Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia (NCT05099471)

What this study is about

The study's own summary, as published on ClinicalTrials.gov. Underlined terms have a short explanation.

In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease. Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM.

Interventions being studied

Being studied in this trial does not mean the treatment or procedure is approved or available for this condition.

Drug: Venetoclax; Rituximab
DRC

Eligibility

The criteria exactly as listed on ClinicalTrials.gov. Only the study team can say whether they apply to you.

Inclusion criteria

Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second International Workshop on WM (IWWM). Histopathology has to be perfomed before randomization but within the last 4 months before start of treatment. In addition, pathological specimens have to be sent to the national pathological reference center prior to randomization for the determination of the mutational status of MYD88 and CXCR4 prior to randomization if the mutational status hasn't been determined before. Pathological reference center must confirm the diagnosis of WM.
De novo WM independent of the genotype.
Patients must have at least one of the following criteria to start study treatment as partly defined by consensus panel criteria from the Seventh IWWM and ESMO Guideline:
Recurrent fever, night sweats, weight loss, fatigue (at least one of them).
Hyperviscosity.
Lymphadenopathy which is either symptomatic or bulky (≥ 5 cm in maximum diameter).
Symptomatic hepatomegaly and / or splenomegaly.
Symptomatic organomegaly and / or organ or tissue infiltration.
Peripheral neuropathy due to WM.
Symptomatic cryoglobulinemia.
Symptomatic Cold agglutinin anemia.
Autoimmune hemolytic anemia and/or thrombocytopenia.
Nephropathy related to WM.
Amyloidosis related to WM.
Hemoglobin ≤ 10 g/dL (patients should not have received red blood cells transfusions for at least 7 days prior to obtaining the screening hemoglobin).
Platelet count < 100 x 109/L (caused by bone marrow [BM] infiltration of the lymphoma).
Serum monoclonal protein > 5 g/dL, even with no overt clinical symptoms.
IgM serum concentration ≥ 6 g/dL.
and other WM associated relevant symptoms
Subject must be ≥ 18 years of age.
Life expectancy > 3 months.
World Health Organization (WHO) / ECOG performance status ≤ 2.
Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE).
Baseline platelet count ≥ 50x109/L, absolute neutrophil count ≥ 0.75x109/L (if not due to BM infiltration by the lymphoma).
. Adequate hepatic function per local laboratory reference range as follows:
Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x ULN.
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
Women of childbearing potential (WCBP), i.e. fertile, following menarche and until becoming postmenopausal must have negative results for pregnancy test and must agree to use a highly effective method of birth control for the duration of the therapy up to 12 months after end of therapy
Men must agree not to father a child for the duration of therapy and 12 months after and must agree to advice their female partner to use a highly effective method of birth control. Males must refrain from sperm donation for the duration of treatment and at least 12 months after the last dose of study medication.
Each patient must voluntarily date and sign an informed consent form in the native language of the patient indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Affiliation to a social security scheme (relevant for France only).

Exclusion criteria

Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study.
Subject is known to be positive for HIV.
Active severe infection
Congenital or acquired severe immunodeficiency not attributed to lymphoma (clinical appearance: recurrent infections, necessity of immunoglobulin substitution therapy, patients after transplantation)
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
Uncontrolled systemic infection (viral, bacterial or fungal).
Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
inadequate pulmonary function as demonstrated by DLCO ≤ 65% or FEV1 ≤ 65%.
Creatinine clearance ≥ 30 mL/min to < 45 ml/min
Uncontrolled diabetes mellitus (as indicated by metabolic derangements and / or severe diabetes mellitus related uncontrolled organ complications).
Uncontrolled hypertension.
Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina.
Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to start therapy.
Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia.
Subject has a cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
History of stroke or intracranial haemorrhage within 6 months prior start of treatment
Known pericardial disease.
Known interstitial lung disease.
Infiltrative pulmonary disease, known pulmonary hypertension.
Prior history of malignancies unless the subject has been free of the disease for ≥ 3 years. Exceptions include the following:
Basal cell carcinoma of the skin,
Squamous cell carcinoma of the skin,
Carcinoma in situ of the cervix,
Carcinoma in situ of the breast,
Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
Known cirrhosis (meeting child-pugh stage C).
Chemotherapy with approved or investigational anticancer therapeutic within 21 days prior to start of therapy
Glucocorticoid therapy within 14 days prior to therapy that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent dose of other corticosteroids given for anti-neoplastic intent.
Treatment with any of the following within 7 days prior to the first dose of study drug:
moderate or strong cytochrome P450 3A (CYP3A) inhibitors (such as fluconazole, ketoconazole, and clarithromycin).
moderate or strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort).
Contraindication to the active substances or any of the other excipients of the Investigational Medicinal Products as well as to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs.
Vaccination with live attenuated vaccines within 4 weeks prior to start of therapy.
History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or sponsor, if consulted, would pose a risk to subject safely or interfere with the study evaluation, procedures or completion.
Women who are pregnant as well as women who are breast-feeding and do not consent to discontinue breast-feeding.
Participation in another clinical trial within four weeks before start of therapy in this study.
No consent for registration, storage and processing of the individual disease-characteristics.
Administration or consumption of any of the following within 3 days prior to the first dose of study drug:
grapefruit or grapefruit products.
Seville oranges (including marmalade containing Seville oranges).
star fruit.
Person of legal age who is incapable of comprehending the nature, significance and implications of the clinical trial and of determining his/her will in the light of these facts

