Rituximab for subcutaneous delivery: Clinical management principles from a nursing perspective

bs_bs_banner International Journal of Nursing Practice 2015; 21 (Suppl. 2), 1 13 SUPPLEMENT ARTICLE Rituximab for subcutaneous delivery: Clinical management principles from a nursing perspective Julia Carlson BSc Cabrini Hospital, Malvern, Victoria, Australia Keith Cox RN OncCert NP Chris O Brien Lifehouse, Sydney, Australia The University of Sydney, Sydney, Australia Kylie Bedwell BScVB BScVMS Roche Products Pty. Ltd, Dee Why, New South Wales, Australia Mathew Ku MBBS FRACP FRCPA Austin Hospital, Heidelberg, Victoria, Australia Carlson J, Cox K, Bedwell K, Ku M. International Journal of Nursing Practice 2015; 21 (Suppl. 2): 1 13 Rituximab for subcutaneous delivery: Clinical management principles from a nursing perspective Nurses play an integral role in administering treatments to patients with non-hodgkin s lymphomas. Intravenous (IV) rituximab was approved by the Australian Therapeutic Goods Administration in 1998, and a novel subcutaneous (SC) formulation was approved in 2014. Fixed-dose SC rituximab is highly concentrated; co-formulation with a fully human recombinant vorhyaluronidase alfa enzyme helps overcome the physiological barriers of the SC space, facilitating drug dispersion. Despite a different pharmacokinetic profile to the IV preparation, SC rituximab demonstrates a comparable efficacy/safety profile. Most frequently occurring rituximab-related adverse events include neutropenia, nausea and constipation, and administration-related reactions are more frequent with the SC preparation. Compared with IV, SC delivery reduces treatment times and nurse workload, and patients report greater comfort and convenience. This article sets out nursing considerations for optimal administration of SC rituximab, including premedication, drug handling/preparation, injection technique, after-care and management of adverse events, particularly administration-related reactions. Key words: monoclonal antibody, non-hodgkin s lymphoma, nursing, rituximab, subcutaneous. INTRODUCTION The incidence of non-hodgkin s lymphoma (NHL) is increasing globally, 1 and with populations ageing rates are anticipated to continue to rise. 2 Among B-cell NHLs, the most prevalent types include diffuse large B-cell lymphoma (~24 30%) and follicular lymphoma (~13 25%). 3 6 These and most other B-cell NHL subtypes carry the CD20 B-lymphocyte surface marker 7 ; with the advent of monoclonal antibody therapy, rituximab s selective targeting of this marker has made it a mainstay treatment Correspondence: Julia Carlson, Cabrini Hospital, 183 Wattletree Road, Malvern, VIC 3144, Australia. Email: jcarlson@cabrini.com.au doi:10.1111/ijn.12413

2 JCarlsonet al. for NHL. 7 9 In addition to killing malignant B-cells, rituximab has been shown to sensitize them to the effects of chemotherapy. 10 The addition of rituximab to chemotherapy regimes has demonstrated increased likelihood of response and prolonged survival in patients with NHL. 11 16 Intravenous (IV) rituximab was first approved in 1997 by the US Food and Drug Administration (FDA) and in 1998 by the European Union (EU), for the treatment of adult patients with NHL. Further approval was granted in 2009 (EU) and 2010 (FDA) for rituximab use in patients with chronic lymphocytic leukaemia. 17 19 In Australia, rituximab received Therapeutic Goods Administration s (TGA) approval in 1998 for CD20-positive, previously untreated stage III/IV follicular B-cell NHL, relapsed or refractory low-grade or follicular B-cell NHL and CD20-positive diffuse large B-cell NHL. 9,16 The TGA further approved rituximab use for patients with chronic lymphocytic leukaemia as first-line treatment in 2009, followed by approval for second-line use in 2010. 9,16,20 Nurses play an integral role in administering treatments and managing patients with NHL throughout the continuum of care. It is essential that nurses have a full understanding of the rationale and implications of each type and phase of treatment to ensure patients achieve optimal clinical benefit and to maximize their safety and quality of life. In this article, we discuss the two modes of rituximab delivery and the rationale for development of the novel subcutaneous (SC) formulation. We present key nursing considerations for safe handling and successful administration of SC rituximab, prevention and management of adverse reactions. Intravenous delivery of rituximab Intravenous rituximab is dosed according to the patient s body surface area (BSA), 16 and this traditional IV drug delivery requires BSA and dosage calculations, aseptic preparation of infusion fluids, long infusion durations and extended medical staff input times, including lengthy postinfusion observation periods. 