Efficacy of Ibrutinib in Treating Autoimmune Hemolytic Anemia in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or CLL-like MBL

Trial ID: 2023-509793-38-00
Protocol: CLL2323
Sponsor: Fondazione Gimema Franco Mandelli Onlus

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Diseases & Conditions

Chronic lymphocytic leukaemia

Objectives

The primary objective of this study is to assess the **efficacy** of ibrutinib therapy for the treatment of autoimmune hemolytic anemia (AIHA) in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or CLL-like monoclonal B-cell lymphocytosis, specifically in terms of overall response rate (ORR). This evaluation is clinically relevant as it aims to determine the therapeutic potential of ibrutinib in managing AIHA, a condition that can complicate the clinical course of CLL/SLL and impact patient outcomes.

Secondary objectives include:

Evaluating the efficacy of ibrutinib therapy for AIHA treatment in terms of ORR at intermediate and end-of-treatment timepoints.
Assessing the duration of response to AIHA induced by ibrutinib.
Determining AIHA-related ibrutinib-induced relapse-free survival.
Estimating blood transfusion frequency during ibrutinib treatment in patients with AIHA.
Evaluating the need for further AIHA-directed treatments during ibrutinib therapy.
Assessing the safety and tolerability profile of ibrutinib treatment in patients with AIHA.
Establishing response to ibrutinib treatment for CLL according to IWCLL guidelines.
Estimating the duration of response to ibrutinib treatment for CLL.
Evaluating CLL-specific survival outcomes.
Describing the quality of life of patients with AIHA during treatment.
Assessing quantitative changes in peripheral blood T-cell subtypes, immunofluorescence characteristics, and cytokine profile during treatment with ibrutinib at the end of cycle 6 and cycle 12 compared to baseline in patients with AIHA.

Participants

The clinical trial involves participants diagnosed with **Chronic Lymphocytic Leukemia** (CLL), Small Lymphocytic Lymphoma (SLL), or CLL-like monoclonal B-cell lymphocytosis (MBL). The study population includes both male and female subjects, aged 18 years and older, with active autoimmune hemolytic anemia (AIHA) that is either relapsed, steroid-resistant, or steroid-dependent. Participants are required to have adequate renal and hepatic function and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The trial population was selected based on specific inclusion criteria, including the ability to swallow oral medication and adherence to contraceptive measures for men and women of childbearing potential. The sponsor has not provided information regarding the total number of participants. The trial does not exclude vulnerable populations, and lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include a confirmed diagnosis according to IWCLL guidelines and laboratory evidence of hemolysis. The trial aims to assess the efficacy of ibrutinib therapy in terms of overall response rate (ORR) for the treatment of AIHA in patients with CLL/SLL or CLL-like MBL.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **ibrutinib** in treating autoimmune hemolytic anemia (AIHA) in patients diagnosed with **Chronic Lymphocytic Leukemia** (CLL), Small Lymphocytic Lymphoma (SLL), or CLL-like monoclonal B-cell lymphocytosis. This is a Phase IV, randomized, double-blind, controlled study. The trial is expected to commence on November 24, 2023, and conclude by November 24, 2026, with an estimated duration of three years. Participants will be involved in the study for a maximum treatment period of 12 months, with the primary endpoint being the overall response rate (ORR) of AIHA after six cycles of therapy, each cycle lasting 28 days.

The study will include several visits, starting with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and renal and hepatic function. Participants must be over 18 years old, have active AIHA, and meet other specific health criteria. Following the screening, participants will undergo regular follow-up visits to monitor their response to the treatment and any adverse effects. These visits will occur at baseline and after 3, 6, and 12 cycles of therapy. The end-of-study visit will assess the long-term outcomes and any potential side effects experienced during the trial.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will also monitor secondary endpoints, including AIHA response duration, relapse-free survival, and the frequency of red blood cell transfusions. The study aims to provide comprehensive data on the safety and efficacy of ibrutinib in this patient population, contributing valuable insights into the management of AIHA in CLL/SLL patients.

Treatment

The clinical trial involves the use of **ibrutinib**, a synthetic chemical compound, as the experimental medication. Ibrutinib is administered in the form of a hard capsule, with each capsule containing the active substance **ibrutinib**. The route of administration is oral. The maximum daily dose of ibrutinib is 420 mg, and the total maximum dose over the treatment period is 141.12 g. The treatment period is set for a maximum of 12 months. Participants are required to adhere to the dosing schedule as prescribed, and compliance will be monitored throughout the study.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of ibrutinib in treating autoimmune hemolytic anemia in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma or CLL-like monoclonal B-cell lymphocytosis. The primary objective is to assess the overall response rate (ORR) to ibrutinib therapy in the specified patient population.

