Long-Term Safety and Effectiveness of Rituximab Biosimilar RTXM83: A Retrospective Extension Study in Brazilian Patients with Diffuse Large B-Cell Lymphoma

Abstract

Introduction

RTXM83, a biosimilar of rituximab, was approved after physicochemical, functional, non-clinical, and clinical studies demonstrated their similarity; these studies included RTXM83-AC-01-11, a multicentric double-blind international prospective pivotal study. Long-term data on biosimilars can potentially elucidate their clinical robustness and facilitate their broader adoption.

Methods

In this retrospective observational study, we analyzed a dataset from a Brazilian cohort previously randomized in the RTXM83-AC-01-11 study followed by the assessment of long-term outcomes in an observational extension phase from randomization in the RTXM83-AC-01–11 study to the last recorded evaluation. Patients with diffuse large B cell lymphoma (DLBCL) received either reference rituximab (R) or RTXM83 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as adjuvant treatment.

Results

The median follow-up period was 77.0 months. Patients with initial DLBCL stages III and IV comprised 50% of the R-CHOP group and 40% of the biosimilar group. Five (18.5%) patients, including two RTXM83-CHOP-treated and three R-CHOP-treated individuals, experienced late adverse events (AEs) of interest. No new safety signs were established. At the final assessment, the progression-free survival (PFS) rates were 93.3% and 50.0% in the RTXM83-CHOP and R-CHOP groups, respectively. Median PFS was not achieved in the RTXM83-CHOP group, which was 40.5 months in the R-CHOP group. The overall survival (OS) rates were 100% and 66.7% in the RTXM83-CHOP and R-CHOP groups, respectively. The median OS was not reached in any group.

Conclusion

This study demonstrated the long-term safety and effectiveness of RTXM83 in treating DLBCL; outcomes comparable to those of the reference product and potentially improved access to treatment have been indicated. However, further research with more diverse patient groups can validate these findings and advocate the broader adoption of biosimilars in cancer care.

Trial Registration

ClinicalTrials.gov Identifier: NCT04928573. June 16, 2021, “retrospectively registered”.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40487-024-00282-7.

Key Summary Points

Long-term clinical events are crucial factors that influence the clinical effectiveness of biosimilar molecules.

In this study, we aimed to analyze long-term data regarding the safety and effectiveness of RTXM83 as an adjuvant therapy for diffuse large B-cell lymphoma (DLBCL).

The efficacy of RTXM83 was comparable to that of the reference drug; no new safety signs were reported during the 77.0-month-long follow-up.

The long-term data collected in this study suggest that the biosimilar RTXM83 is as safe and effective as the reference product.

Introduction

Non-Hodgkin lymphoma (NHL), the most frequent hematological malignancy worldwide [1], accounted for 74% of all lymphoma cases in Brazil between 2010 and 2020 [2]. Among these cases, diffuse large B-cell lymphoma (DLBCL) accounts for 30–35% of new NHL cases reported in Brazil [3]. The CD20 antigen, expressed in mature B cells and more than 95% of B-cell neoplasms, is a target for B-cell NHL therapy [4].

Rituximab (Rituxan^® [USA] and MabThera^® [European Union and Brazil]) is a chimeric monoclonal IgG1-antibody that exhibits high affinity to the CD20 antigen [5]. Rituximab has been approved for the treatment of various cancers, including chronic lymphocytic leukemia, CD20 + follicular NHL, CD20 + B-cell NHL, and DLBCL [6–8] and various autoimmune disorders; it presents one of the most well-known antibody-based treatments [9, 10]. The first-line treatment of DLBCL includes chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [11–13].

Nevertheless, until the arrival of biosimilars, use of rituximab remained limited owing to its high cost [14]. Biosimilars are biological products that are comparable to their reference medicines in terms of pharmacokinetic, analytical, and functional structures as well as clinical endpoints [15, 16]. The implementation of robust pharmacovigilance protocols is crucial for the ongoing monitoring of product safety and efficacy [17]. RTXM83, a rituximab biosimilar developed by mAbxience Research S.L. (Madrid, Spain), is marketed as Vivaxxia^® (Libbs Farmacêutica Ltda) in Brazil [15, 18]. It is the first monoclonal antibody produced in Brazil and marks a pivotal advancement in the accessibility of critical therapies.