21 Difficulties could arise with IV catheter placement, and infusion-related reactions (IRRs) and complications can lead to hospitalization, additional inconvenience, distress and expenditure. 21 Subcutaneous rituximab: a novel approach In an effort to improve the treatment experience for patients, a novel SC formulation of rituximab was recently developed. SC rituximab was approved for treatment of patients with follicular lymphoma and diffuse large B-cell lymphoma by both the EU and the TGA in Australia in 2014, 9,22 largely on the basis of the pivotal randomized phase III SABRINA study (Table 1). 23 When drugs are administered SC, the interstitial matrix physiologically limits both the volume of drug that can be injected at a particular site and the rate and amount of drug able to reach the vascular system and lymphoid tissues. 21,24 To achieve the change in drug delivery, the formulation of rituximab was highly concentrated to substantially reduce the volume to 11.7 ml, but developers also needed a way to overcome the barriers of the SC space. A highly purified, DNA-derived, fully human recombinant enzyme, vorhyaluronidase alfa, was developed to help overcome these barriers to SC drug bioavailability. By depolymerizing the viscoelastic component of the extracellular matrix (hyaluronan), vorhyaluronidase alfa reversibly alters the matrix architecture, increasing the speed of drug absorption and decreasing resistance to facilitate dispersion of locally injected drugs. 24,25 Through co-formulation with vorhyaluronidase alfa, rituximab delivered SC at a fixed dosage is able to attain equivalent bioavailability with the traditional IV formulation. 9,25 Importantly for patients, these changes to the interstitial matrix also allow rituximab to be injected into the interstitial space without notable tissue distortion, oedema or tissue irritation, 25 and any treatment-induced changes to the matrix are reversible within ~24h of injection. 21,25 CLINICAL PRACTICE CONSIDERATIONS Benefits for service providers The SC formulation is provided in a ready-to-use vial 9 requiring no dose calculation, preparatory compounding by the pharmacy or IV bag preparation. The administration time is ~5 min, 9 compared with the several hours of infusion time required with IV rituximab. In addition, SC delivery requires only a short 15 min postadministration observation period. 9 By contrast to BSA-based IV dosing, the fixed-dose schedule on which SC administration is delivered eliminates the risk of dosing errors; it also allows standardized vial usage that minimizes drug wastage. Further, the potential benefits of the reduction in administration time are appreciable. It simplifies the treatment experience for both patients and health-care professionals, reduces the burden on health-care resources and is likely to improve patient quality of life and treatment adherence. 8,21,26,27 One multinational study demonstrated

Subcutaneous rituximab: nursing practice 3 Table 1 Subcutaneous rituximab development programme: studies evaluating SC vs. IV rituximab Population Design/phase Endpoints Outcomes Comment Cynomolgus monkeys (N = 14) 38 Preclinical PK; serum rituximab concentrations, peripheral B-cell depletion and durability of CD20 target coverage Follicular lymphoma patients in the maintenance therapy setting (stage 1, N = 124 and stage 2, N =154) 29 CD20 + follicular lymphoma patients (N = 127 to date and target N =900) 23 Previously untreated CD20 + diffuse large B-cell lymphoma or follicular lymphoma (N = 433 to date and target N = 700) 31 Phase Ib randomized open-label parallel-assignment two-stage study Phase III randomized multi-centre open-label parallel-assignment two-stage study Phase IIIb randomized multinational open-label (one cycle IV rituximab, then either three cycles of SC followed