Infectious Complications in Hematological Patients Under Treatment With Bispecific Antibodies.

In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic option in hematologic malignancies, offering novel mechanisms of action by simultaneously binding two different targets. While the clinical efficacy of BsAbs has been demonstrated in several trials, their impact on the immune system, particularly in the context of infection risk, remains less well-understood. Hematologic patients are already at heightened risk of infectious complications due to immunosuppression from the disease and other therapies. However, the unique immunomodulatory effects of BsAbs may further alter the infectious risk profile in these patients, necessitating closer evaluation. Real-world data on large populations receiving these drugs is thus urgently needed to reduce morbidity and mortality from infections.

Study Design This is a prospective, multicenter, observational cohort study involving patients with hematologic malignancies who are receiving bispecific antibody therapy.

All European centers involved in hematological patients' care are invited to include their patients, on behalf of the European society of Hematology ( EHA).

Sample size A minimum of 150-200 patients to be included.

Data Collection Data will be recorded on an online platform ( www.clinicalsurveys.com) and each center will receive a code to anonymize clinical data.

The collection, processing, and analysis of data will be carried out in compliance with the General Data Protection Regulation 2016/679 (GDPR) of December, the Organic Law 03/2018 of December 5 on the protection of personal data and the guarantee of digital rights, and Law 41/2002 of November 14, which regulates patient autonomy and rights and obligations regarding information and clinical documentation.

The data collected for these studies will be recorded in:

A database identified solely by a code, so no information that could identify participants will be included. Only the study investigator and their collaborators with authorized access to the source data (medical records) will be able to link the data collected in the study with the patient's medical record.

The identity of participants will not be accessible to anyone else except in cases of medical emergencies or legal requirements.

Authorized access to personally identifiable information may be granted to health authorities, the Ethics Committee for Research with Medicinal Products (CEIm), and personnel authorized by the study sponsor when necessary to verify study data and procedures, always maintaining confidentiality in accordance with current legislation.

Transfers Only coded data will be transferred to third parties and other countries, which will never contain information that could directly identify the participant. In the event of such a transfer, it would be for the same purpose as the study described, ensuring confidentiality.

If a transfer of coded data is made outside the EU, whether to entities related to the hospital where the patient participates, service providers, or researchers collaborating with us, the participants' data will be protected by safeguards such as contracts or other mechanisms established by data protection authorities. Data will be collected at baseline (prior to BsAb initiation) and at pre-specified intervals during the study period (e.g., monthly for 12 months).

Data to be collected include:

Demographic and Clinical Data: Age, sex, comorbidities, hematologic diagnosis, disease stage, prior treatments, baseline immune status.

• Treatment Data: Type of BsAb, dosing regimen, concomitant immunosuppressive or supportive therapies (e.g., corticosteroids, prophylactic antibiotics).
• Infection Data: Type, severity, and timing of infections (e.g., bacterial, viral, fungal).

Infections will be defined as:

1. Confirmed infection: where a causative pathogen is microbiologically identified.
2. Probable infection: presence of fever plus localized physical exam and/or radiological findings.

Culture-negative neutropenic or non-neutropenic fever in the absence of localized infection within 30 days of BsAbs will be excluded from recording, due to the high overlap with CRS.

Multiple infectious events can be recorded for each patient. Once patient relapse after bispecific treatment and start a new line of therapy, will be excluded from the study.

Site of infection (e.g., bloodstream, lung, urinary tract). Microbiological findings (e.g., cultures, serologies, PCR results).

Severe infections (grade 3 or higher) are defined as requiring intravenous anti-infective therapy and/or hospitalization.

- Outcome Data: Hospitalizations due to infection, need for ICU admission, use of broad-spectrum antimicrobials, infection-related mortality. Impact of infections on BsAb treatment (e.g., delays, dose reductions, discontinuation).

Data Processing:

As project sponsors, we are committed to processing data in accordance with EU Regulation 2016/679. Therefore, we will maintain a record of the processing activities we carry out and conduct a risk assessment of the processing activities to determine the measures we need to apply and how to implement them.

In addition to the rights of access, modification, opposition, and cancellation of data, participants may restrict the processing of data collected for the project if the data is inaccurate, request a copy of the data, or request that the data be transferred to a third party. To exercise these rights, participants should contact the principal investigator of the study. They also have the right to contact the Data Protection Agency if they are not satisfied.

Data cannot be deleted, even if a patient withdraws from the study, to ensure the validity of the research and comply with legal obligations and requirements for drug authorization.

Researchers will retain essential study documentation and materials for at least 5 years after the study's conclusion, or for a longer period if required by other legal regulations.

Endpoints Primary Endpoint: Incidence of infections during treatment with bispecific antibodies.

Secondary Endpoints:

Characterization of infections (type, pathogen, severity). Factors associated with increased infection risk (e.g., neutropenia, hypogammaglobulinemia).

Comparison of infection rates among different BsAbs and hematologic diagnoses. Overall survival and progression-free survival, with infection as a time-dependent covariate.

Statistical Analysis Descriptive statistics will be used to summarize the patient population, infection rates, and outcomes. Kaplan-Meier survival curves will assess the impact of infections on overall survival and progression-free survival. Cox proportional hazards models will be used to evaluate risk factors for infection and outcomes. Subgroup analyses will be performed based on BsAb type, hematologic malignancy, and infection type.

Ethical Considerations The study will be conducted in accordance with the Declaration of Helsinki and will receive approval from local ethics committees at all participating centers. Written informed consent will be obtained from all participants.

To maintain subject confidentiality, no demographic data that could identify the patient will be collected. Only the data specified in the research plan will be sent for biostatistical analysis.

The rights, safety, and well-being of the study patients are the primary considerations and must take precedence over the interests of science and society.

Additionally, this study will comply with the specific regulations of the Autonomous Communities where it is conducted. The study's development will not interfere with the prescribing habits of the physicians. Suspected adverse reactions will be recorded and reported in accordance with current legislation and good pharmacovigilance practices.

Informed Consent:

For patients included in the study after its approval date, informed consent will be requested. The process for obtaining informed consent will take into account, where applicable, the ethical norms and principles related to the provisions for the collection, storage, and potential future use of the subjects' biological samples.

Study flowchart The study will be conducted over the 36 months following the approval of this protocol, during which data collection and subsequent statistical analysis will take place. The expected duration of the follow-up period is 12 months.

The stages of the study will be distributed as follows:

STEPS period Data collection start March 2025 Data collection stop March 2026 Data analysis Abril 2026 Final análisis of results March 2027 Results diffusion Abril 2027

The results will be presented at national and international conferences and published in journals to ensure broader dissemination.

Collaborating Centers The study will involve collaboration from several European centers on behalf of the European Hematology Association.

Each center will contribute patients and data, ensuring a diverse and representative cohort.

Significance This study aims to provide critical insights into the infectious risks associated with bispecific antibody therapy in hematologic patients.

By identifying specific risk factors and infection patterns, the study may inform guidelines for infection prevention and management, ultimately improving patient outcomes in this vulnerable population.