Received: 9 September 2022 | Revised: 21 October 2022 | Accepted: 21 October 2022 DOI: 10.1111/cts.13450 ARTICLE Safety and tolerability of a 90-­minute rapid infusion of Sandoz biosimilar rituximab in B-­cell lymphoproliferative disorders in a real-­world setting Ana Muntañola1 | José María Arguiñano-­Pérez2 | Julio Dávila3 | Sonia González de Villambrosia4 | Cecilia Carpio5,6 | Ana Jiménez-­Ubieto7 | Antonio Salar8,9,10 | the GELTAMO (Grupo español de linfomas y trasplante de médula ósea) 1 Department of Hematology, Hospital Universitari Mutua Terrassa, Terrassa, Spain 2 Department of Hematology, Hospital Universitario de Navarra, Pamplona, Spain 3 Department of Hematology, Complejo Asistencial de Ávila, Ávila, Spain 4 Department of Hematology, Hospital Universitario Marqués de Valdecilla/IDIVAL, Santander, Spain 5 Department of Hematology, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain 6 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 7 Department of Hematology, Hospital 12 de Octubre, Madrid, Spain 8 Department of Hematology, Hospital del Mar, Barcelona, Spain 9 Group of Applied Clinical Research in Hematology, Cancer Research Program-­IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain 10 Pompeu Fabra University, Barcelona, Spain Correspondence Antonio Salar Silvestre, Passeig Marítim Abstract 25-­29, 08003 Barcelona, Spain. Although rituximab is generally well-­tolerated, infusion-­related reactions (IRRs) Email: asalar@psmar.cat are common with the initial dose when administered intravenously according Funding information to standard recommendations. To prevent IRRs, premedication and low-­speed Sandoz infusion rates have been recommended. Consequently, intravenous (i.v.) infu- sion of rituximab can become a labor-­intensive process. Rapid i.v. rituximab infu- sion over 90 min has demonstrated a favorable safety profile for the second and subsequent infusions during the course of therapy. The aim of this study was to investigate the safety and tolerability of 90-­min rapid infusion of Sandoz rituxi- mab biosimilar (SDZ-­RTX) for patients with CD20+ lymphoma or chronic lym- phocytic leukemia (CLL). We retrospectively reviewed all patients with CD20+ lymphoma or CLL who received SDZ-­RTX infusions in 90 min from July 2019 to July 2021 at seven Spanish hospitals. The primary end point was the incidence of IRRs. We identified 124 patients and 576 rapid administrations of SDZ-­RTX, with an average of five rapid infusions per patient. Most rapid infusions of SDZ-­ RTX were in combination with CHOP/CHOP-­like therapy (48.4%), followed by This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. Clin Transl Sci. 2023;16:305–312.  www.cts-journal.com | 305 306 |    MUNTAÑOLA et al. SDZ-­RTX alone (15.1%), in combination with bendamustine (14.5%), or with other regimens (22%). The 90-­min SDZ-­RTX infusion schedule was well-­tolerated with no grade 3/4 IRRs. The incidence of any grade IRR during the first rapid infusion was 1% (5 grade 1 IRRs and 1 grade 2 IRR). In conclusion, rapid 90-­min i.v. administration of SDZ-­RTX for the second and subsequent infusions during the course of therapy is well-­tolerated in patients with CD20+ lymphoma or CLL. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Rituximab, an anti-­ CD20 monoclonal antibody, is associated with infusion-­ related reactions (IRRs). To reduce the risk of IRRs, premedication with aceta- minophen and an antihistamine, together with slow infusion of rituximab, are recommended. WHAT QUESTION DID THIS STUDY ADDRESS? This study aimed to investigate the safety and tolerability of 90-­min rapid i.v. infusion of SDZ-­RTX for patients with CD20+ lymphoma or chronic lymphocytic leukemia (CLL). WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Intravenous administration of SDZ-­RTX in a rapid infusion is well-­tolerated and feasible for patients with CD20+ lymphoma or CLL. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our study provides meaningful information for clinical practice, as rapid i.v. in- fusions of SDZ-­RTX could lead to improved patient convenience and reduced burden on healthcare systems, including resources and costs. I N T RO DU CT ION 5–­6 h for the first infusion and 3–­4 h for subsequent infu- sions, are recommended.4 The mean time for rituximab Rituximab is a chimeric monoclonal antibody against i.v. infusion varies across countries as shown in clinical the CD20 antigen. It is currently an integral component and real-­world studies.5–­7 This labor-­intensive process is of therapy for B-­cell non-­Hodgkin's lymphomas (NHL), not only inconvenient and impacts quality of life for pa- chronic lymphocytic leukemia (CLL), and other non-­ tients, but also consumes healthcare resources and reduces malignant conditions.1 Compared with classical chemo- treatment capacity in day-­care units. Several studies have therapy, rituximab has a more favorable safety profile. confirmed the favorable safety profile of rapid i.v. infusion However, intravenous (i.v.) administration of the drug of rituximab over 90 min (or even 60 min) if the previous is associated with infusion-­related reactions (IRRs), in- i.v. administration was well-­tolerated.8–­14 Consequently, cluding hypersensitivity reactions that can result in fever, rapid i.v. infusion of rituximab has been granted approval rash, cardiovascular and/or respiratory compromise, and, by several medical agencies and has been widely adopted rarely, cytokine release syndrome. It is well known that as the standard form of administration in many centers the incidence and severity of these IRRs decrease with worldwide. the second and subsequent administrations of rituximab.2 Biosimilars are biologics that match their reference In addition, several risk factors for developing IRRs have biologic in terms of safety, efficacy, and quality.15–­18 been identified, such as bulky tumors, pulmonary infil- Sandoz biosimilar rituximab (SDZ-­RTX) is a biosimilar trates, elderly patients, and type of tumor.3 Indeed, IRRs of rituximab (MabThera; Roche). SDZ-­RTX (Rixathon) are more frequent in CLL or mantle cell lymphoma, likely received a marketing authorization valid throughout due to high lymphocyte counts in peripheral blood.3 the European Union on June 15, 2017 (further informa- To reduce the risk of IRRs, premedicating patients with tion on Rixathon is publicly available at the European acetaminophen and an antihistamine, as well as adminis- Medicines Agency's webpage: ema.europa.eu/medi- tering rituximab over a prolonged period of time, generally cines/human/EPAR/Rixathon). Therefore, it is expected SANDOZ BIOSIMILAR RITUXIMAB IN NHL AND CLL    | 307 that rapid i.v. administration of SDZ-­RTX will match Patients were treated with i.v. SDZ-­RTX administered that of reference rituximab. For this reason, we retro- over 90 min with a total volume of 250 ml. During the 90-­ spectively analyzed the safety of rapid i.v. infusion of min infusion, 20% of the total volume (50 ml) was given SDZ-­RTX in a cohort of patients with B-­cell lymphoid in the first 30 min and the remaining 80% (200 ml) over malignancies. 60 min.11 Premedication was administered 30 min prior to i.v. infusion and consisted of acetaminophen and di- phenhydramine according to label information. Steroid M ET H O DS premedication was also allowed in patients who were receiving steroid-­containing chemotherapy or at the dis- Study design cretion of the treating physician. Patients were monitored and vital signs were measured according to standard This was an open-­label, multicenter, retrospective, ob- practice in the treating centers. In the absence of IRRs, servational, post-­authorization study designed to investi- patients continued to receive rapid SDZ-­RTX infusion for gate the safety of 90-­min rapid i.v. infusion of SDZ-­RTX their remaining