by four cycles of IV, or the reverse sequence) PK: brief differences between IV and SC rituximab in initial peak serum rituximab levels Efficacy: IV and SC formulations showed comparable efficacy (reflected by rate and durability of B-cell depletion) and long-term durability of CD20 target coverage. Stage 1: dose-finding PK: Stage 1: 1400 mg fixed-dose SC formulation resulted in comparable C trough to the approved 375 mg/m 2 IV dose. Stage 2: Stage 2: rituximab SC C trough levels at the 1400 mg fixed dose were non-inferior to Primary endpoint: C trough the IV formulation. Animal model SparkThera trial: NCT00930514 Secondary endpoints: AUC 0-last, C max, Safety: overall safety profiles were similar, although local ARRs were more frequent t max, t 1/2 and safety with SC rituximab. Stage 1: PK: SABRINA trial: Primary endpoint: Ctrough at cycle 7 (SC Stage 1: PK profile of SC rituximab was non-inferior to IV rituximab. NCT01200758 vs. IV) Secondary endpoints: other PK parameters, Efficacy: overall RR. Stage 1: overall RR was similar between IV and SC postinduction therapy. CR Stage 2: was higher with SC rituximab, but study was not designed to evaluate superiority. Primary endpoint: overall RR BSA and patient sex subgroup analyses did not suggest any difference in response. postinduction treatment (SC vs. IV) Secondary endpoints: Stage 2: ongoing efficacy evaluations Safety, CR rate, PFS, EFS, OS and Safety: immunogenicity. Stage 1: safety profiles were similar between IV and SC, with the exception of a higher rate of ARRs in the SC group. Stage 2: ongoing safety evaluations Primary endpoint: proportion of patients indicating overall preference for SC or IV rituximab (assessed via PPQ) Secondary endpoints: safety, administration times, patient satisfaction (via RASQ), CR rate, EFS, DFS, PFS, OS and immunogenicity Patient preference: ongoing, preliminary results show that SC delivery was preferred by 83 86% of patients, compared with 8 9%whopreferredIVdelivery. Reasons for preferring SC administration included less time required in the clinic, less emotional distress and a higher level of comfort during delivery. PREFMAB trial: NCT01724021 (Continues)

4 JCarlsonet al. Table 1 (Continued) Population Design/phase Endpoints Outcomes Comment Patients with previously untreated CD20 + follicular lymphoma or diffuse large B-cell lymphoma Patients with previously untreated, CD20 + diffuse large B-cell lymphoma (N = 576) 32 Phase III single-arm open-label study Primary endpoint: ARR rate Safety/efficacy: ongoing, data not yet available Phase IIIb randomized (2:1 SC:IV) multicentre open-label parallel-group study Secondary endpoints: grade 3 AEs, EFS and OS Primary endpoint: investigator-assessed CR rate Secondary endpoints: patient satisfaction, administration times, EFS, DFS, PFS, OS and safety Efficacy: end-of-treatment CR rates were comparable between SC and IV treatment arms overall (52% vs. 51%) and when stratified by age (~50%/arm). Safety: AE rates were comparable between SC and IV treatment arms overall (92% vs. 91%) and in cycle 1 (61% vs. 64%). ARR rates were similar in each arm (28%) in each arm, during cycle 1 (11% vs. 14%) and during cycles 2 8(22%vs. 20%). Grade 3 ARRs: 2% vs. 5%. General disorders and administration site conditions were the most common ARR symptoms in cycles 2 8 (10% vs. 4%). MabRella study: NCT01987505 Ongoing, recruitment complete MabEase study (MO28107): NCT01649856 Ongoing, recruitment complete light increase in overall AEs with increasing SC doses, but not for grade 3or serious AEs. Higher frequency of ARRs with SC vs. IV rituximab (primarily transient injection site pain and erythema). Patient/nurse preference: Part 1: > 90% of patients and nurses preferred SC administration. Patients with relapsed/refractory Phase IV randomized CD20 + indolent NHL 30 open-label parallelgroup (one cycle IV rituximab, then rituximab SC plus six to eight chemo cycles followed by maintenance therapy) Patients with indolent NHL 27 Multinational observational time-and-motion study Primary endpoint: PFS from randomization Secondary endpoints: safety, EFS, time to next lymphoma treatment, OS, overall RR, PR-to-CR conversion rate and PFS from day of first induction dose Endpoints: descriptive study, difference in mean active HCP time (time actively dedicated to a patient) and chair time for rituximab SC vs IV Patient preference: ongoing, results to date demonstrate consistent patient satisfaction MABCUTE study: and preference for SC vs. IV rituximab. 