituximab (Rituxan/Mabthera) is a chimeric monoclonal antibody directed against CD-20 antigen, a hydrophobic transmembrane protein located on normal B lymphocytes and B cell lymphomas.1 As Rituximab binds to the B lymphocytes, it triggers a host cytotoxic immune response leading to programmed cell death (apoptosis) of the B lymphocytes. The mechanism of how Rituximab can induce apoptosis is explained through activation of complement-dependent cytotoxicity1,2 and antibody-dependent cellular toxicity.1 Rituximab was the first monoclonal antibody approved for the cancer treatment by the Food and Drug Administration (FDA) in United Stated (US) in 1997.1 Since then, the drug has been widely used specifically for Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukaemia (CLL).1 The use of Rituximab is rapidly expanding to other diseases in addition to its application in cancer. There are also ongoing clinical trials and research studies of Rituximab in non cancerous conditions such as Multiple Sclerosis,3 Refractory Thrombotic Thrombocytopenic Purpura,4 Systemic Lupus Erythematosus,5 Epidermolysis Bullosa Acquisita6 and Rheumatoid Arthritis.7 So far, only treatment of Rheumatoid Arthritis has been approved by the FDA in 2006 to be treated with Rituximab.7 During various Rituximab clinical trials, the most common adverse reactions are infusion reactions, fever, lymphopenia, chills, infection, and asthenia for lymphoid malignancies. In treatment for CLL the most common adverse reactions are infusion reactions and neutropenia.8 The infusion reactions have been described as hypotension, fever, chills, rigors, urticaria, bronchospasm, angioedema (sensation of tongue and throat swelling), nausea, fatigue, headache, pruitus, dyspnoea, rhinitis, vomiting, flushing and pain at the disease site.9 The reactions usually occur at the beginning of the first infusion within 30 minutes to 2 hours 8-10 Other possible and more serious adverse reactions are tumour lysis syndrome (TLS), mucocutaneous reaction, progressive multifocal leukoencephalopathy, hepatitis B reactivation with fulminant hepatitis, infection, cardiac arrhythmias, renal toxicity and bowel obstruction and perforation.8-9 The incidence of first infusion related reactions has been reported as 77%, with 7% of it grade 3 and 4 adverse events, and 33% with 2% grade 3 and 4 adverse events at subsequent infusions.9 Apart from the acute adverse reactions associated with Rituximab, exposure to the drug may possibly create lasting adverse reaction for patients. A study11 shows that 13 patients who received Rituximab in combination with Adriamycin-based chemotherapy had a decrease in left ventricle ejection fraction (LVEF) >10% compared to their pre-treatment baseline 3 months later. They recovered normally, but another 6 patients whose LVEF dropped >15% from baseline did not recover to the acceptable range. Adriamycin is known to cause cardiac toxicity and there is no decrease of LVEF among patients who did not receive it. Therefore, this suggests that Rituximab alone may not be responsible for cardiac toxicity. However, it possibly increases the risk of cardiac toxicity when used in combination with other drugs. The terminology of describing and measuring adverse reactions is non-standardised.12 However, some studies13-14 have used the National Cancer Institute (NCI) severity grading system in order to standardise reporting for adverse reactions. The most commonly used NCI severity grading scales are Common Toxicity Criteria (CTC) or Common Terminology Criteria for Adverse Events (CTCAE) using a scale of 0-4 for CTC15 or 1-5 for CTCAE.16 An example of CTC and CTCAE can be found in Appendix I. CTCAE is the revised version of CTC. In these tools, an adverse event is defined by any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.16 The tools are appropriate for measuring Rituximab related adverse reactions which are defined as adverse effects specifically associated with a drug.12 There is no conflict between the interchangeable uses of the two terms. The pathogenesis of the Rituximab induced infusion reactions has been investigated through clinical study. One study17 explains that infusion of Rituximab can cause rapid complement activation, leading to further activation of macrophages and mast cells. As a result, they produce complement activation products (C3b/c C4b/c) and release of cytokines (TNF-α, IL 6 & IL 8).17 Therefore, the patients experience fever, chills, dyspnoea, and flushes. 