The pivotal, multicenter, double-blind, international, prospective study RTXM83-AC-01–11 (Phase 3) demonstrated that RTXM83 was similar to the reference rituximab in terms of efficacy (overall response rate of 83.6% and 82.9% for the biosimilar and the reference, respectively), and it presented comparable pharmacokinetic, pharmacodynamic, safety, and immunogenicity profiles as a first-line treatment for DLBCL. Additionally, its binding capacity to CD20 + human cells and antibody-dependent cell-mediated cytotoxicity potency was similar to that of a reference product [9]. Owing to the strictly regulated production, clinical efficacy, safety, and tolerability, RTXM83 has been approved and marketed in several countries [19, 20].

In addition to clinical trial outcomes, long-term safety and effectiveness should be validated for the effective use of biosimilar molecules and to ensure consistency in clinical responses [18]. The aim of this research (the LB2002 study) was to provide additional data to the pivotal RTXM83-AC-01-11 study and to support the caregivers with suitable information regarding the safety and effectiveness of biosimilars. Here, we present the retrospective analysis of the long-term clinical safety and effectiveness in Brazilian participants (treatment groups: RTXM83-CHOP and R-CHOP) with a median follow-up of 77 months. To our knowledge, this is the longest follow-up of patients with DLBCL who were treated with a rituximab biosimilar.

Methods

Study Design

LB2002 is a retrospective observational study that analyzed a dataset of a previous randomized study, RTXM83-AC-01-11, conducted using a Brazilian cohort, followed by an observational extension phase included to assess long-term outcomes from randomization to the last recorded evaluation. Upon consent, the patient's last recorded evaluation was considered as the final assessment.

We re-engaged all 28 Brazilian participants included in the RTXM83-AC-01-11 study considering the previously specified inclusion and exclusion criteria [15]. The LB2002 study population encompassed intention-to-treat (ITT) participants who had completed at least one treatment cycle with reference rituximab (MabThera^®, Roche Químicos e Farmacêuticos S.A.) + CHOP (R-CHOP) or RTXM83 (Vivaxxia^®, Libbs Farmacêutica Ltda) + CHOP (RTXM83-CHOP) from July 2013 to December 2016. Each participant participating in the extension phase provided a new informed consent form.

To evaluate the long-term safety of RTXM83-CHOP and R-CHOP, we analyzed adverse events (AEs) during the extension phase. Long-term effectiveness was assessed in terms of disease progression rate, progression-free survival (PFS), and overall survival (OS) as secondary study objectives, whereas subsequent treatment approaches after recurrence were assessed as exploratory objectives.

Subanalyses of data from RTXM83-AC-01-11 (response rates after 6 treatment cycles, common AEs, and AEs severity) are presented in the Electronic Supplementary Material. The demographic data and baseline characteristics of the participants with DLBCL provide a comprehensive overview of the study population and their initial clinical presentation.

In the extension phase, data were captured using a study-specific electronic case report form (eCRF). The procedure is summarized in Fig. 1.

Fig. 1.

Flow chart presenting the LB2002 study design, a retrospective analysis of the Brazilian population; processes from randomization in the pivotal RTXM83-AC-01–11 trial to the last recorded evaluation during the extension phase. AEs adverse events, OS overall survival, PFS progression-free survival, RCT randomized clinical trial

Safety Assessments

During the extension phase, we recorded several late AEs of interest selected based on the late-onset toxicity previously described for rituximab [21]: secondary neoplasia, severe infections, progressive multifocal leukoencephalopathy, neutropenia, hepatitis B reactivation, and gastrointestinal perforation. These events were recorded regardless of severity. The frequency and details of the late AEs of interest were described, including their severity/intensity, seriousness, relationship with rituximab and CHOP, and outcomes.

In the safety sub-analysis from RTXM83-AC-01-11, AEs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0) [22]. Only severe AEs (Grade 3 or higher) were recorded within 30 days after the last dose.

Long-term Effectiveness Assessments

PFS was defined as the time (in months) from the date of randomization in the RTXM83-AC-01-11 study to disease progression or death from any cause.

OS was defined as the time (in months) from the date of randomization in study RTXM83-AC-01-11 to the event of death from any cause.

The participants were censored either at their last assessment or at the time of progressive disease or death.

Exploratory Assessments

The treatment data for patients experiencing disease progression were gathered, and the treatment approach was determined at the discretion of the treating physician.

Statistical Analysis

Demographic data are summarized. The follow-up duration in the LB2002 study was calculated from the randomization date in the RTXM83-AC-01-11 study to the last assessment in the extension phase. Disease progression rates were reported as absolute numbers and percentages. The PFS and OS rates for both treatment groups were analyzed using the Kaplan-Meier method, and statistical analyses were conducted using SAS software (version 9.4). Individual descriptions of the subsequent treatment approaches after recurrence are provided.

