Randomised Trial in Waldenstrom's Macroglobulinaemia
Randomised Trial in Waldenstrom's Macroglobulinaemia
The purpose of this trial is to assess tolerability and efficacy of the Bortezomib,
 Cyclophosphamide and Rituximab combination as initial therapy for previously untreated
 patients with symptomatic Waldenstrom's macroglobulinaemia.
Waldenstrom macroglobulinaemia (WM) is a low grade nonHodgkin lymphoma characterised by bone
 marrow infiltration and the presence of an abnormal protein in the blood (IgM paraprotein.
 Most patients require treatment at presentation but there is no agreed standard of first line
 therapy. Current treatment is unsatisfactory with responses often incomplete and slow to
 attain, while recurrence is inevitable.

 The aim of this study is to find out whether a new combination of Bortezomib (Velcade®),
 Cyclophosphamide and Rituximab (MabThera), is well tolerated and effective for patients with
 WM. R2W is a randomised, noncomparative, phase II trial of subcutaneous bortezomib,
 cyclophosphamide, rituximab (BCR, experimental arm) versus fludarabine, cyclophosphamide,
 rituximab (FCR, control arm) for initial therapy of WM. This is a two stage trial where six
 patients will be treated initially with BCR to assess tolerability. If BCR is considered
 tolerable, a further 50 patients will be randomised between BCR and FCR (2:1) in the second
 stage of the trial. Patients will receive 3 cycles of treatment and then be reassessed. Those
 with evidence of progression will stop trial treatment. All other patients will continue with
 a further 3 cycles (to a total of 6) unless there is a clear clinical contraindication to
 further treatment.
Inclusion Criteria:

 -  Age ≥ 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 <10 g/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)

 -  Performance status grade 0 - 2

 -  Life expectancy of greater than 6 months

 -  Informed consent

 -  Agreed compliance with recommended contraceptive precautions where appropriate

 Exclusion Criteria:

 -  Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein

 -  Severe pre-existing neuropathy (> grade 2)

 -  Autoimmune cytopenias

 -  Evidence of active Hepatitis B or C infection (patients with evidence of past HepB
 infection may be eligible - see appendix 6)

 -  Serological positivity for HIV

 -  Pregnant or lactating women

 -  Life expectancy severely limited by other illness

 -  Renal failure (creatinine clearance <30 ml/min)

 -  Severe impairment of liver function: alkaline phosphatase/bilirubin >2.5 times upper
 limit of normal (ULN), ALT/AST >2.5 times ULN not related to lymphoma (patients with
 Gilbert syndrome are eligible)

 -  History of allergic reaction to compounds containing boron or mannitol

 -  Known hypersensitivity to murine compounds.

 -  Diagnosed or treated for a malignancy other than WM within 5 years before day 1 of
 Cycle 1 with the exception of complete resection of basal cell carcinoma, squamous
 cell carcinoma of the skin or any other in situ malignancy

 -  Active systemic infection requiring treatment

 -  Concurrent treatment with another investigational agent

 -  Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic
 disease