30 NCT01461928 Ongo- Safety: interim safety data indicate SC rituximab is well tolerated; no new safety ing, recruitment signals reported. ARRs were transient and mild-to-moderate in severity. 33 complete Time-and-motion: SC formulation reduced mean active HCP time by 6.8 38.4 min vs. IV (proportionate reductions ranged between 27 57%). Mean time saved in the treatment room was 0.3 25.4 min. Estimated total reduction in HCP time over a year was 0.9 5.1 h per patient. 64 91% reduction in mean chair time. SC data collected alongside MABCUTE study and IV data collected in a real-world setting (23 centres in eight countries) (Continues)

Subcutaneous rituximab: nursing practice 5 Table 1 (Continued) Population Design/phase Endpoints Outcomes Comment Previously untreated CLL 39 (N =240to date and N =64inPart1,Part2enrolment ongoing) Phase Ib randomized multicentre open-label two-part study Part 1: SAWYER trial Primary endpoint: Ctrough of SC NCT01292603 rituximab Secondary endpoints: AUC, safety, immunogenicity, change in B-cell levels and patient/nurse preference. Part 2: Primary endpoint: Ctrough noninferiority between SC and IV Secondary endpoints: physician/nurse opinion on convenience/time saving, AUC, immunogenicity, change in B-cell levels and safety light increase in overall AEs with increasing SC doses, but not for grade 3or serious AEs. Higher frequency of ARRs with SC vs. IV rituximab (primarily transient injection site pain and erythema). Patient/nurse preference: Part 1: > 90% of patients and nurses preferred SC administration. AE, adverse event; ARR, administration-related reaction; AUC, area under the curve; BSA, body surface area; CLL, chronic lymphocytic leukaemia; CR, complete response; DFS, disease-free survival; EFS, event-free survival; HCP, health-care professional; IV, intravenous; IWG, International Working Group; NHL, non-hodgkin s lymphoma; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; PPQ, patient preference questionnaire; RASQ, Rituximab Administration Satisfaction Questionnaire; RR, response rate; SC, subcutaneous; C trough, serum trough concentration.

6 JCarlsonet al. reductions of between 64% and 91% in patient chair time following a switch from IV to SC administration of rituximab, which translated to a reduction of 17 33h of chair time per patient over the first year of treatment. Furthermore, health-care professional time was substantially reduced, by between 7 and 38min per session, equating to 0.9 5.1 h less resource input per patient over the first year of treatment. Patient throughput, waiting list times and hospital efficiency were greatly improved. 26,27 Nurses experiences to date support the use of the SC formulation of rituximab in routine clinical practice. In a published survey of 65 nurses who had administered SC rituximab to a total of 166 patients at various investigational sites, 72% reported the SC rituximab delivery process as easy or very easy ; 95% rated the experience as positive or very positive and 95% of nurses indicated they would recommend SC administration to patients. 28 Clinical equivalence The clinical development programme for SC rituximab is ongoing (Table 1). The Phase Ib dose-finding SparkThera trial 29 demonstrated that the SC formulation could be administered quickly and relatively comfortably, with serum trough concentrations (reflecting minimum drug exposure) at least as high as those reached with the approved IV formulation in the maintenance therapy setting. Stage 2 tested the 1400 mg fixed-dose SC preparation vs. standard IV rituximab as maintenance therapy in 154 treatment-naïve or relapsed patients with follicular lymphoma who had previously responded to standard induction therapy. The fixed-dose SC preparation demonstrated non-inferior pharmacokinetics and a comparable safety profile to the standard IV preparation. 