17 Another study also reports a similar finding that an increase of cytokine can be correlated with the patient experiencing hypotension and dyspnoea.18 Nevertheless, complement activation cannot account for all the infusion reactions. Other contributing factors, including high expression of circulating CD 20 positive B lymphocytes18-19 rapid tumour lyses syndrome19 and increased age of patients20 are associated with the infusion reactions. As Rituximab can cause possible fatal adverse reactions, a very strict administration regimen8 is recommended by the drug's manufacturers. At the first infusion, the infusion rate is started at 50mg/hr. If the patient tolerates the drug without severe acute reactions and maintains stable vital signs, the infusion rate is allowed to increase by an increment of 50mg/hr every 30 minutes to a maximum of 400mg/hr. When patients tolerate the first infusion, the subsequent infusion is started at 100mg/hr and increased to 100mg/hr increment at every 30 minutes interval to a maximum rate of 400mg/hr. The dosage of Rituximab is calculated based on patient's body surface area. The recommended dosage for Lymphoma is 375mg/m2 and 375mg/m2 at first infusion and followed by 500mg/m2 for CLL at subsequent infusion. Therefore, with the regimen recommended by the drug manufacturer, a patient is required 5-6 hours and 3-4 hours to complete the first and subsequent infusion.8 In addition to the precautionary measures related to the rate of infusion and vital signs monitoring, Paracetamol, Diphenhydramine13,20-22 and steroids23-24 will usually be administered 30 minutes before the Rituximab with the aim of decreasing infusion reactions to the minimum. The variation of the administration rate between the first and subsequent infusion is due to the rapid break down of the circulating B lymphocytes which will occur after the first infusion leading to more adverse reactions. Subsequent cycles, when the numbers of B lymphocytes are remarkably decreased in the blood stream, are therefore less likely to cause fewer adverse reactions.1 As a result of the decreased number of circulating lymphocytes, it is safe for the subsequent infusion to be run over a shorter duration. This also explains why patients may react at the first infusion, and have no severe adverse reactions at a subsequent infusion. The treatment of the Rituximab induced adverse reactions can be treated by simply stopping the infusion until all the symptoms subside.18 When patients develop chills and rigors, a steroid and Pethidine/Meperidine are frequently administered to them. Other supportive treatments include oxygen support and the application of a heater blanket. When all of the adverse reactions subside, Rituximab is restarted at a slower rate or half of the previous rate. In the event where patients experience cytokine storm which is considered as an oncology emergency, advanced therapy such as epinephrine, bronchodilator, and administration of vasopressin18,20,25 is used and patients may be transferred to intensive care unit for closer monitoring. In 2009, statistics from the US show that the number of people being diagnosed and living with NHL and CLL are 452,723 and 85,713 respectively. 26 So far, 1.5million of patients worldwide have been treated with Rituximab.24The diagnosis of NHL and CLL is continuously rising and it is anticipated that many will require Rituximab as part of their treatment regimen. Therefore, lengthy infusion has a great impact on the health care provider; it challenges them to work within limited resources such as space constraints, human resources and long waiting times for patients to receive their treatment on schedule. In addition patients or insurance companies have to pay more for the long infusion hours as some medical centres charge treatment fees based on the duration of the infusion.21 Many medical centres from different regions across the world including the US and Canada, Europe, Middle East and Asia have conducted research studies11,13-14,20-21,24,27-30to evaluate the feasibility and safety of rapid Rituximab infusion. In 2004, a report showed that more than 1200 patients have received rapid infusion of Rituximab in the United Kingdom (UK).30 In addition, 20 independent NHS trusts were interviewed on their Rituximab administration policy and it found that 70% of the units administer second and subsequent Rituximab infusions over 90 minutes and 5% administer Rituximab over 60 minutes.24The benefits of rapid Rituximab infusion are clearly evidenced. Studies 21,31 demonstrate that rapid Rituximab infusion is safe and able to translate into cost saving, better resource utilisation and increased patients' satisfaction. However, one study32 highlights the down side of the cost issue where the occurrence of the infusion reactions can require more staff time (33%) resulting in higher human resource costs. The efficacy of rapid Rituximab infusion is examined by only one study.23 The results ascertain that rapid infusion is as effective as conventional rate infusion among patients with Diffuse Large B Cell Lymphoma, a subtype of NHL. When Rituximab is infused intravenously, it is absorbed immediately, resulting in a rapid depletion of B-lymphocytes. 