Zanubrutinib in Patients With Waldenström's Macroglobulinemia, Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma and Follicular Lymphoma

Study Overview
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Brief Summary
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The objective of this NIS is to evaluate medical resource utilization, where data is rare in all cohorts, patient's QoL and effectiveness of zanubrutinib treatment in adult patients with WM, CLL, MZL and FL in a real-world setting.

Detailed Description
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ARIADNE will collect and analyze data of adult patients with WM, CLL, MZL or FL in need of treatment. The study will explore the medical resource utilization during therapy with zanubrutinib (Brukinsa®). Further aims are to assess effectiveness, safety and tolerability of the treatment as well as treatment satisfaction and biomarkers. These data will be supplemented by the assessment of patient-reported outcomes (PROs)/ health-related quality of life (QoL). Since treatment options for MW, CLL, MZL or FL are limited and the most important factor is to keep or improve QoL of the patients, there is an urge for real-world clinical data of patients treated with zanubrutinib, especially focusing on patients already treated upfront with a BTK inhibitor, older patients and patients with comorbidities.

Official Title
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Zanubrutinib (Brukinsa®) in Patients With Waldenström's Macroglobulinemia (WM), Chronic Lymphocytic Leukemia (CLL), Marginal Zone Lymphoma (MZL) and Follicular Lymphoma (FL) - a Prospective Multicenter Observational Cohort Study

Conditions
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Waldenström's Macroglobulinemia, Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma, Follicular Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Waldenström's macroglobulinemia (all treatment lines) OR Chronic lymphocytic leukemia (all treatment lines) OR Marginal zone lymphoma (≥2 treatment line and at least one anti-CD20 antibody-based previous therapy) Follicular lymphoma (≥3 treatment line) Signed and dated informed consent form Treatment with zanubrutinib according to current SmPC for WM, CLL and MZL Treatment with zanubrutinib + obinutuzumab for FL according to current SmPC Treatment decision before inclusion into this non-interventional study Age ≥18 years. Exclusion Criteria: Contraindications according to SmPC for patients with WM, CLL, MZL or FL Participation in an interventional clinical trial during zanubrutinib treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Waldenström's Macroglobulinemia<br>75 patients (excluding screening failures, patients with off-label use or with violation of inclusion/exclusion criteria identified after treatment start) receiving zanubrutinib (Brukinsa®) | Drug: Zanubrutinib<br>* according to the Summary of Product Characteristics (SmPC).<br>* Other names: Brukinsa®;|
| Chronic Lymphocytic Leukemia<br>250 patients (excluding screening failures, patients with off-label use or with violation of inclusion/exclusion criteria identified after treatment start) receiving zanubrutinib (Brukinsa®) | Drug: Zanubrutinib<br>* according to the Summary of Product Characteristics (SmPC).<br>* Other names: Brukinsa®;|
| Marginal Zone Lymphoma<br>37 patients (excluding screening failures, patients with off-label use or with violation of inclusion/exclusion criteria identified after treatment start) receiving zanubrutinib (Brukinsa®) | Drug: Zanubrutinib<br>* according to the Summary of Product Characteristics (SmPC).<br>* Other names: Brukinsa®;|
| Follicular Lymphoma<br>38 patients (excluding screening failures, patients with off-label use or with violation of inclusion/exclusion criteria identified after treatment start) receiving zanubrutinib (Brukinsa®) in combination with obinutuzumab (Gazyvaro®) | Drug: Zanubrutinib<br>* according to the Summary of Product Characteristics (SmPC).<br>* Other names: Brukinsa®;Drug: Obinutuzumab<br>* according to the Summary of Product Characteristics (SmPC).<br>* Other names: Gazyvaro®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Medical resource utilization | Frequency of hospitalizations, i.e. number of hospital stays plus number of emergency unit visits (without hospitalization) per patient | During zanubrutinib treatment, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global health-related quality of life (QoL) collected via EORTC QLQ-C30 during course of treatment and follow-up | Course of QoL during treatment and follow-up (collected via European Organisation for research and treatment of cancer quality of life in cancer patient questionnaire (EORTC QLQ-C30). Scoring of the questionnaire will be performed according to the respective manual. | During zanubrutinib treatment and follow-up, up to 5 years | 