29 Induction and maintenance therapy using 1400 mg SC rituximab vs. standard IV rituximab was then assessed in the SABRINA study 23 in 127 patients with untreated follicular lymphoma. Again, SC rituximab demonstrated a noninferior pharmacokinetic profile and a safety profile comparable with the IV formulation, with the exception of a higher incidence of administration-related reactions (ARRs) in patients receiving SC rituximab. Importantly, the SABRINA study also showed no impairment of antilymphoma activity with a switch to SC dosing. Investigator-assessed overall response rates with IV vs. SC administration were 84% vs. 90%, respectively, whereas rates of investigator-assessed complete response were 30% vs. 46%, respectively. 23 This non-inferiority pattern wasobservedregardlessofpatientbsaorchoiceofchemotherapy backbone. 23 Patient perspectives Use of the SC rituximab formulation has improved the treatment experience for many patients with NHL. 8,30,31 In patient preference studies, the majority of patients preferred SC over IV delivery. 30,31 In the PrefMab study, 218 patients were randomly assigned to undergo four cycles of IV rituximab followed by four cycles of SC rituximab, whereas a further 215 patients were randomly assigned to undergo their first cycle IV, followed by three SC cycles and then four IV cycles. Among 190 evaluable patients who remained on-treatment, 157 (83%) preferred SC rituximab after six cycles of therapy, with 36% and 38% expressing very strong or fairly strong preference, respectively. Only 8% of patients preferred IV delivery. Percentages remained similar after 8 weeks of therapy. The main reasons for preferring SC delivery included less time spent in the clinic, less emotional distress and improved comfort during administration. 31 Findings were similar in the MABCUTE study, where the majority of patients also preferred SC over IV delivery, reporting greater convenience and satisfaction, lower levels of physical and psychological impact and less impact on daily life with SC rituximab. 30 Importantly, SC injection entails one-on-one time for the patient with their nurse and the opportunity for patients to discuss any concerns. 28 Nursing practice considerations: rituximab preparation and subcutaneous administration Nurses play a pivotal role in the administration of SC rituximab. This section highlights key practical considerations to optimize the patient s treatment experience through successful injection delivery, vigilant patient observation and proactive management of any adverse events. Patients must always receive their first rituximab cycle by IV infusion to allow close monitoring for any potential IRRs, and to enable counteractive treatment adjustment by slowing or halting the infusion as necessary. The SC formulation could be administered from the second cycle only. 9 If, however, a patient was unable to receive their first full rituximab IV dose because of an IRR which might be more likely to occur in the first cycle subsequent cycles should only be administered IV. Once the patient is able

Subcutaneous rituximab: nursing practice 7 to successfully receive a full IV dose, they might receive subsequent cycles SC. 9 Key nursing considerations related to the preparation, dosing and administration of the rituximab SC injection are detailed in Figure 1. Note that the rituximab dosing schedule varies slightly between induction therapy, maintenance therapy and in patients with relapsed or refractory follicular lymphoma (Fig. 1/Table i). Management of adverse events Rituximab safety The fixed-dose SC formulation of rituximab is generally well tolerated, with an adverse event profile comparable with the IV formulation 23,29,32 regardless of the patient s BSA. 23 In clinical studies, incidence of adverse events of any grade ranges between 79 92% for both SC and IV rituximab, 23,29,32,33 whereas the incidence of grade 3 events is approximately 32 53% with SC rituximab, 23,29,32,33 and 47 50% with IV rituximab. 23,29,32 In the phase III SABRINA trial in patients with previously untreated follicular lymphoma, the most frequent adverse events with both rituximab preparations included neutropenia, nausea and constipation (Table 2). 23 The most frequent grade 3 (severe but not life-threatening) to 4 (life-threatening) adverse events with SC vs. IV rituximab included neutropenia (26% vs. 21%, respectively), febrile neutropenia (10% vs. 3%) and leukopenia (8% vs. 2%). 23 Figure 1. Rituximab subcutaneous (SC): handling, preparation, administration and after-care.

