Waldenstrom Macroglobulinaemia (WM) is a distinct B cell lymphoma with lymphoplasmacytic bone marrow infiltration and presence of an IgM monoclonal paraprotein. Patients with asymptomatic WM with a low beta-2 microglobulin and Hb greater than120 g/L, may have an indolent course and not require therapy. Symptomatic patients with WM should be considered for immediate treatment to control symptoms, as well as to reverse or prevent complications of WM.
The Fourth International Workshop on WM, held in June 2007, recommended through their consensus panel of experts that the use of extended-dose rituximab as well as combination therapy with alkylating agents and/or nucleoside analogs were reasonable choices for the first-line or salvage treatment of WM in comparison to single agent therapy.r However, randomised studies to address the efficacy and impact of such novel regimens were recommended, and that individually tailored therapy including eligibility for autologous transplantation would impact on the choice of first line and salvage therapy of such patients. For patients eligible for autologous transplantation, exposure to alkylating agents and nucleoside analogs should be limited due to risk of stem cell damage by these agents.rr
A multicentre, prospective trial was conducted by Dimopoulos et. al between 2002 to 2006. 72 patients were enrolled and received the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen as first line therapy for symptomatic WM. Courses were repeated every 21 days for 6 courses. Patients median age was 69 years. The majority of these patients had advanced disease with a median serum monoclonal paraprotein of 36 g/L (range 3 to 117 g/L) which was predominantly kappa in 78%. Treatment consisted of dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally twice a day on days 1 to 5 (total dose 1000 mg/m2). Patients who achieved stable disease or no disease progression were observed.r
Complete response (CR) was defined as a complete disappearance of disease at all involved sites and a negative serum immunofixation. Partial response (PR) was defined as a greater than 50% reduction of serum monoclonal paraprotein along with a greater than 50% reduction of tumour burden at all sites of involvement. A minor response was defined as an equal to 25% but less than a 50% reduction in serum monoclonal paraprotein and no new signs of active disease.r
Longer-term follow-up of these data have been published.r After a minimum follow-up of 7 years for all patients, 83% achieved a response, with median progression-free survival (PFS) of 35 months. This data was felt to compare favourably with results achieved in other front-line studies.
No randomised comparative data of DRC against other therapies has been published. At ASH 2016, Paludo et al.rr presented a retrospective review of patients treated at the Mayo clinic between January 2007 and December 2014. This analysis looked at the outcomes in WM patients who received DRC (n=50) and Bendamustine-Rituximab (BR; n =44). Patients achieved similar overall response rates (ORR) with both regimens, although there was a non-significant trend to more rapid achievement of best response in the BR group (11 v 6.1 months, p=0.13). 2 year PFS was not statistically different, but with a strong trend favouring the BR group (53% v 66%, p=0.08).
This study also investigated the role of DRC in the relapsed setting. 50 patients had a median time to best response of 6.8 months, with an ORR of 87%, (68% ≥ PR). Median PFS was 32 months.
The 10th International Workshop on Waldenstrom’s Macroglobulinaemiar considered DRC to be an appropriate first-line combination therapy, especially in frail patients. Furthermore, they agreed, in general terms, that DRC could be considered in the relapsed setting for patients treated with an alternative therapy in first-line, or where first-line DRC was associated with a prolonged response duration (> 2 years).
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Dimopoulos et al., 2007r
Kastritis et al., 2015r
|
Yes |
Yes |
Trial performed in previously untreated patients with symptomatic WM |
Case series |
Paludo et al., 2016r |
Yes |
N/A |
Previously untreated and relapsed/refractory patients with WM |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
2023 |
Yes |
N/A |
- |
BCCA |
N/A |
N/A |
N/A |
- |
ESMO |
2018 |
Yes |
N/A |
- |
Efficacy
On an intent-to-treat basis, 83% of patients (95% CI, 73 to 91%) achieved a response, including 7% complete, 67% partial and 9% minor responses. The median time to response was 4.1 months. The 2 year PFS rate for all patients was 67%; and for patients who responded to DRC, it was 80%. The 2 year disease-specific survival rate was 90%.r
Figure 1. Time to progressionr
© Journal of Clinical Oncology 2007
Toxicity
Treatment was well tolerated, with 9% of patients experiencing grade 3 to 4 neutropenia and approximately 20% of patients experienced rituximab related toxicity.r
Table 1. Toxicity of treatment with DRCr
© Journal of Clinical Oncology 2007