Introduction

Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.

The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.

As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5,6,7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.

Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.

In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.

The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12,13,14,15.

After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.

The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).

Methods

The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.

The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).

Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.

During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).

Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.

NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.

Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.

We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.

Results and discussion

Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).

Table 1 Characteristics of patients.
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During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).

Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.

Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
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The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).

The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).

After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).

To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.

Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.

The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.

The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.

A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.

In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).