cycles. Most of the infusions were admin- in adult patients with B-­cell lymphoid malignancies who istered on an outpatient basis. received treatment with rituximab in Spain. All partici- pating centers had extensive experience with 90-­min i.v. infusions of reference rituximab. Physicians included all Data analysis patients treated with 90-­min i.v. infusions of SDZ-­RTX in the study. The study was performed in seven Spanish Patient information was reviewed from databases and centers and was approved by the Scientific Committee of medical records. IRRs were categorized according to GELTAMO, and the Ethics Committee of Hospital Mutua CTCAE v5.0. All data were de-­identified and secured to Terrassa, and was performed in accordance with the ensure patient privacy. A descriptive analysis of patient Declaration of Helsinki. characteristics, as well as incidence and type of IRR, was The primary objective of this study was to evaluate the performed. incidence of grade greater than or equal to 3 IRRs follow- ing rapid i.v. infusion of SDZ-­RTX in patients who had previously received rituximab at the standard infusion RESULTS rate without experiencing a grade 3 or 4 IRR according to the Common Terminology Criteria for Adverse Events Of 130 patients treated with SDZ-­ RTX in the seven version 5.0 (CTCAE v5.0). Secondary objectives were the Spanish sites, six patients received their first dose of rapid incidence of IRRs per rapid infusion cycle regardless of i.v. SDZ-­RTX after July 12, 2021 and were excluded from grade, and the incidence and severity of all adverse events this analysis. The remaining 124 patients were included in (AEs) occurring in the first 24 h following rapid SDZ-­RTX the analysis (Table S1-­S2). administration. Overall, 115 patients (92.7%) had B-­cell lymphoma and nine (7.3%) had CLL. CD20 positivity was confirmed in all cases. Patient characteristics are listed in Table 1. Patients Rapid rituximab infusion protocol received a cumulative total of 576 rapid i.v. SDZ-­RTX in- fusions. Each patient received a median of five rapid infu- Inclusion criteria were: age greater than or equal to sions (range, 1–­11). Overall, 86 patients (69.4%) received 18 years; histological diagnosis of any type of CD20+ NHL rapid SDZ-­RTX infusion as part of first-­line treatment. All or CLL amenable to treatment with rituximab as mono- patients received initial standard SDZ-­RTX infusion, fol- therapy, in combination with chemotherapy or in main- lowed by rapid SDZ-­RTX infusion. The cycle immediately tenance; previous standard i.v. infusion of SDZ-­RTX with prior to the first rapid SDZ-­RTX infusion was: the first cycle CTCAE v5.0. toxicity grade less than or equal to 2; and in 101 patients (81.5%), the second in 12 (9.7%), the third administration of rapid SDZ-­RTX infusion before July 12, in five (4.0%), and the fourth in six (4.8%). Fourteen out of 2021. Exclusion criteria were: lymphocytosis greater than 124 patients (11.3%) had an AE in the SDZ-­RTX standard 5 × 109/L prior to administration of SDZ-­RTX in rapid in- infusion cycle immediately before the first rapid SDZ-­RTX fusion; experience of toxicity grade greater than or equal infusion (all but one were grade 1). The median time from to 2 during the previous SDZ-­RTX infusion; and dose less the previous standard i.v. infusion of SDZ-­RTX to the first than 375 mg/m2 in the previous or planned treatment rapid i.v. infusion of SDZ-­RTX was 21 days (range, 6–­64). schedule and hypersensitivity to rituximab or other anti- Schedules for the first rapid SDZ-­RTX infusion were: ­CD20 monoclonal antibodies.11 R-­CHOP/R-­CHOP-­like 48.4%, R-­bendamustine 14.5%, 308 |    MUNTAÑOLA et al. TABLE 1 Baseline patient characteristics SDZ-­RTX infusions and tolerated therapy without any fur- N, % ther complications. Age, years, median (range) 71 (32–­99) ≤60 26 (21) >60 98 (79) DISC USSION Gender Our study showed that rapid i.v. infusion