33 The drug is detected in the blood after completion of treatment 3-6 months later.33 The pharmacodynamics of rapid Rituximab infusion is unknown as no study comparing the rapid versus conventional infusion rate has been found. The benefit of rapid Rituximab infusion is well articulated in term of cost saving and better resources utilisation without compromising its effectiveness. A good quality of systematic review that examines the adverse reactions of a drug will have to consider studies report on the definition, number, seriousness and severity of the adverse reactions. Other consideration factors will be a clear description of the standard scale, mode and timing of data collection on adverse reactions. The mode of the data collection can be either active such as measurement of vital signs or passive through self-reporting from patients or both. 12 Randomised controlled trials (RCT) have been considered the gold standard to evaluate effectiveness study as well as study examines safety.12 However, the majority of the study designs 21,27,30,34 which examine the tolerability of rapid Rituximab infusion are case series. Nevertheless, this systematic review will report on best available evidence based on both experimental and non experimental studies. The proposed systematic review will focus on adult patients with NHL and CLL as they are approved by FDA to date for cancer population even though Rituximab has been used widely for other diseases. The results from the review will be presented into different sections with a separate analysis for NHL and CLL.Subgroup analysis will be perform for patients with high circulating B-lymphocytes (>25 x 109/L) as it has been associated with more adverse reactions.10 In this proposed systematic review, rapid Rituximab infusion will be defined as Rituximab infusion completes at equal or less than 120 minutes. From the literature review, the most popular rapid infusion rate is at either 60 or 90 minutes of duration. Therefore, outcome measures will be presented according to the different infusion rates. The primary outcome from the proposed systematic review will measure the presence or absence of acute adverse reactions, and their severity, on different scales or ranking frameworks proposed by the authors of the primary study. The example of these adverse reactions include hypotension, fever, chills, rigors, urticaria, bronchospasm, angioedema (sensation of tongue and throat swelling), nausea, fatigue, headache, pruitus, dyspnoea, rhinitis, vomiting, flushing and pain at the disease site. Premedication are recommended by the drug manufacturer to minimize the adverse reactions from Rituximab infusion9 and it can be considered as confounding factor in the review. Therefore, a sub-group analysis will be performed for patients who receive premedication. Inclusion criteria Types of participants The participants of interest include adults 18 years old and older, scoring between 0-4 in Eastern Cooperative Oncology Group Performance Status (ECOG), having any comorbidity for example but not limited to cardiac and respiratory diseases and one of the following diagnosis: Non-Hodgkin lymphoma -based on histology finding-of any stage from I to IV based on Ann-Arbor staging36(Appendix II)-any subtypes but not limited to Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL) and Burkitt's Lymphoma-who receive Rituximab as monotherapy or combination with any types of chemotherapy not limited to CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone),and CVP (Cyclophosphamide, Vincristine and Prednisone)-prior exposure to Rituximab infusionChronic Lymphocytic Leukemia -based on cytology or phenotype finding- any stage from A-C based on Binet staging36 (Appendix III) or- any stage from O-IV based on Rai classification36(Appendix IV) who receive Rituximab as monotherapy or combination with any types of chemotherapy not limited to Fludarabine, FC (Fludarabine,Cyclophosphamide), CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) -prior exposure to Rituximab infusion Patients who diagnosed with autoimmune diseases such as Thrombotic Thrombocytopenic Purpura(TTP), Autoimmune Haemolytic Anaemia (AIHA), Systemic Lupus Erythematosus(SLE), Epidermolysis Bullosa Acquisita(EBA) and Rheumatoid Arthritis(RA) will be excluded. Types of intervention(s)/phenomena of interest The