Efficacy of Venetoclax in Combination With Rituximab in Waldenström's Macroglobulinemia

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