| Global health-related quality of life (QoL) collected via EQ-5D-5L during course of treatment and follow-up | Course of QoL during treatment and follow-up (collected via European quality of life 5 dimension 5 level version (EQ-5D-5L)). Scoring of the questionnaire will be performed according to the respective manual. | During zanubrutinib treatment and follow-up, up to 5 years | 
| Incidence of (serious) adverse events ((S)AEs) | Incidence of (S)AEs; (S)AEs will be summarized by the most recent Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. | Start of zanubrutinib treatment until 30 days after end of zanubrutinib treatment | 
| Incidence of (serious) adverse drug reactions ((S)ADRs) | Incidence of (S)ADRs related to zanubrutinib | Start of zanubrutinib treatment until end of study, up to 5 years | 
| Incidence of adverse events of special interest (AESIs) | Incidence of AESIs | Start of zanubrutinib treatment until 30 days after end of zanubrutinib treatment | 
| Time to AESIs | The time to first onset of AESIs. | Start of zanubrutinib treatment until 30 days after end of zanubrutinib treatment | 
| Time to neutropenia | The time to first onset of neutropenia grade ≥3 (MedDRA terms: neutropenia and neutrophil count decrease). | Start of zanubrutinib treatment until 30 days after end of zanubrutinib treatment | 
| Rate of neutropenia grade ≥3 | Rate of patients with neutropenia grade ≥3 during zanubrutinib treatment. Neutropenia incorporates the MedDRA terms: neutropenia and neutrophil count decrease. | Start of zanubrutinib treatment until 30 days after end of zanubrutinib treatment | 
| Proportion of patients with complete response (CR) or very good partial response (VGPR) (best reported response) | The proportion of patients with a best overall response of CR or VGPR. | During zanubrutinib treatment, up to 5 years | 
| In the WM cohort only: Major response rate (MRR) | MRR is defined as the proportion of patients with a best overall response ≥ PR (partial response) | During zanubrutinib treatment, up to 5 years | 
| In the WM cohort only: Best response | Best response is defined as best reported response during study treatment CR (complete response) or VGPR (very good partial response). | During zanubrutinib treatment, up to 5 years | 
| In the WM cohort only: IgM levels | Change of IgM levels until end of zanubrutinib treatment for WM cohort. | During zanubrutinib treatment, up to 5 years | 
| Progression-free Survival (PFS) | PFS is defined as the time from treatment start until progression or death from any cause, whichever comes first. | Treatment start with zanubrutinib until end of study, up to 5 years | 
| 6-, 12-, 18- and 24-month PFS rate | Percentage of patients without disease progression or death from any cause at 6, 12, and 24 months after start of zanubrutinib treatment. | 6, 12, and 24 months after start of zanubrutinib treatment | 
| Overall Survival (OS) | OS is defined as the time from treatment start until death. | Treatment start with zanubrutinib until end of study, up to 5 years | 
| 6-, 12-, 18- and 24-month OS rate | Percentage of patients alive at 6, 12, and 24 months after start of zanubrutinib treatment. | 6, 12, and 24 months after start of zanubrutinib treatment | 
| WM Cohort: Overall response rate (ORR) | For the WM cohort, overall response rate is defined as CR, VGPR and PR (partial response). | During zanubrutinib treatment, up to 5 years | 
| WM Cohort: Best overall response rate (ORR) | For the WM cohort, best overall response rate is defined as CR, VGPR, PR (partial response), MR (minor response), SD (stable disease) or PD (progressive disease). | During zanubrutinib treatment, up to 5 years | 
| CLL Cohort: Overall response rate (ORR) | For the CLL cohort, overall response rate is defined as CR and PR. | During zanubrutinib treatment, up to 5 years | 
| CLL Cohort: Best overall response rate (ORR) | For the CLL cohort, best overall response rate is defined as CR, PR, SD or PD. | During zanubrutinib treatment, up to 5 years | 
| MZL Cohort: Overall response rate (ORR) | For the MZL cohort, overall response rate is defined as CR, pMRD (probable minimal residue disease), PR and rRD (responding residual disease). | During zanubrutinib treatment, up to 5 years | 
| MZL Cohort: Best overall response rate (ORR) | For the MZL cohort, best overall response rate is defined as CR, pMRD, PR, rRD, No change/SD or PD | During zanubrutinib treatment, up to 5 years | 
| FL Cohort: Overall response rate (ORR) | For the FL cohort, overall response rate is defined as CR or PR. | During zanubrutinib treatment, up to 5 years | 
| FL Cohort: Best overall response rate (ORR) | For the FL cohort, best overall response rate is defined as CR, PR, MR, SD or PD. | During zanubrutinib treatment, up to 5 years | 