intervention of interest is rapid Rituximab infusion less than or equal to 120 minutes not limited to 60 or 90 minutes at second and all Subsequent cycles at a range from 4-8 cycles. All different numbers of cycles of Rapid Rituximab infusion will be included. Types of outcomes The primary outcome will measure the following: -cycles of infusion completed by the number of patients without acute adverse reactions -frequency, type and severity of the acute adverse reactions -type, amount and route of premedication for example but not limited to PO Paracetamol 1g and IV Diphenhydramine 50mg The secondary outcomes will measure the following: -number of patients that continue the rapid Rituximab infusion regardless of the acute adverse reactions -number of patients who discontinue from the study due to adverse reactions -type of treatment rendered to patients after acute adverse reactions for example but not limited to stop infusion immediately and restart at a slower rate -all causes of mortality including death caused by the underlying diseases or treatment related. Types of studies The proposed systematic review will consider any experimental, quasi experimental and observational studies that report information for example but not limited to definition, number, seriousness and severity of the adverse reactions of Rituximab at different infusion rates. Other included criteria for example but not limited to a clear description of the standard scale, mode and timing of data collection on adverse reactions. Search strategy Before undertaking the systematic review, the Cochrane Library, Joanna Briggs Institute Library of Systematic Review, MEDLINE and the CRD Database of Abstracts and Review were searched and no available systematic review on this topic was found. The search strategy aims to find both published and unpublished studies. A three steps search strategy is developed to guide the systematic review. MESH terms from MEDLINE are used to determine the words used to search in MEDLINE and MEDLINE. The first search from MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and the text terms used to describe the article. A second search using all the identified keywords and the index terms will be utilised across all accessible databases and websites. As some databases are different in their search features, modified block building will be used to accommodate their differences. Thirdly, the relevant list of all identified reports and articles will be searched for additional studies. Rituximab has been approved since 1997. Therefore, the search will start from 1997 to date with no language restrictions. The primary author will be contacted for further details where necessary. Databases to search will include: MEDLINE Web of science Scopus Cochrane Central Register of Controlled Trials Science Direct CINAHL Scifinder Mednar Other potential sources of relevant material to be searched include: FDA post market drug safety information http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm European Public Assessment Reports from the European Medicines Evaluation Agency http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&jsenabled=true Current Problems in Pharmacovigilance http://www.mhra.gov.uk/Publications/Safetyguidance/CurrentProblemsinPharmacovigilance/index.htm Australian Adverse Drug Reactions Bulletin http://www.tga.gov.au/adr/aadrb.htm Roche http://www.roche-australia.com/portal/eipf/australia/au/corporate Agency for Healthcare Research and Quality (AHRQ) http://www.ahrq.gov Health Technology Assessment Programme (HTA) http://www.hta.ac.uk US National Institutes of Health, ClinicalTrials.gov http://www.clinicaltrials.gov Assessment of methodological quality Articles selected for retrieval will be appraised by 2 reviewers independently for methodological validity prior to inclusion in the review using the standardised critical appraisal instruments from Joanna Briggs Institute Systems Meta Analysis of Statistical Assessment and Review Instrument (JBI-MAStARI).(Appendix VI) Any disagreements that arise between the reviewers will be resolved through discussion with a third reviewer. Data collection Data will be extracted from the studies included in the review using standardised data extraction tools from the JBI-MAStARI. (Appendix VII). Data synthesis Quantitative articles will be pooled in statistical meta-analysis using JBI-MAStARI, where appropriate. All results will be subjected to double data entry. Odd ratios (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form. Conflicts of interest The primary and secondary reviewers have no potential conflicts of interest

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