Efficacy

The efficacy of ibrutinib in the treatment of **Autoimmune Hemolytic Anemia (AIHA)** in patients with Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), or CLL-like monoclonal B-cell lymphocytosis (MBL) will be assessed primarily through the Overall Response Rate (ORR) after six cycles of therapy, with each cycle lasting 28 days. Secondary endpoints include AIHA ORR after three and twelve cycles, AIHA response duration, AIHA-specific relapse-free survival, frequency of packed red blood cell transfusion, and the rate of patients requiring further AIHA-directed treatment during ibrutinib therapy. Additionally, the incidence and type of treatment-related toxicity will be evaluated.

For CLL, the ORR, Partial Response (PR), and Complete Response (CR) rates will be assessed after three, six, and twelve cycles, with response definitions following the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines. Other secondary endpoints include the duration of CLL response, CLL-specific event-free survival, progression-free survival, and overall survival, which will be evaluated both in the entire cohort and specifically in the CLL/SLL cohort. Quality of life will be measured at baseline and after three, six, and twelve cycles. Additionally, the number and percentage of T-cell subsets, the percentage of T cells expressing activation markers and checkpoint molecules, and serum concentrations of T-cell related cytokines will be assessed at baseline and after six and twelve cycles.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Diagnosis of CLL/small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL) according to IWCLL guidelines
Patients >18 years old
Active AIHA (warm AIHA, wAIHA, or cold hemagglutinin disease, CAD) that i) is relapsed after previous treatment with corticosteroids (with or without rituximab), or ii) is steroid-resistant (failure to obtain hematologic response within 3 weeks on at least 1 mg/kg predniso(lo)ne (2)), or iii) is steroid-dependent (need to continue on predniso (lo)ne at a dose of >10 mg/day to maintain a response (2)). AIHA is defined as: anemia (hemoglobin =10 g/dL; or hemoglobin >10 g/dL dependent on transfusions to maintain this level of hemoglobin) and laboratory evidence of hemolysis (presence of 3 of 4 markers: increased reticulocyte count, increased indirect bilirubin, increased lactate dehydrogenase, decreased haptoglobin) and positive DAT (either IgG DAT, C3 DAT or both).
Eligibility of patients with DAT-negative active AIHA should be confirmed by the Principal Investigator and co-Principal Investigator for the trial
Signed written informed consent according to ICH/EU/GCP and national local laws
Eastern Cooperative Oncology Group (ECOG) =2
Adequate renal and hepatic function, per laboratory reference range at screening as follows: o Aspartate aminotransferase (AST) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy) o Alanine aminotransferase (ALT) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy) o Creatinine clearance of >= 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula (within 30 days prior to day 1 of protocol therapy)
Ability to swallow oral study medication
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test within the screening window prior to receiving the first dose of study medication and monthly pregnancy test until the end of systemic exposure
Willingness of men and WOCBP, and their partners, to observe the contraceptive measures until the end of systemic exposure
Willingness of men not to father a child or donate sperm while receiving ibrutinib, and for 3 months following completion of treatment

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Exclusion Criteria

Contraindication to ibrutinib therapy as per treating physician’s discretion.
Contraindication to ibrutinib therapy as per ibrutinib data sheet (severe hepatic impairment, known allergy to the drug or to one of the excipients, concomitant treatment with warfarin or other vitamin K antagonists)
Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or known positive human immunodeficiency virus (HIV) o Participants who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. o Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded o Subjects who have an undetectable or unquantifiable HIV viral load with CD4 > 300 and are on highly active antiretroviral therapy (HAART) medication are allowed. Testing to be done only in patients suspected of having infections or exposures - Previous exposure to ibrutinib as CLL-directed therapy
Previous exposure to ibrutinib as CLL-directed therapy
Treatment with another investigational drug or device, or approved therapy for investigational use – with the exception of corticosteroids - 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer
Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the oral-administered study treatments
Vaccination with a live vaccine within 28 days prior to Cycle 1 Day 1
Female patients who are currently in pregnancy or are willing to be pregnant or are lactating.