Study description and what participation involves

The study's detailed description, as published on ClinicalTrials.gov.

Show the detailed description from the registry

In Waldenström's macroglobulinemia (WM) chemotherapy induces only low CR/VGPR rates and response duration is limited. In addition, WM patients are often elderly, partly not tolerating chemotherapy related toxicities. Thus, innovative approaches are needed which combine excellent activity and tolerability in WM. Chemotherapy-free approaches are highly attractive for this patient group. Based on its high activity and favorable toxicity profile in indolent B-NHL such as CLL, Venetoclax was approved for the treatment of this diseases by the FDA and the European Medicines Agency (EMA). First data in relapsed/refractory WM have documented high activity and low toxicity of Venetoclax also in WM, including patients with prior Ibrutinib treatment or patients carrying CXCR4 mutations. Ibrutinib itself has high activity and a relatively low toxicity profile in WM, but has also major disadvantages: the main disadvantage is the need to apply this drug continuously. Furthermore, Ibrutinib efficacy depends largely on the genotype with a substantial drop in major responses and PFS in the presence of CXCR4 mutations and non-mutated MYD88. In particular the need of continuous treatment for Ibrutinib has prevented that Ibrutinib has become the standard of care outcompeting conventional Rituximab/chemotherapy. This is reflected in current guidelines such as the NCCN and the ESMO guidelines, which still see immunochemotherapy as a backbone of treatment, largely because of the advantage of a timely fixed application. Data in CLL in the relapsed as well as in the first line setting have convincingly shown that in contrast to Ibrutinib Venetoclax is highly efficient also when used in a timely defined application scheme over 12 months in combination with the anti-CD20 antibody Rituximab. Data documented deep responses including molecular responses and a highly significant advantage over immunochemotherapy in large international Phase III trials, changing the standard of care in this disease. Based on this the hypothesis is that timely fixed application of the combination of Venetoclax and Rituximab induces significantly superior treatment outcomes compared to chemotherapy and Rituximab (DRC) in patients with treatment naïve WM, regardless of the genotype. A first indication for this assumption in the proposed trial will allow the performance of confirmatory phase 3 trials that might change the standard of care in WM. This study is an International phase II explorative, multicenter, open label, and randomized trial. The study will consist of an open labeled, stratified 1:1 randomization between Arm A and Arm B for de novo WM patients in need of treatment (phase II). Stratification factors are MYD88 and CXCR4 status (positive vs. negative). A stratified central block randomization will be used. The central randomization service will be used to avoid predictability of the treatment arm. The primary goal of this study is to explore the efficacy of Venetoclax plus Rituximab versus Dexamethasone/Cyclophosphamide/Rituximab in the treatment of de novo WM patients (Arm A vs. Arm B). 80 patients are planned to be recruited for this study at approcimately 30 sites in Germany, Greece and France.

AI summaryWhat participation may involve, in plain languageShow ▾Hide ▴

AI-written from the registry record, not the study's own wording. May contain errors or omissions. Check the registry text on this page and the original record ↗ before acting on it.