8 JCarlsonet al. Figure 1. (Continued) Administration-related reactions with subcutaneous rituximab Whereas the overall safety profiles of SC and IV rituximab are similar, one key characteristic distinguishing the SC delivery route is a higher likelihood of local ARRs. Trials indicate that 31 50% of patients might experience local ARRs with SC delivery, compared with 4 32% of patients receiving rituximab via IV infusion. 23,29 Most local skin reactions are reversible and of mild-to-moderate intensity 23 and could include erythema, pain, swelling, pruritis, rash, bruising and local myalgia. 9,23,29 In the SABRINA trial, two patients (3%) experienced grade 3 ARRs after the first SC rituximab injection (injection-site rash and dry mouth), and one other patient in the SC group experienced (grade 3) decreased urine output/tumour lysis syndrome after their initial IV rituximab infusion, before initiating SC delivery. In the IV group, one patient (2%) experienced a grade 3 ARR (vomiting). 23 To help mitigate the risk of an ARR, recommendations for standard practice are for an analgesic/antipyretic (e.g. paracetamol) and an antihistamine (e.g. loratadine or

Subcutaneous rituximab: nursing practice 9 Figure 1. (Continued) promethazine) to be administered 30 60 min before each rituximab SC injection. These could be taken by the patient prior to arriving for their appointment once their chemotherapy induction cycles have been completed. Premedication with a systemic glucocorticoid should also be considered. 9 Based on experience in the clinical trial setting, patients can be reassured that the majority of ARRs require observation only and resolve spontaneously within 1 2 days. If required, treatment of symptoms could include topical steroid creams in line with local institutional practice, and/or the use of a cold compress. The patient should be advised to continue to monitor the injection site at home and report any changes promptly to the clinical team. To reduce the severity of injection-site pain, it is recommended that rituximab is never injected in areas where the skin is red, bruised, tender, hard or areas where there are moles or scars. 9 In the case of excessive pain on injection delivery, incorrect needle angle or location should be suspected. The needle should ideally be inserted at an angle

10 JCarlsonet al. Figure 1. (Continued) of 45 90. Stop the administration without removing the needle, assess pain severity and discuss with the clinical team whether to resume the injection or reposition the needle. A cold compress might be useful to alleviate pain. If leakage of the drug from the injection site occurs, the clinical team should consider removing the syringe and administering the injection at a different abdominal site. Infusion-related reactions with intravenous rituximab As patients must receive their first rituximab dose IV, it is important to be aware that monoclonal antibody treatments, like many cancer therapies administered by IV infusion, have the potential to induce infusion reactions. 34,35 This mandates vigilance in nursing care. 35 The three main types of infusion reaction are cytokine release syndrome (loosely referred to as an IRR ), hypersensitivities or allergies and tumour lysis syndrome (TLS). These are discussed in more detail in the obinutuzumab article published elsewhere in this supplement. Documentation of adverse events A final nursing consideration is that of routine, accurate documentation. Important aspects to document include

Subcutaneous rituximab: nursing practice 11 Table 2 Most frequent rituximab adverse events in the phase III SABRINA trial 23 AE, N (%) Subcutaneous delivery N=62 Intravenous delivery N=65 Any-grade AE 57 (92) 57 (88) Neutropenia 22 (35) 12 (35) Nausea 18 (29) 15 (23) Constipation 14 (23) 17 (26) Asthenia 14 (23) 10 (15) Vomiting 12 (19) 13 (20) Paraesthesia 12 (19) 7 (11) Alopecia 12 (19) 7 (11) Diarrhoea 10 (16) 11 (17) Cough 9 (15) 7 (11) Anaemia 9 (15) 8 (12) Pyrexia 8 (13) 11 (17) Any grade 3AE 29(47) 30(46) Neutropenia 16 (26) 14 (21) Febrile 6 (10) 2 (3) neutropenia Leukopenia 5 (8) 1 (2) Serious AEs 14 (23) 14 (22) AE, adverse event. the premedication schedule used, the cycle number when the reaction occurred, the infusion rate, specific clinical symptoms, duration of treatment pause, a complete list of rescue medications and patient outcomes, including the time taken for symptoms to resolve. Thorough documentation is imperative because it enables accurate retrospective review of patients treatment history and facilitates future accurate bedside decision-making to improve patient outcomes. CONCLUSION Subcutaneous delivery of rituximab provides an alternative route of administration to an IV infusion. The comprehensive clinical trial programme for SC rituximab is ongoing, but published literature to date indicates that it is at least as effective as the IV preparation, with comparable overall tolerability. 