| Time to treatment failure (TTF) | TTF is defined as time interval from treatment start to discontinuation of treatment because of disease progression, treatment toxicity, switch of therapy of any reason, and death. | Treatment start with zanubrutinib until end of treatment, up to 5 years | 
| Frequency of blood product transfusion | The number of patients receiving blood product transfusion, the number of transfusions per patient and the kind of transfusion (e.g., erythrocytes, thrombocytes). | During zanubrutinib treatment, up to 5 years | 
| WM Cohort: Change of IgM levels until end of zanubrutinib treatment | Difference between the baseline value and the end of treatment value of the IgM level. | Baseline and end of zanubrutinib treatment, up to 5 years | 
| Therapy decision making | Frequency and weighting of distinct parameters affecting therapy choice of the treating physician assessed by project specific questionnaire | Baseline | 
| Time from first diagnosis of WM, CLL, MZL or FL to zanubrutinib treatment start | Time from first diagnosis of WM, CLL, MZL or FL to zanubrutinib treatment start including timing and duration of possible watch & wait strategy. | Baseline | 
| Previous therapies | Key details of previous therapies (including plasmapheresis for WM, transplantations for WM, CLL and FL, radiotherapy for CLL, MZL and FL and surgery for CLL, MZL and FL). | Baseline | 
| Daily dose of zanubrutinib | Frequency tables including the daily dose (mg) will be given using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| FL cohort: Daily dose of obinutuzumab | Frequency tables including the daily dose (mg) will be given using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| Dose modifications of zanubrutinib | Frequency tables will be provided including therapy modifications (reduction and increase) with reasons using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| FL cohort: Dose modifications of obinutuzumab | Frequency tables will be provided including therapy modifications (reduction and increase) with reasons using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| Therapy interruptions of zanubrutinib | Frequency tables will be provided including treatment interruptions with reasons as well as reasons for treatment termination. | During zanubrutinib treatment, up to 5 years | 
| FL cohort: Therapy interruptions of obinutuzumab | Frequency tables will be provided including treatment interruptions with reasons as well as reasons for treatment termination. | During zanubrutinib treatment, up to 5 years | 
| Dose intensity of zanubrutinib | Frequency tables will be provided including the dose intensity (absolute and relative) using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| FL cohort: Dose intensity of obinutuzumab | Frequency tables will be provided including the dose intensity (absolute and relative) using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| Treatment duration with zanubrutinib | Frequency tables will be provided including the treatment duration will be given using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| FL cohort: Treatment duration with obinutuzumab | Frequency tables will be provided including the treatment duration will be given using descriptive statistics. | During zanubrutinib treatment, up to 5 years | 
| Subsequent antineoplastic therapies | Key details of subsequent antineoplastic therapies after zanubrutinib (including plasmapheresis for WM, stem cell transplantations for WM, CLL and FL, radiotherapy for CLL, MZL and FL and surgery for CLL, MZL and FL): duration (descriptive statistics), number, substances and reason for end of subsequent treatments (frequencies). | End of zanubrutinib treatment until end of study, up to 5 years | 
| Frequency for concomitant medication during zanubrutinib treatment | Substances (WHO-ATC level 2), ongoing status and indication (frequencies) | During zanubrutinib treatment, up to 5 years | 
| Frequency of antibiotic use for prophylactic reasons during zanubrutinib treatment | Proportion of patients with at least one-time antibiotic use for prophylactic reasons during zanubrutinib treatment. | During zanubrutinib treatment, up to 5 years | 
| Frequency of antibiotic use for treatment of AEs during zanubrutinib treatment | Proportion of patients taking at least one-time antibiotics for treatment of AEs during zanubrutinib treatment. | During zanubrutinib treatment, up to 5 years | 
| Frequency of antibiotic use in patients with neutropenia during zanubrutinib treatment | Proportion of patients presenting with neutropenia during zanubrutinib treatment taking at least one-time antibiotics. | During zanubrutinib treatment, up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Waldenström's Macroglobulinemia, Zanubrutinib, Brukinsa, Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma, Follicular Lymphoma