A Study on Fractionated Rituximab to Avoid Lysis Syndrome in Aggressive B-Lymphoma (FRILLY)

May 2, 2023 updated by: Noémie Lang, University Hospital, Geneva

FRILLY: A Retrospective Single-centre Study on Fractionated Rituximab to Avoid Lysis Syndrome in Aggressive B-Lymphoma

Tumour lysis syndrome (TLS) occurs as a consequence of the rapid destruction of malignant cells, spontaneously and/or in response to cytotoxic agents and immunotherapies. TLS is a feature of highly proliferative diseases with heavy tumor burden, such as high-grade non-Hodgkin lymphomas (NHL, typically Burkitt's lymphoma). We evaluated fractionating first rituximab dose to prevent TLS in a real-life B-cell NHL cohort of patients treated at University Hospital of Geneva between 2010 and 2020.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Tumour lysis syndrome (TLS) occurs as a consequence of the rapid destruction of malignant cells, spontaneously and/or in response to cytotoxic agents and immunotherapies. TLS is a feature of highly proliferative diseases with heavy tumor burden, such as acute lymphoblastic leukemia (B-ALL) and high-grade non-Hodgkin lymphomas (NHL, typically Burkitt's lymphoma). TLS usually develop during the first week of treatment due to the sudden release of intracellular ions, nucleic acids and protein metabolites. These metabolic disturbances can manifest as hyperuricemia, hyperkaliemia, hyperphosphatemia, hypocalcemia and uremia, exposing the patient to acute renal insufficiency, lactic acidosis and ultimately death in the absence of appropriate management.

In order to make them more practical and reproducible, TLS criteria were modified in 2004 by Cairo and Bishop, who also developed a grading classification as: 1) biochemical TLS occurring 3 days before to 7 days after the start of therapy, and 2) clinical TLS in case of seizure, cardiac arrhythmia or significant acute renal injury (AKI). TLS is burdened with significant morbidity and mortality.

Historically, TLS incidence among high-grade non-Hodgkin's lymphoma (NHL) patients was reported in as high as 42% of cases, with 6% of clinically significant TLS. In a more recent multicentric retrospective analysis performed on 722 patients (37% NHL, 36% ALL, 27% AML), 5.2 % of the patients developed TLS, and among them 25% required intensive care unit admission with a relative mortality rate of 15%.

Rituximab (Mabthera®, Swissmedic 54378) is a therapeutic monoclonal antibody that binds with high affinity to cells expressing the CD20 antigen found on the surface of malignant and normal B cells, inducing complement-dependent and antibody-dependent cellular cytotoxicity. Approved in 1997 for the treatment of CD20-positive B-cell low-grade NHL, rituximab is now widely used in all the spectrum of B-cell malignancies. Initially administered on a weekly schedule for a total of 4 to 8 infusions, rituximab is currently infused together with other cytotoxic agents every 3 to 4 weeks. Rituximab may cause a massive cytolysis of B-cells in some patients leading to an acute onset TLS. Notably, TLS was reported as the second significant safety signal after rituximab administration in 1998.

Since the development of uricolytic agents (rasburicase), TLS incidence has significantly been reduced. Nevertheless, early risk-stratification and initiation of a comprehensive supportive care are mandatory in TLS. The mainstays of TLS prophylaxis and treatment include hydration and diuresis, control of hyperuricaemia with xanthine oxidase inhibitors blocking endogenous uric acid production from purine nucleotides (eg. allopurinol) or uricolytic agents (rasburicase), and vigilant monitoring of electrolyte abnormalities.

In addition, preemptive strategies of tumor debulking were developed such as steroids or low-dose chemotherapy prophase or gradual dose ramp-up of the cytotoxic agent as exemplified with the administration of the Bcl2 inhibitor Venetoclax in chronic lymphocytic leukemia.

To prevent TLS, but also other side effects such as allergy and cytokine-release syndrome during the first administration of rituximab, a few studies suggested the use of a fractionated and dose ramp-up schedule of rituximab administration in B-cell malignancies. In Geneva University Hospital (HUG), this strategy was widely applied to most cases of patients having a B-cell malignancy at high-risk for TLS since the publication of these pioneer studies. We aim at investigating the incidence and severity of TLS in high-grade B-cell lymphoma patients treated at HUG over the last ten years.

Main objective To evaluate the incidence of biochemical lysis syndrome (LTLS) and clinical lysis syndrome (CTLS) in patients receiving fractionated Rituximab infusion for high-grade B-cell lymphoma.

Inclusion

• Newly diagnosed or relapsing histologically proven B-cell lymphoma patients treated with fractionated Rituximab infusion, considered as ≥ 2 consecutive infusions, at least 24 hours apart

Exclusion

  • Unproven histologically B-cell lymphoma
  • Patients who receive a single day Rituximab infusion
  • Patients under long-term dialysis before Rituximab started
  • Age ≤ 18 years
  • Absence of written informed consent

Study Type

Observational

Enrollment (Actual)

94

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Geneva, Switzerland, 1205
        • University Hospital Geneva

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

histologically proven high-grade B-cell lymphoma patients

Description

Inclusion Criteria:

  • Newly diagnosed or relapsing histologically proven high-grade B-cell lymphoma patients treated with fractionated Rituximab infusion, considered as ≥ 2 consecutive infusions, at least 24 hours apart

Exclusion Criteria:

  • Unproven histologically high-grade B-cell lymphoma
  • Patients who receive a single day Rituximab infusion
  • Patients under long-term dialysis before Rituximab started
  • Age ≤ 18 years
  • Absence of written informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of clinical lysis syndrome (CTLS) in patients receiving fractionated Rituximab infusion for high-grade B-cell lymphoma.
Time Frame: 10 days (day -2 and day + 7 after first rituximab infusion)
To evaluate the incidence of clinical tumor lysis syndrome (CTLS) in patients receiving fractionated Rituximab infusion for high-grade B-cell lymphoma.
10 days (day -2 and day + 7 after first rituximab infusion)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of biochemical lysis syndrome (LTLS) in patients receiving fractionated Rituximab infusion for high-grade B-cell lymphoma.
Time Frame: 10 days (day -2 and day + 7 after first rituximab infusion)
To evaluate the incidence of biochemical tumor lysis syndrome (LTLS) in patients receiving fractionated Rituximab infusion for high-grade B-cell lymphoma.
10 days (day -2 and day + 7 after first rituximab infusion)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Geneva

Investigators

  • Principal Investigator: Noemie Lang, MD, University Hospital, Geneva

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 24, 2020

Primary Completion (Anticipated)

May 1, 2023

Study Completion (Anticipated)

May 1, 2023

Study Registration Dates

First Submitted

April 21, 2023

First Submitted That Met QC Criteria

April 21, 2023

First Posted (Actual)

May 3, 2023

Study Record Updates

Last Update Posted (Estimate)

May 4, 2023

Last Update Submitted That Met QC Criteria

May 2, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2020-01659

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All anonymised IPD that underlie results in a publication will be shared upon request with other researchers.

Types of supporting information that will be shared, in addition to the individual participant data set and data dictionaries will include the study protocol, informed consent form and clinical study report

IPD Sharing Time Frame

10 years

IPD Sharing Access Criteria

Upon reasonable scientific request

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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