Ethical Approval

This study was performed following the Helsinki Declaration of 1964 and its subsequent amendments and was approved by the Research Ethics Committee (CEP) of Centro de Hematologia e Hemoterapia-HEMOCENTRO, number 4.737.891 (CAAE: 46518321.2.1001.5404). All participants provided the signed informed consent form before participating in the study. The participants remained anonymous and were granted the right to step out of the study at any time during the research period.

Results

Patients

In this study, we revisited 28 patients from 12 centers in Brazil. One patient included in the RTXM83-CHOP group was excluded because the corresponding research center declined to participate, and we used data from 27 participants: 15 (55.6%) and 12 (44.4%) in the RTXM83-CHOP and R-CHOP groups, respectively. The distribution of study participants across the centers is detailed in Supplementary Materials Table S1. The overall median follow-up period was 77.0 months, which underscores the efficacy of this study in evaluating long-term outcomes. The detailed follow-up data are presented in Table 1. The demographic data and DLBCL history are depicted in Table 2.

Table 1.

The follow-up duration in the LB2002 study: medians, quartiles, and range for entire cohort

	Overall (n = 27)	RTXM83-CHOP (n = 15)	R-CHOP (n = 12)
Median (months)	77.0	79.2	48.4
Q1–Q3 (months)	16.2–80.6	69.9–81.1	7–79.2
Minimum–maximum (months)	0.2–85.3	15–85.3	0.2–85

^*First quartile (Q1) includes 25% of the data that fall below this value, while 75% exceed it; the third quartile (Q3) indicates that 75% of the data fall below this value, and 25% exceed it

^**The maximum follow-up duration is similar across groups. The shorter minimum follow-up in the R-CHOP group results from one patient's early withdrawal (after 5 days [0.2 months]) and the death of four patients before 20 months of follow-up

Table 2.

Demographic data and DLBCL history

		Treatment
Characteristics—n (%)	Overall (n = 27)	RTXM83-CHOP (n = 15)	R-CHOP (n = 12)
Age (years) at the randomization in the RTXM83-AC-01–11 Median (minimum–maximum)	50.0 (19–64)	45.0 (19–61)	55.5 (35–64)
Age (years) at the onset of the LB2002 study Median (minimum–maximum)	56.0 (27–71)	52.0 (27–68)	62.0 (41–71)
Gender—n (%)
Male	11 (40.7%)	6 (40.0%)	5 (41.7%)
Female	16 (59.3%)	9 (60.0%)	7 (58.3%)
Race—n (%)
Black	5 (18.5%)	4 (26.7%)	1 (8.3%)
White	20 (74.1%)	9 (60.0%)	11 (91.7%)
Other (Pardo* or Brown)	2 (7.4%)	2 (13.3%)	0 (0.0%)
Current smoking status—n (%)
Active	2 (7.4%)	2 (13.3%)	0 (0.0%)
Not active	25 (92.6%)	13 (86.7%)	12 (100.0%)
BMI (kg/m2)
Median (minimum–maximum)	26.4 (16.9–48.9)	25.7 (16.9–48.9)	28.3 (21.9–34.1)
Initial DLBCL stage—n (%)
Stage I	4 (14.8%)	2 (13.3%)	2 (16.7%)
Stage II	11 (40.7%)	7 (46.7%)	4 (33.3%)
Stage III	3 (11.1%)	2 (13.3%)	1 (8.3%)
Stage IV	9 (33.3%)	4 (26.7%)	5 (41.7%)
Presence of extranodal lesions—n (%)
No	10 (37.0%)	5 (33.3%)	5 (41.7%)
Yes	17 (63.0%)	10 (66.7%)	7 (58.3%)
Any bulky lesion—n (%)
Yes	17 (63.0%)	8 (53.3%)	9 (75.0%)
No	10 (37.0%)	7 (46.7%)	3 (25.0%)
Age-Adjusted International Prognostic Index (IPI)—n (%)
0	10 (37.0%)	6 (40.0%)	4 (33.3%)
1	17 (63.0%)	9 (60.0%)	8 (66.7%)
ECOG status—n (%)
0	15 (57.7%)	9 (64.3%)	6 (50.0%)
1	11 (42.3%)	5 (35.7%)	6 (50.0%)
Time from DLBCL diagnosis to RTXM83-AC-01–11 study (months)**
Median (minimum–maximum)	1.3 (0.1–4.9)	1.4 (0.1–4.9)	1.2 (0.4–2.1)