of SDZ-­RTX Male 66 (53.2) in a 90-­min infusion schedule was well-­tolerated in a Female 58 (46.8) cohort of patients with B-­cell malignancies in the real-­ Diagnosis world setting, with no safety concerns identified. In Diffuse large B-­cell lymphoma 49 (39.5) our cohort of 124 patients, including nine patients with High grade lymphoma (DH/TH) 4 (3.2) CLL, a total of 576 rapid i.v. infusions of SDZ-­RTX were Follicular lymphoma 27 (21.8) administered. Only 12 (2.1%) AEs were reported during Marginal zone lymphoma 10 (8.1) i.v. infusions, six of which were considered to be related to SDZ-­RTX administration, thereby indicating a favora- Mantle-­cell lymphoma 9 (7.3) ble safety profile of the rapid infusion. All but one of the Post-­transplant lymphoproliferative disease 5 (4.0) AEs related to SDZ-­RTX were grade 1. The patient who Transformed large B cell lymphoma 7 (5.6) experienced a grade 2 AE after the first rapid infusion Other lymphomas 4 (3.2) had been diagnosed with marginal zone lymphoma and Chronic lymphocytic leukemia 9 (7.3) was receiving SDZ-­RTX as monotherapy induction ther- Line of therapy of first rapid infusion apy19; the four subsequent infusions of SDZ-­RTX were First 86 (69.4) administered over 90 min and were well-­tolerated by the Second 29 (23.4) patient with no further clinically significant toxicity. In terms of IRRs, the safety profile of SDZ-­RTX was compa- Third or later 9 (7.3) rable to that reported with reference rituximab, suggest- Note: Other lymphomas: lymphoplasmacytic lymphoma (1), nodular ing that SDZ-­RTX could replace reference rituximab in lymphocyte predominant lymphoma (1), B-­cell lymphoma not otherwise specified. a rapid infusion setting.3 Abbreviation: DH/TH, double/triple hit. It is well known that most IRRs occur during the first infusion of rituximab, with a decreased incidence during the second and subsequent infusions. For instance, in a R-­gemcitabine/R-­GEMOX 8.9%, rituximab 15.1% (mono- phase III study in 425 patients with lymphoma who re- therapy in 11.3% or maintenance in 3.8%), and others ceived the first infusion at the standard rate, 85.4% were 13.1%. The dose of SDZ-­RTX was 375 mg/m2 in 115 pa- able to receive the 90-­min infusion for the second cycle. tients (92.7%) and 500 mg/m2 in nine patients (7.3%). Interestingly, only 1.1% of patients experienced a grade Schedules used for all 576 rapid SDZ-­RTX infusions are 3 IRR with the rapid infusion during the second cycle, described in Table S2. All patients received standard and only 2.8% experienced a grade 3/4 IRR during cy- premedication: 31.4% with acetaminophen and diphen- cles 2–­8.8 In the present study, the frequency of IRRs hydramine, and 68.6% with acetaminophen, diphenhydr- occurring after the first rapid i.v. SDZ-­RTX infusion was amine, and steroids. low, but in our cohort, patients could receive their first Overall, a total of 12 (2.1%) AEs were recorded after rapid i.v. SDZ-­RTX infusion for the second cycle or be- rapid i.v. SDZ-­RTX infusion. Of these, six (50%) occurred yond, and those patients who presented with a grade after the first rapid infusion, five (42%) between infusions greater than or equal to 2 AE in the previous cycle were two and six, and one (8%) beyond infusion seven. There excluded from the analysis. Curiously, all our patients were no severe or fatal AEs, or AEs leading to SDZ-­RTX experiencing IRRs received standard premedication interruption or dose modification. A detailed summary of plus corticosteroids. At present, there is still some con- each AE is provided in Table 2. No grade greater than or troversy around the role of corticosteroids for prevent- equal to 3 IRRs were reported (primary end point). The in- ing or reducing the occurrence of IRRs during rituximab cidence of IRRs grade 1–­2 during the first rapid SDZ-­RTX i.v. administrations at standard or rapid infusion rates. infusion was 1.2% (n = 7), but only