Rituximab and Ibrutinib (RI) Versus Dexamethasone, Rituximab and Cyclophosphamide (DRC) as Initial Therapy for Waldenström's Macroglobulinaemia

Inclusion criteria

• Patients ≥ 18 years
• Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein
• Previously untreated disease at any stage requiring therapy at the discretion of the treating physician. Suggested criteria for initiating treatment include:

• haematological suppression to Hb <10g/dl, or neutrophils <1.5x109/l or platelets <150x109/l
• clinical evidence of hyperviscosity
• bulky lymphadenopathy and/or bulky splenomegaly
• presence of B symptoms
• No previous chemotherapy (prior plasma exchange and steroids are permissible)
• Eastern Cooperative Oncology Group (ECOG) performance status grade 0 - 2
• Life expectancy of greater than 6 months
• Written informed consent
• Willing to comply with the contraceptive requirements of the trial
• Negative serum or urine pregnancy test for women of childbearing potential (WOCBP)

Exclusion criteria

• Prior therapy for WM
• Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein
• CNS involvement with WM
• Autoimmune cytopenias
• Major surgery within 4 weeks prior to randomisation
• Clinically significant cardiac disease including the following:

• Myocardial infarction within 6 months prior to randomisation
• Unstable angina within 3 months prior to randomisation
• New York Heart Association class III or IV congestive heart failure
• History of clinically significant arrhythmias (e.g. sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
• QTcF > 480 msecs based on Fredericia's formula or Bazette's formula
• History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
• Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mm Hg
• Cardiac event within 6 months of screening (e.g. coronary artery stent) requiring dual antiplatelet treatment
• History of stroke or intracranial haemorrhage within 6 months prior to randomisation
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (direct oral anticoagulants (DOACs) allowed)
• History of severe bleeding disorders considered not to be disease related (Haemophilia A, B or von Willebrand's disease)
• Requires ongoing treatment with a strong CYP3A inhibitor or inducer
• Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows:

• Presence of hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the patient will be excluded
• Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable
• Women who are pregnant or breastfeeding or males expecting to conceive or father children at any point from the start of treatment until the end of the "at risk period"
• Renal failure (creatinine clearance <30 ml/min as estimated by the Cockroft-Gault equation)
• Patients with chronic liver disease with hepatic impairment Child-Pugh class B or C
• Known history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies.
• Inability to swallow oral medication
• Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (e.g. malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease)
• Active systemic infection requiring treatment
• Concomitant treatment with another investigational agent
• Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator's opinion, could compromise the patient's safety, or put the study at risk
• Unwilling or unable to take PCP prophylaxis (e.g. cotrimoxazole)
• History of prior malignancy, with the exception of the following:

• Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma, superficial bladder cancer, carcinoma in situ of the cervix or breast or localized Gleason score 6 prostate cancer without current evidence of disease.