BMI body mass index, DLBCL diffuse large B-cell lymphoma, ECOG Status Eastern Cooperative Oncology Group Performance Status

^*Pardo indicates mixed Brazilian ethnicities (white, black, and/or indigenous)

^**Time gap from DLBCL diagnosis to enrollment in the RTXM83-AC-01-11 study, 26 valid observations (15 for the RTXM83-CHOP group and 11 for the R-CHOP group) were considered

Long-Term Safety Assessment

Five patients experienced late AEs of interest between the conclusion of the RTXM83-AC-01-11 study and the last assessment in the LB2002 study (Table 3).

Table 3.

Frequency of the late AEs of interest in the extension phase

	Overall (n = 27)	RTXM83-CHOP (n = 15)	R-CHOP (n = 12)
Late AEs of interest—total occurrence—n (%)	5 (18.5%)	2 (13.3%)	3 (25.0%)
Secondary neoplasia	2 (7.4%)	1 (6.7%)	1 (8.3%)
Severe infections	1 (3.7%)	1 (6.7%)	0 (0.0%)
Progressive multifocal leukoencephalopathy	0 (0.0%)	0 (0.0%)	0 (0.0%)
Neutropenia	2 (7.4%)	0 (0.0%)	2 (16.7%)
Reactivation of hepatitis B	0 (0.0%)	0 (0.0%)	0 (0.0%)
Gastrointestinal perforation	0 (0.0%)	0 (0.0%)	0 (0.0%)

AEs adverse events

Detailed descriptions of AEs in each patient and the treatment groups are presented in Table 4. Three patients were treated pharmacologically for neutropenia, immune system disorders, and severe infections, which led to various outcomes. Two of these patients experienced recovery or resolution; however, one case of necrotizing fasciitis led to sequelae. Patient 2 died after a febrile neutropenia event. However, the correlation between these events could not be established in the medical records owing to the unknown cause of death.

Table 4.

Details of the late AEs of interest

Patient*	Treatment	Late AE of interest (description)	Severity/ intensity	Serious AE?	Relationship to rituximab	Relationship to CHOP	Outcome
2	R-CHOP	Neutropenia	Grade 3	No	Definite	Unlikely	Recovered or resolved
2	R-CHOP	Febrile Neutropenia	Grade 3	No	Unlikely	Unlikely	Unknown
5	R-CHOP	Endometrial adenocarcinoma	Grade 2	Yes	Possible	Possible	Recovered or resolved
6	R-CHOP	Neutropenia	Grade 4	No	Unlikely	Unlikely	Recovered or resolved
6	R-CHOP	Neutropenia	Grade 4	No	Unlikely	Unlikely	Recovered or resolved
14	RTXM83-CHOP	Prostate cancer	Grade 3	No	Unlikely	Possible	Recovered or resolved with sequelae
18	RTXM83-CHOP	Pneumonia	Grade 4	Yes	Unlikely	Unlikely	Recovered or resolved
		Hypogammaglobulinaemia	Grade 4	Yes	Definite	Unlikely	Recovered or resolved
		Orbital cellulitis	Grade 4	Yes	Unlikely	Unlikely	Recovered or resolved
		Necrotizing fasciitis	Grade 4	Yes	Unlikely	Unlikely	Recovered or resolved with sequelae

^*Patient numbers in Table 4 correspond to the identifiers used in the waterfall chart (Fig. 4), facilitating cross-referencing of individual patient data. AEs adverse events

Additionally, a patient with endometrial adenocarcinoma successfully underwent hysterectomy and lymphadenectomy and recovered without sequelae; another patient with prostate cancer experienced sequelae post-laparoscopic radical prostatectomy.

In this sub-analysis of the RTXM83-AC-01-11 study, major differences in the frequency or severity of common AEs were not identified between treatments (Supplementary Materials Tables S2 and S3).

Effectiveness Assessments

After 77 months of median follow-up, the disease progression was detected in 6.7% (1 of 15 patients) of the RTXM83-CHOP group and 41.7% (5 of 12 patients) of the R-CHOP group. This difference was reflected in the PFS rates; Kaplan-Meier analysis revealed a higher rate of PFS was detected in RTXM83-CHOP (93.3%) than in R-CHOP (50%). The median PFS was 40.5 months in the R-CHOP group, while the median PFS had not been achieved in the RTXM83-CHOP group (Fig. 2). The response rates of the Brazilian cohort are detailed in Supplementary Materials Fig. S1.