six of these were re- Mechanisms for IRRs include IgE mediated hypersensi- lated to SDZ-­RTX. Only one patient with splenic marginal tivity, immunogenicity of rituximab, complement activa- zone lymphoma treated with SDZ-­RTX monotherapy suf- tion, and cytokine-­release syndrome.20,21 Unfortunately, fered a grade 2 IRR (hypotension). All patients with IRRs clinicians may not be able to clinically discriminate be- grade less than or equal to 2 continued to receive rapid tween IgE-­mediated and non-­IgE-­mediated reactions.22 TABLE 2 Adverse events Rapid Relationship infusion AE Time of appearance with Dose Case cycle Type of AE grade in relation to infusion SDZ-­RTX Outcome of AE Diagnosis Treatment (mg/m2) Premedication SANDOZ BIOSIMILAR RITUXIMAB IN NHL AND CLL 1 1 Hypotension 2 During Yes Resolved MZL R monotherapy 375 A-­PP-­S 2 1 Paresthesia 1 >24 h No Resolved DLBCL R-­CHOP 375 A-­PP-­S 3 1 Rash 1 >24 h No Resolved FL R-­B 375 A-­PP-­S 4 1 Anemia 3 >24 h No Improved to Grade 1 HGL R-­CHOP 375 A-­PP-­S 5 1 IRR 1 During Yes Resolved DLBCL R-­EPOCH 375 A-­PP-­S 6 1 Febrile 3 >24 h No Resolved DLBCL R-­CHOP 375 A-­PP-­S neutropenia 7 2 Dyspepsia 1 During Yes Resolved FL R-­CHOP 375 A-­PP-­S 8 3 Pruritus 1 During Yes Resolved FL R-­B 375 A-­PP-­S 9 3 Paresthesia 1 >24 h No Resolved DLBCL R-­CHOP 375 A-­PP-­S 10 3 IRR 1 During Yes Resolved LPL R-­B 375 A-­PP-­S 11 5 Rash 1 During Yes Resolved DLBCL R-­GEMOX 375 A-­PP-­S 12 10 Vomiting 1 During No Resolved DLBCL R-­B + polatuzumab 375 A-­PP-­S Abbreviations: AE, adverse event; A-­PP-­S, antipyretic plus antihistaminic plus steroid; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; DLBCL, diffuse large B-­cell lymphoma; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide, methylprednisolone; ESHAP, etoposide, methylprednisolone, cisplatin, cytarabine; FL, follicular lymphoma; GEMOX, gemcitabine, oxaliplatin; HGL, high grade lymphoma; LPL, lymphoplasmacytic lymphoma; MZL, marginal zone lymphoma; R, rituximab.    | 309 310 |    MUNTAÑOLA et al. Corticosteroids may prevent or dampen non-­IgE medi- nursing monitoring.35 Subcutaneous rituximab is admin- ated infusion or inflammatory reactions, but have little istered at a fixed-­dose of 1400 mg and has also shown impact in preventing IgE-­mediated hypersensitivity.22,23 improvement in these factors, although this formulation To date, there is no definitive consensus on the role of is associated with higher costs and is not available in all premedication or even its components, because a spe- centers.5,7,36,37 cific schedule has never been validated in controlled Limitations of this analysis include the relatively small studies.24 Meanwhile, our current results and previous sample size of patients and SDZ-­RTX infusions, as well data from our group and others show that rapid i.v. rit- as the retrospective nature of data collection on IRRs and uximab infusion is well-­tolerated in patients whether their outcome. Despite these limitations, our study pro- they receive premedication with or without corticoste- vides relevant clinical findings that could guide physicians roids.8–­14 Further studies are needed to provide high-­ considering introducing a 90-­min SDZ-­RTX infusion as a quality evidence regarding the role of premedication in treatment option for hematologic malignancies. this setting. In conclusion, 90-­min rapid i.v. infusion of SDZ-­RTX Rituximab has become a standard component of treat- is feasible and well-­tolerated in select patients with B-­cell ment regimens for CD20+ NHL. In our study, rapid i.v. lymphoma and CLL who did not experience severe IRRs SDZ-­RTX was administered alongside various standard with the standard administration rate during the previous chemotherapies, such as CHOP, CVP, and GEMOX, but cycle. Our results support previous evidence with refer- also with chemo-­ free schedules, such as lenalidomide ence rituximab, and indicate an opportunity to improve or venetoclax. Rituximab-­lenalidomide (R2) has become patient convenience and reduce the burden on healthcare frequently used for treatment of relapsed FL,25 and com- resources. bination of R2 with other agents is being studied.26,27 Rituximab-­venetoclax is licensed in the European Union AUTHOR CONTRIBUTIONS for relapsed CLL,28 and the combination of this regimen A.M. and A.S. wrote the manuscript. A.M. and A.S. de- with other agents is also been explored in MCL and other signed the research. A.M., J.M.A.