After screening and pathology/genetic testing, participants are randomized to one of two treatment arms: a fixed-duration oral venetoclax regimen plus periodic IV rituximab infusions, or a Dexamethasone + oral cyclophosphamide regimen with IV rituximab. Participation involves regular clinic visits for IV infusions (rituximab), daily oral study drugs, frequent blood tests and ECGs, safety monitoring, and quality‑of‑life questionnaires (FACT‑Lym); responses are assessed during treatment and up to months/years of follow‑up as specified. You will need pregnancy testing and must follow contraception requirements; you will be asked to avoid certain foods/medicines (for example grapefruit and some interacting drugs) and some recent vaccines or trial treatments before starting. Pathology samples must be submitted to the reference center before randomization if genotype testing has not already been done.

How the study is structured. Randomized, open-label phase II trial with two parallel treatment arms. Patients are assigned 1:1 to venetoclax plus rituximab or to DRC, using central stratified randomization by MYD88 and CXCR4 status. The primary outcome is CR/VGPR rate at 12 months; multiple secondary outcomes include response timing, duration, survival measures, safety, and quality of life.

Questions you could ask

These questions are suggestions for a conversation with the study team or your own clinician, not advice.

The listed sites are in Germany, Greece. Is any of them reachable for me, and does the study help with travel?
Which of the eligibility criteria would need to be checked with tests before I could join?

More on Waldenström macroglobulinemia

Clinical trials63 trials listed for Waldenström macroglobulinemiaEvery trial the registry lists for Waldenström macroglobulinemia, with recruitment status, phase and sites, updated from ClinicalTrials.gov.See all trials →Research updatesWhat changed in Waldenström macroglobulinemia researchLatest monthly update: September 2026. Includes: Upfront treatment outcomes. New research summarized each month in plain language, with links to every source paper.Read the latest update →

Important dates

Study start: Mar 21, 2025
Primary completion: March 2028 (estimated)
Study completion: March 2033 (estimated)
Target enrollment: 80 participants (estimated)
Last updated on registry: May 5, 2026
Data verified: Oct 10, 2026

Sponsor and research team

The lead sponsor funds and oversees the trial. A pharmaceutical or biotech company sponsor typically means the study is testing that company's drug or device; a hospital, university, or government agency usually indicates investigator-initiated or publicly funded research.

Lead sponsor: Christian Buske
Collaborators: Ludwig-Maximilians - University of Munich
Zentrum für Klinische Studien Ulm
AbbVie
Pfizer
University of Ulm
University Hospital Schleswig-Holstein

Central study contact

If you're interested in participating, the central contact can answer general questions about the study — including eligibility requirements and how to find a recruiting site near you. Actual eligibility is determined by the site's medical team.

Dajana Kaszynski, MSc 📞 +49 731 500 ext. 65833 ✉ studien.gla@uniklinik-ulm.de

Participating sites (14)

Filter by country:

Onkologische Schwerpunktpraxis BielefeldRecruiting
Bielefeld, 33604 · Germany
- Paul Düwel, Dr. · +49521-9887770 · studien@onkologie-bielefeld.de
Klinikum Chemnitz gGmbHRecruiting
Chemnitz, 09116 · Germany
- Annette Haenel, Dr. · +49371-333 ext. 44519 · a.haenel@skc.de
Klinikverbund Allgaeu gGmbHRecruiting
Kempten, 87439 · Germany
- Christian Langer, Prof. Dr. · +49831-530 ext. 2228 · christian.langer@klinikverbund-allgaeu.de
Universitaetsklinikum Schleswig-Holstein AöRRecruiting
Kiel, 24105 · Germany
- Christiane Pott, Prof. Dr. · +49431500-25 ext. 55 · c.pott@med2.uni-kiel.de
Gemeinschaftsklinikum Mittelrhein gGmbHRecruiting
Koblenz, 56073 · Germany
- Jens-Marcus Chemnitz, Prof. Dr. · +49261-137 ext. 7226 · jensMarcus.Chemnitz@gk.de
Dr. Vehling-Kaiser MVZ GmbHRecruiting
Landshut, 84036 · Germany
- Florian Kaiser, Dr. · +4987197403445 · studien@vehling-kaiser.de
Kliniken Maria Hilf GmbH MoenchengladbachRecruiting
Mönchengladbach, 41063 · Germany
- Ullrich Graeven, Prof. Dr. · +492161-892 ext. 2201 · ullrich.graeven@mariahilf.de
Kliniken Ostalb, Standort Stauferklinikum Schwäbisch GmündNot Yet Recruiting
Mutlangen, 73557 · Germany
- Holger Hebart, Prof. Dr. med. · 07171-7011 ext. 302 · Holger.Hebart@kliniken-ostalb.de
Haematologie und Onkologie Muenchen-Pasing MVZ GmbHRecruiting
München, 81241 · Germany
- Matthias Zingerle, Dr. · +49898299660 · zingerle@onkologie-pasing.de
Universitaet MuensterRecruiting
Münster, 48149 · Germany
- Andrea Kerkhoff, Dr. · +49251-83 ext. 46020 · Andrea.Kerkhoff@ukmuenster.de