Fig. 2.

Kaplan-Meier estimates for the cumulative probability of progression-free survival during the final assessment for patients receiving RTXM83-CHOP or R-CHOP treatment. The number of patients at risk at each time point is indicated (bottom). CI confidence interval, NR not reached

Furthermore, during our comprehensive follow-up, the RTXM83-CHOP group exhibited a 100% cumulative OS rate with no fatalities, whereas, the R-CHOP group exhibited a cumulative OS rate of 64.2%, with 4 of 12 included patients deceased. Consequently, the median OS was not achieved in either group (Fig. 3).

Fig. 3.

Kaplan-Meier estimates for the cumulative probability of overall survival during the final assessment of patients treated with RTXM83-CHOP or R-CHOP. The number of patients at risk at each time point is indicated (bottom). CI confidence interval, NR not reached

The waterfall chart (Fig. 4) summarizes the monitoring of individual patients and indicates the occurrence of late AEs of interest, disease progression, and death.

Fig. 4.

Waterfall chart illustrates the follow-up time in the LB2002 study, between the diagnosis in the RCT and extension phase. The time of analyzing disease progression, late adverse events of interest, and death is indicated. Each bar represents a patient, separated according to the treatment group, R-CHOP or RTXM83-CHOP. RCT randomized clinical trial

Regarding causes of death, patient 1 died from febrile neutropenia/septic shock after 3.4 months of follow-up. Patient 2 was presumed to have died because of neutropenia and/or active disease 12.4 months after recruitment in this study; however, specific details were not fully documented. Patient 3 died because of disease progression, with specific involvement of the lung and rectal areas after 13.6 months of follow-up. Patient 4 died from septic shock after 17.0 months of follow-up. The death of patient 1 was possibly related to rituximab and definitively associated with CHOP. The correlation of the deaths in patients 2, 3, and 4 with treatments has not been established.

Subsequent Treatment Approaches After Recurrences

Splenectomy appeared ineffective in the RTXM83-CHOP-treated patient with relapsed disease. In the R-CHOP group, four non-transplant candidates received various second-line treatments: GEMOX (gemcitabine, oxaliplatin), R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) + GEMOX, ICE (ifosfamide, carboplatin, and etoposide), and ICE + DHAP (cisplatin, cytarabine, and dexamethasone). A patient received R-GDP (rituximab, gemcitabine, cisplatin, and dexamethasone) followed by autologous transplant therapy.

Discussion

This study provides valuable insights into the long-term safety and effectiveness of the RTXM83-CHOP regimen administered as a six-cycle therapeutic scheme over a follow-up duration of 77 months (approximately 6.4 years). To our knowledge, this is the longest follow-up of patients with DLBCL who were treated with a rituximab biosimilar and surpassed previous 36-month-long observations [23–26]. Significant data regarding rituximab indications in the most sensitive patient population are presented [27]. Extended surveillance underscores the stable safety profile of RTXM83 and the enduring effectiveness of the treatment in a Brazilian cohort.

The assessment of late AEs of interest, an essential element of our study, highlighted critical long-term safety concerns such as secondary neoplasia and severe infections. Hence, continuous monitoring is crucial for addressing therapy-related risks; however, we identified no new safety signals during this extension phase. Furthermore, the AEs in RTXM83-treated Brazilian patients are comparable to those reported in the RTXM83-AC-01-11 trial [15] and related studies involving rituximab plus CHOP for controlling DLBCL. In this Brazilian cohort, a comparable frequency of common AEs, particularly grade 1–3 events, was detected in both the RTXM83-CHOP and R-CHOP groups. Notably, three fatalities were reported in the R-CHOP group during the extension phase; however, no treatment-related deaths were reported in the RTXM83-CHOP group.

Promising PFS and OS detected in the biosimilar group validated the long-term effectiveness of the RTXM83-CHOP regimen. Nonetheless, making definitive comparative conclusions was difficult owing to the exploratory nature of this study and the differences in participant demographics.

The RTXM83-CHOP group exhibited a post-follow-up disease progression rate of 6.7%, highlighting the enduring efficacy of the regimen. This outcome and a 66.7% initial complete response rate aligned with the 70% cure rate expected in standard R-CHOP treatment [28]. Contrastingly, the R-CHOP group showed a higher disease progression rate (41.7%).