-­P., J.D., S.GdV., C.C., malignancies.29,30 The favorable safety profile of chemo-­ A.J.-­U., and A.S. performed the research. A.S. analyzed free schedules shown in this study is therefore relevant, the data. because many of these are becoming part of standard clin- ical practice. ACKNOWLEDGMENTS Rapid i.v. infusions of rituximab have previously Factual review and proofreading were provided by Ines been administered at a dose of 375 mg/m2. Recently, Brueckmann of Hexal AG, a Sandoz company. The au- rapid infusion of rituximab at doses ranging from 500–­ thors would like to thank the patients who participated 750 mg/m2 were administered in a cohort of 11 patients in this study, and Angel Cedillo and Ana Mendez for with primary central nervous system lymphoma and no logistics. IRRs of any grade were observed during the 44 rapid rituximab infusions.31 In our cohort, patients with CLL FUNDING INFORMATION were treated with SDZ-­RTX-­chlorambucil or SDZ-­RTX-­ This study was funded by Sandoz Group, a Novartis venetoclax, both with rituximab at a dose of 500 mg/ Division, as an investigator project in the GELTAMO m2.32,33 Our data show that patients with CLL fulfilling group. our inclusion and exclusion criteria (in particular, lym- phocytosis <5 × 109/L and prior tolerance of a standard CONFLICT OF INTEREST rituximab i.v. infusion) can receive a 90-­min i.v. infu- A.M. provides consultancy and/or honoraria from Roche, sion of SDZ-­RTX at 500 mg/m2 without additional safety AbbVie, AstraZeneca, and Janssen; speaker honorarium concerns. and travel grants from Roche, AbbVie, AstraZeneca, and In addition, as previously reported,11 most of the rapid Janssen. J.-­M.A. provides consultancy and/or Honoraria infusions were administered in the outpatient setting, from Novartis, Amgen, Janssen, BMS, GSK, AstraZeneca, which is very convenient for patients, as well as for re- and Sanofi. J.D. receives speaker honorarium from ducing healthcare costs. Rapid infusion of rituximab over Sandoz. S.G. receives consultancy and/or Honoraria from 90 min has been shown to improve patient satisfaction.3 Takeda, Janssen, Incyte, Eusa Pharma, and Novartis. C.C. The mean infusion time saved in a single rapid i.v. infu- provides consultancy and/or Honoraria from Novartis, sion is ~2.9 h.34 Moreover, rapid i.v. rituximab infusions Kite/Gilead, Takeda, Regeneron, and AstraZeneca. A.S. save an average of 10.2 h per patient over the course of provides consultancy and/or Honoraria from Janssen, rituximab treatment, thereby offering an economic ad- BMS/Celgene, and BeiGene; speaker honorarium from vantage by reducing chair time, resource utilization, and Roche, Incyte, and Janssen; and research funding from SANDOZ BIOSIMILAR RITUXIMAB IN NHL AND CLL    | 311 16. Weise M, Bielsky MC, Smet K, et al. Biosimilars: what clinicians Roche, AbbVie, and Gilead. All other authors declared no should know. Blood. 2012;120:5111-­5117. competing interests for this work. 17. Pasina L, Casadei G, Nobili A. Biological agents and biosimi- lars: essential information for the internist. Eur J Intern Med. ORCID 2016;33:28-­35. Antonio Salar https://orcid.org/0000-0002-4652-4825 18. Urru SAM, Spila Alegiani S, Guella A, Traversa G, Campomori A. Safety of switching between rituximab biosimilars in onco-­ hematology. Sci Report. 2021;11(1):1-­5. REFERENCES 19. 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