Efficacy of First Line DRC +/- Bortezomib for Patients With Waldenström's Macroglobulinemia
Efficacy of First Line DRC +/- Bortezomib for Patients With Waldenström's Macroglobulinemia
In Waldenström macroglobulinemia (WM) conventional chemotherapy induces only low CR rates and
 responses of short duration compared to other indolent lymphomas. Thus innovative approaches
 are needed which combine excellent activity and tolerability in patients with WM, who are
 mostly of advanced age. The immunochemotherapy DRC (dexamethasone, rituximab,
 cyclophosphamide) was shown to be highly effective in patients with WM without inducing major
 hematological toxicities. On the other hand the proteasome inhibitor Bortezomib showed
 substantial activity as a single agent in WM with only very few side effects when given in a
 weekly schedule. Based on these observations it is the aim of this study to test whether the
 efficacy of the well tolerated DRC regime can be further improved by adding Bortezomib.
Waldenström's macroglobulinemia (WM) is defined by a bone marrow infiltration by
 lymphoplasmacytic cells and the presence of a monoclonal immunoglobulin (Ig) M gammopathy in
 the peripheral blood. The clinical understanding of the disease has been greatly improved by
 the identification of internationally recognized criteria for initiating therapy, the
 description of an international prognostic index for patients requiring a first-line therapy
 and the definition of response criteria. These criteria are mainly based on the evolution of
 serum IgM concentration. However, delayed IgM monoclonal protein responses may cause
 important difficulties in response assessment. In addition, discrepancies between the
 kinetics of serum M protein reduction and the clearance of monoclonal B-cells from the bone
 marrow have been reported. Despite continuing advances in the therapy of WM, the disease
 remains incurable with a median survival of 5 to 8 years from the time of diagnosis thereby
 necessitating the development and evaluation of novel treatment approaches.
Inclusion Criteria:

 Clinicopathological diagnosis of WM as defined by consensus panel one of the Second
 International Workshop on WM. Pathological diagnosis has to occur before study inclusion
 and randomization. In addition, pathological specimens have to be sent to the national
 pathological reference center at study inclusion and randomization. The positivity for CD20
 can be assumed from any previous bone marrow immunohistochemistry or flow cytometry
 analysis performed up to 6 months prior to enrollment. Inclusion in the study will be based
 on morphological and immunological criteria. Immunophenotyping will be performed in each
 center and saved locally. Flow cytometry of bone marrow and blood cells will include at
 least one double staining and assess the expression of the following antigens: surface
 immunoglobulin, CD19, CD20, CD5, CD10 and CD23. Patients are eligible if tumor cells
 express the following antigens: CD19, CD20, and if they are negative for CD5, CD10 and CD23
 expression. Patients with tumor cells positive for CD5 and/or CD23 and morphologically
 similar to WM cells may be included after ruling out other low grade B-cell malignancies.

 -  Presence of at least one criterion for initiation of therapy, according to the 2nd
 Workshop on WM:

 -  Recurrent fever, night sweats, weight loss, fatigue

 -  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

 -  Cold agglutinin anemia

 -  IgM related immune hemolytic anemia and/or thrombocytopenia

 -  Nephropathy related to WM

 -  Amyloidosis related to WM

 -  Hemoglobin ≤10g/dL

 -  Platelet count <100x109/L

 -  Serum monoclonal protein >5g/dL, even with no overt clinical symptoms Cumulative
 illness rating scale (CIRS) score less than 6

 -  World Health Organization (WHO)/ECOG performance status 0 to 2.

 -  Other criteria:

 -  Age ≥ than 18 years

 -  Life expectancy >3 months.

 -  Baseline platelet count ≥ 50 ×109/L, absolute neutrophil count ≥ 0.75×109/L (if
 not due to BM infiltration by the lymphoma).

 -  Meet the following pretreatment laboratory criteria at the Screening visit
 conducted within 28 days of study enrollment:

 -  ASAT (SGOT): ≤3 times the upper limit of institutional laboratory normal
 value

 -  ALAT (SGPT): ≤3 times the upper limit of institutional laboratory normal
 value

 -  Total Bilirubin: ≤20 mg/L or 2 times the upper limit of institutional
 laboratory normal value, unless clearly related to the disease (except if
 due to Gilbert's syndrome)

 -  Serum creatinine: ≤ 2mg/dl

 -  Premenopausal fertile females must agree to use a highly effective method of birth
 control for the duration of the therapy up to 6 months after end of therapy. A highly
 effective method of birth control is defined as those which result in a low failure
 rate (i.e. less than 1% per year) when used consistently and correctly such as
 implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or
 vasectomised partner.

 -  Men must agree not to father a child for the duration of therapy and 6 months after
 and must agree to advice a female partner to use a highly effective method of birth
 control.

 -  Voluntary written informed consent before performance of any study-related procedure
 not part of normal medical care, with the understanding that consent may be withdrawn
 by the subject at any time without prejudice to future medical care.

 Exclusion criteria:

 -  Prior systemic treatment of the WM (plasmapheresis and short- term administration of
 corticosteroids < 4 weeks administered at a dose equivalent to < 20 mg/day prednisone
 is allowed)

 -  Patient with hypersensitivity to dexamethasone.

 -  Serious medical or psychiatric illness likely to interfere with participation in this
 clinical study.

 -  Uncontrolled bacterial, viral or fungal infection

 -  Active HIV, HBV or HCV infection

 -  Known interstitial lung disease

 -  Prior allergic reaction or severe anaphylactic reaction related to humanized or murine
 monoclonal antibody.

 -  Central Nervous System involvement by lymphoma

 -  Prior history of malignancies unless the subject has been free of the disease for ≥ 5
 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).

 -  Uncontrolled illness including, but not limited to:

 -  Uncontrolled diabetes mellitus mellitus (as indicated by metabolic derangements
 and/or severe diabetes mellitus related uncontrolled organ complications)

 -  Chronic symptomatic congestive heart failure (Class NYHA III or IV).

 -  Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within
 6 months

 -  Clinically significant cardiac arrhythmia that is symptomatic or requires
 treatment, or asymptomatic sustained ventricular tachycardia.

 -  Known pericardial disease

 -  Subjects with ≥ Grade 2 neuropathy.

 -  Women who are pregnant as well as women who are breastfeeding and do not consent to
 discontinue breast-feeding.

 -  Participation in another clinical trial within four weeks before randomization in this
 study

 -  No consent for registration, storage and processing of the individual
 disease-characteristics and course as well as information of the family physician
 about study participation.