Discrepancies in effectiveness data are potentially attributed to variations in age and disease staging within the Brazilian cohort. At the beginning of the RTXM83-AC-01-11 RCT, the R-CHOP group was 10 years old; however, the median age at enrollment was 45.0 years for RTXM83-CHOP and 55.5 years for R-CHOP. Nevertheless, previous studies evaluating the impact of age on the prognosis of DLBCL reported mortality risks in 40–49- and 50–59-year-old patients treated with rituximab [29].

Noticeably, the R-CHOP group comprised a higher proportion of patients with initial DLBCL stages III and IV (50%) compared to that in the biosimilar group (40%). Additionally, ECOG status 1 was more frequently detected in the R-CHOP group (50%) than in the RTXM83-CHOP group (35.7%). This variation in disease stage and performance status distribution possibly contributed to the higher mortality rate in the R-CHOP group, with all deaths occurring within the first 18 months of follow-up.

Although rituximab can significantly enhance DLBCL treatment [28], its cost limits accessibility, especially in low-income regions such as Brazil [14]. After the reference rituximab patent expiry, numerous biosimilars were developed worldwide, with eight and six biosimilars approved in the EU and Brazil, respectively [28, 30, 31]. Biosimilars present financially sustainable options and enhance treatment access [32–34]. This is highlighted by a recent report demonstrating that biosimilars are 36.3% (average) less costly than their reference products [35].

The retrospective nature of our study and its limited sample size necessitated a careful interpretation of the results. However, the study outcomes reinforce the value of biosimilar RTXM83 as an economically viable alternative to its reference counterparts.

Our research contributes to the ongoing dialogue on the integration of biosimilars into oncology practices, particularly when the financial burden of immunotherapy is a concern. Notably, our findings highlight the role of biosimilars in enhancing the accessibility of vital treatments, underscoring their importance in global health equity efforts.

Conclusions

The extended follow-up provided a comprehensive knowledge of the long-term safety and effectiveness of RTXM83, a biosimilar to rituximab, in DLBCL treatment. RTXM83 is effective in achieving clinical outcomes comparable to those of the reference product and improving treatment accessibility. Further studies involving larger and more diverse patient cohorts can confirm these results. Our research offers valuable insights into oncology practices and indicates the effectiveness of biosimilars for improved cancer care.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Marcia Torresan Delamain, Ana Carolina Ferreira Cardoso, and Vivienne Castilho contributed to the study conception and design. Patient material preparation and data collection were performed by Marcia Torresan Delamain, Fernando Pericole, Sérgio Shusterschitz da Silva Araújo, Laura Maria Fogliatto, Marcia Higashi, Juliana Pereira, Roberto Luiz da Silva, Gustavo Werutsky, Patrícia de Paulo Giacon Radtke, and Marco Aurélio Salvino. Data analysis and interpretation were performed by Marcia Torresan Delamain and Ana Carolina Ferreira Cardoso. All authors participated in writing and reviewing the manuscript and approved its final version.

Funding

This study was supported by Libbs Farmacêutica. Moreover, the publication of this manuscript and the journal’s Rapid Fee Service were funded by Libbs Farmacêutica.

Data Availability

The datasets generated and/or analyzed in the current study are not publicly available owing to privacy and confidentiality considerations. Requests for specific data subsets may be made to the corresponding author, which are subject to applicable data-use agreements.

Declarations

Conflict of Interest

Financial interests: Marcia Torresan Delamain, Fernando Pericole, Sérgio Shusterschitz da Silva Araújo, Laura Maria Fogliatto, Juliana Pereira, Roberto Luiz da Silva, Patrícia de Paulo Giacon Radtke and Marco Aurélio Salvino declare they do not have financial interests. Gustavo Werutsky received consultant honoraria from Libbs Farmaceutica. Marcia Higashi received honoraria for presentations from Pfizer, AstraZeneca, and Janssen and honoraria for participation in scientific meetings from Roche, Pfizer, and Janssen. Ana Carolina Ferreira Cardoso and Vivienne Castilho are currently employed at Libbs Farmacêutica.

Ethical Approval

This study was performed following the Helsinki Declaration of 1964 and its subsequent amendments, and was approved by the Research Ethics Committee (CEP) of Centro de Hematologia e Hemoterapia—HEMOCENTRO, number 4.737.891 (CAAE: 46,518,321.2.1001.5404). All participants provided the signed informed consent form before participating in the study. The participants remained anonymous and were granted the right to step out of the study at any time during the research period.