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The following websites contain valuable information regarding the research and treatment of Waldenstrom's Macroglobulinemia:

Please visit our main program website: Bing Center for Waldenstrom's Research. This site contains information on the latest treatment recommendations, abstracts, news and events, current and pending clinical trials and participating institutions, basic research, and publications, as well as photos and brief bios of the Bing Center staff.


Also feel free to visit our WM Workshop Website where you will find information about our most recent conference in August, 2014 in London, UK.

WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 8)

Combination Therapies

Because rituximab is an active and a non-myelosuppressive agent, its combination with chemotherapy has been explored in WM patients. Weber et al145 administered rituximab along with cladribine and cyclophosphamide to 17 previously untreated patients with WM. At least a partial response was documented in 94% of WM patients including a complete response in 18%. With a median follow-up of 21 months no patient has relapsed. In a study by the Waldenstrom’s Macroglobulinemia Clinical Trials Group (WMCTG), the combination of rituximab and fludarabine was evaluated in 43 WM patients, 32 (75%) of whom were previously untreated146. The overall response rate was 95.3%, with 83% of patients achieving a major response (i.e. 50% reduction in disease burden). The median time to progression was 51.2 months in this series, and was longer for those patients who were previously untreated and for those achieving a VGPR (i.e. 90% reduction in disease) or better.  Hematological toxicity was common with grade 3 neutropenia and thrombocytopenia observed in 27 and 4 patients, respectively. Two deaths occurred in this study due to non-PCP pneumonia. Secondary malignanices including transformation to aggressive lymphoma and development of myelodysplasia or AML were observed in 6 patients in this series.  The addition of rituximab to fludarabine and cyclophosphamide has also been explored in the salvage setting by Tam et al, wherein 4 of 5 patients demonstrated a response147. In another combination study with rituximab, Hensel et al148 administered rituximab along with pentostatin and cyclophosphamide to 13 patients with untreated and previously treated WM or lymphoplasmacytic lymphoma. A major response was observed in 77% or patients. In a study by Dimopoulos et al149, the combination of rituximab, dexamethasone and cyclophosphamide was used as primary therapy to treat 72 patients with WM. At least a major response was observed in 74% of patients in this study, and the 2 year progression free survival was 67%. Therapy was well tolerated, though one patient died of interstitial pneumonia.

In addition to nucleoside analogue based trials with rituximab, two studies have examined CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in combination with rituximab (CHOP-R). In a randomized frontline study by the German Low Grade Lymphoma Study Group (GLSG) involving 69 patients, most of whom had WM, the addition of rituximab to CHOP resulted in a higher overall response rate (94% versus 67%) and median time to progression (63 versus 22 months) in comparison to patients treated with CHOP alone.150. Treon et al151 have also evaluated CHOP-R in 13 WM patients, 8 and 5 of whom were relapsed or refractory to nucleoside analogues and single agent rituximab, respectively. Among 13 evaluable patients, 10 patients achieved a major response (77%) including 3 CR and 7 PR, and 2 patients achieved a minor response. In a retrospective study, Ioakimidis et al152 examined the outcomes of symptomatic WM patients who received CHOP-R, CVP-R, or CP-R. Baseline characteristics for all 3 cohorts were similar for age, prior therapies, bone marrow involvement, hematocrit, platelet count and serum beta 2 microglobulin, though serum IgM levels were higher in patients treated with CHOP-R. The overall response rates to therapy were comparable among all three treatment groups: CHOP-R (96%); CVP-R (88%) and CP-R (95%), though there was a trned for more CR among patients treated with CVP-R and CHOP-R. Adverse events attributed to therapy showed a higher incidence for neutropenic fever and treatment related neuropathy for CHOP-R and CVP-R versus CPR. The results of this study suggest that in WM, the use of CP-R may provide analogous treatment responses to more intense cyclophosphamide based regimens, while minimizing treatment related complications.

The addition of alkylating agents to nucleoside analogues has also been explored in WM. Weber et al145 administered two cycles of oral cyclophosphamide along with subcutaneous cladribine to 37 patients with previously untreated WM. At least a partial response was observed in 84% of patients and the median duration of response was 36 months. Dimopoulos et al153 examined fludarabine in combination with intravenous cyclophosphamide and observed partial responses in 6 of 11 (55%) WM patients with either primary refractory disease or who had relapsed on treatment. The combination of fludarabine plus cyclosphosphamide was also evaluated in a recent study by Tamburini et al154 involving 49 patients, 35 of whom were previously treated. Seventy-eight percent of the patients in this study achieved a response and median time to treatment failure was 27 months. Hematological toxicity was commonly observed and three patients died of treatment related toxicities. Two interesting findings in this study was the development of acute leukemia in 2 patients, histologic transformation to diffuse large cell lymphoma in one patient, and 2 cases of solid malignancies (prostate and melanoma), as well as failure to mobilize stem cells in 4 of 6 patients. 