23,29 Premedication can attenuate the likelihood of an ARR, 9 and careful preparation and injection technique combined with vigilant nursing care during and after administration are recommended to achieve a favourable treatment experience for patients. A large majority of patients prefer the SC over the IV mode of delivery because of improved comfort and convenience, 30,31 and this might encourage patients who do not prefer IV drug delivery to persist in completing their full course of therapy. Additionally, SC delivery might be especially appropriate for patients with difficult IV access. There are also benefits in daily nursing practice with use of SC rather than IV formulation, including no requirement for dose calculation or bag preparation, simplified and faster treatment times with reduced workloads and streamlined patient throughput. 27 Taken together, accumulating clinical evidence and experience, including that of the authors, suggests that SC rituximab can help streamline the care of patients with NHL and improve the overall treatment experience for both patients and health-care professionals. ACKNOWLEDGEMENTS Dr Matthew Ku wishes to acknowledge the Cancer Clinical Trials Centre, Austin Hospital. Medical editorial assistance was provided by Geraldine K. Hosking. REFERENCES 1 Muller AM, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-hodgkin s lymphoma (NHL): trends, geographic distribution, and etiology. Annals of Hematology 2005; 84: 1 12. 2 Stienen JJ, Ottevanger PB, Wennekes L et al. Trends in quality of non-hodgkin s lymphoma care: is it getting better? Annals of Hematology 2015; 94: 1195 1203. 3 Salles GA. Clinical features, prognosis and treatment of follicular lymphoma. Hematology 2007: 216 225. 4 SEER Cancer Statistics Factsheets. Non-Hodgkin lymphoma. National Cancer Institute. Bethesda, MD. Table 19.26. All lymphoid neoplasms with detailed non-hodgkin lymphoma subtypes: SEER incidence rates and annual percent change by age at diagnosis; all races, both sexes, 2003-2012. Available from: http://seer.cancer.gov/statfacts/html/nhl.html. Accessed July 2015. 5 Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology American Society of Hematology Education Program 2012; 2012: 402 409. 6 Groves FD, Linet MS, Travis LB, Devesa SS. Cancer surveillance series: non-hodgkin s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. Journal of the National Cancer Institute 2000; 92: 1240 1251. 7 National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Non-Hodgkin s lymphoma,2012. 8 Bittner B, Richter WF, Hourcade-Potelleret F, Herting F, Schmidt J. Non-clinical pharmacokinetic/pharmacodynamic and early clinical studies supporting development of a novel subcutaneous formulation for the monoclonal antibody rituximab. Drug Research (Stuttg) 2014; 64: 569 575.

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Subcutaneous rituximab: nursing practice 13 33 Rule S, Briones J, Carella A et al. Extending subcutaneous rituximab maintenance therapy from 2 years until progression versus observation in patients with indolent non-hodgkin s lymphoma: interim safety data from the MABCUTE study. Abstract no. 162. Paper presented at: 54th Annual Scientific Meeting of the British Society for Haematology Birmingham, UK 28-30 April, 2014. 34 Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. The Oncologist 2007; 12: 601 9. 35 Vogel WH. Infusion reactions: diagnosis, assessment, and management. Clinical Journal of Oncology Nursing 2010; 14: E10 21. 36 Alexander M, King J, Bajel A et al. Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel. Internal Medicine Journal 2014; 44: 1018 1026. 37 Roche Products Pty Limited Australia. MabThera SC subcutaneous injection. Consumer medicine information. Available from: http://www.roche-australia.com/home/ products/pharmaceuticals/mabthera-sc.html 38 Mao CP, Brovarney MR, Dabbagh K et al. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys. PLoS One 2013; 8: e80533. 39 Assouline S, Buccheri V, Delmer A et al. Subcutaneous rituximab in combination with fludarabine and cyclophosphamide for patients with CLL: initial results of a phase Ib study (SAWYER [BO25341]) show non-inferior pharmacokinetics and comparable safety to that of intravenous rituximab. ASH Annual Meeting Abstracts 2012: 1637.