Terms used on this page · explanations by MedicalUpdates.ai

VGPR: A response category used in some blood conditions meaning the disease marker has fallen a great deal but not disappeared. The exact definition depends on the condition and the study.
relapsed/refractory: A condition that has not responded to a treatment. 'Relapsed' means it responded and then came back; 'refractory' means it did not respond in the first place.
PFS: The length of time during and after treatment that a person lives without the condition getting worse, as defined by the study.
standard of care: Treatment generally considered appropriate for a condition in a particular clinical setting. It can vary by patient, place and over time. In many studies the new treatment is added to, or compared with, standard of care.
relapsed: A condition that improved with treatment and has since returned or worsened.
Phase III: A later-stage study, usually with more participants, designed to give stronger evidence about how well a treatment works and how safe it is. It often compares the treatment with standard care or a placebo, and results may support an application for approval.
randomization: Participants are assigned to the study groups by chance, like a coin toss, rather than chosen by the doctor or the participant. This is done so the groups are comparable.
Life expectancy: Some studies require that, in the investigator's judgement, a participant is likely to live long enough to complete the study period. It is a study requirement, not a prediction about any individual.
ECOG performance status: A scale from 0 to 5 that describes how a person's condition affects daily activity. 0 means fully active; 1 means restricted in strenuous activity; 2 means able to self-care but unable to work; higher numbers mean more limitation.
echocardiogram: An ultrasound scan of the heart. A transesophageal echocardiogram is done through a probe passed into the food pipe for a closer view.
Baseline: Measurements taken at the start of the study, before any study treatment, so that later results can be compared with them.
absolute neutrophil count: The number of neutrophils, a type of white blood cell that fights infection, in a blood sample. Studies often require it to be above a set level.
x ULN: The highest value of a blood test that a laboratory considers normal. Criteria such as '≤ 3 × ULN' mean the result must be no more than three times that value.
creatinine clearance: A measure of kidney function, calculated from a blood creatinine level together with age, weight and sex.
Women of childbearing potential: Studies often ask participants who could become pregnant, or could father a child, to use contraception during the study and for a period afterwards, because the effect of the treatment on a pregnancy is unknown.
informed consent form: The process of explaining a study, including its risks and what participation involves, so that a person can decide freely whether to take part. Consent is usually documented in writing, and a participant can choose to leave the study later.
DLCO: A breathing test that measures how well the lungs pass oxygen from the air into the blood.
investigational: A treatment that is being tested and has not been approved for this use. It may be approved for a different condition. Being studied does not mean it works or is available outside the study.
Glucocorticoid: Steroid medicines, such as prednisone, that reduce inflammation. Studies often require a stable dose at entry or measure whether the study treatment allows the dose to be reduced.
Contraindication: A reason a particular test or treatment should not be used for a person, for example a metal implant that rules out an MRI scan.
sponsor: The organisation or person that initiates the study and has authority over it. The sponsor may be a company, hospital, university, government agency or individual, and is not necessarily the organisation that funds the study.
Inclusion Criteria: The conditions a person must meet to be considered for the study, for example a confirmed diagnosis, an age range or a test result.
Exclusion Criteria: The conditions that rule a person out even if they meet the inclusion criteria, for example other illnesses, certain medicines or pregnancy.
open label: No masking is used, so the assigned intervention is not deliberately hidden from participants or study staff.
stratified: Randomisation done separately within subgroups, such as age bands or disease severity, so that each group contains a similar mix.
1:1: How many participants go to each group. In a 2:1 ratio, two are assigned to the first group for every one assigned to the second.
treatment arm: One of the groups in a study. Each arm receives a particular intervention, comparator or no intervention, so the groups can be compared.