In view of the above data, the consensus panel on therapeutics amended its original recommendations for the therapy of WM to include the use of combination therapy with either nucleoside analogues and alkylator agents, or rituximab in combination with nucleoside analogues, nucleoside analogues plus alkylator agents, or cyclophosphamide based therapy as reasonable therapeutics options for the treatment of WM.107,108

SALVAGE THERAPY INCLUDING NOVEL AGENTS

For patients in relapse or who have refractory disease, the consensus panels recommended the use of an alternative first-line agent as defined above, with the caveat that for those patients for whom autologous transplantation was being seriously considered, further exposure to stem-cell damaging agents (i.e. many alkylator agents and nucleoside analogue drugs) should be avoided, and a non-stem-cell toxic agent such as should be considered if stem cells had not previously been harvested.107,108 Recent studies have also demonstrated activity for several novel agents including bortezomib, thalidomide alone or in combination, alemtuzumab and can be considered in the treatment of relapsed/refractory WM. Lastly, autologous stem cell transplant remains an option for the salvage therapy of WM particularly among younger patients who have had multiple relapses, or have primary refractory disease.

Proteosome inhibitor

Bortezomib, a stem cell sparing agent155-157, is a proteasome inhibitor which induces apoptosis of primary WM lymphoplasmacytic cells, as well as the WM-WSU WM cell line at pharmacologically achievable levels158.  Moreover, bortezomib may also impact on bone marrow microenvironmental support for lymphoplasmacytic cells. In a multi-center study of the Waldenstrom’s Macroglobulinemia Clinical Trials Group (WMCTG)159, 27 patients received up to 8 cycles of bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11. All but one patient had relapsed/or refractory disease. Following therapy, median serum IgM levels declined from 4,660 mg/dL to 2,092 mg/dL (p<0.0001). The overall response rate was 85%, with 10 and 13 patients achieving a minor (<25% decrease in IgM) and major (<50% decrease in IgM) response. Responses were prompt, and occurred at median of 1.4 months. The median time to progression for all responding patients in this study was 7.9 (range 3-21.4+) months, and the most common grade III/IV toxicities occurring in > 5% of patients were sensory neuropathies (22.2%); leukopenia (18.5%); neutropenia (14.8%); dizziness (11.1%); and thrombocytopenia (7.4%). Importantly, sensory neuropathies resolved or improved in nearly all patients following cessation of therapy. As part of an NCI-Canada study, Chen et al160 treated 27 patients with both untreated (44%) and previously treated (56%) disease. Patients in this study received bortezomib utilizing the standard schedule until they either demonstrated progressive disease, or 2 cycles beyond a complete response or stable disease. The overall response rate in this study was 78%, with major responses observed in 44% of patients. Sensory neuropathy occurred in 20 pts, 5 with grade >3, and occurred following 2-4 cycles of therapy. Among the 20 patients developing a neuropathy, 14 patients resolved and one patient demonstrated a one-grade improvement at 2-13 months. In addition to the above experiences with bortezomib monotherapy in WM, Dimopoulos et al161 observed major responses in 6 of 10 (60%) previously treated WM patients, while Goy et al162 observed a major response in 1 of 2 WM patients who were included in a series of relapsed or refractory patients with non-Hodgkin’s lymphoma (NHL). In view of the single agent activity of bortezomib in WM, Treon et al163 have examined the combination of bortezomib, dexamethasone and rituximab (BDR) as primary therapy in patients with WM. An overall response rate of 96%, and a major response rate of 83% were observed with the BDR combination. The incidence of grade 3 neuropathy was about 30% in this study, but was reversible in most patients following discontinuation of therapy. An increased incidence of herpes zoster was also observed prompting the prophylactic use of antiviral therapy with BDR. Alternative schedules for administration of bortezomib (i.e. once weekly at higher doses) in combination with rituximab are also being examined by Ghobrial et al164 and Agathocleous et al165 in patients with WM with overall response rates of 80-90%. The impact of these schedules on the development of bortezomib related peripheral neuropathy remains to be clarified, though in one study appeared diminished.164

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