Waldenstrom Macroglobulinemia Treatment Protocols 

Updated: Jan 29, 2015
  • Author: Joseph M Tuscano, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment Protocols

Numerous single and multiagent chemotherapeutic approaches are used in the treatment of Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL); however, none is considered the "standard of care." There is a paucity of phase 3 randomized trials demonstrating a survival benefit of any one regimen over another.

Many recommendations are guided by response rates; however, some responses are more durable than others and may not predict outcome. The prognostic scoring system developed by Morel et al (2009) [1] can help to predict outcome, particularly in patients considered to have high-risk disease. Nonetheless, no prospective studies have defined an optimal regimen in any patient with WM/LPL, including high-risk patients. Many factors must be considered when deciding the best treatment approach for a given patient, including age, comorbid conditions, cytopenias, hyperviscosity, neuropathy, and organ dysfunction.

Initial management of asymptomatic/smoldering disease

Observation/no treatment is recommended.

Asymptomatic/smoldering disease is defined as hemoglobin level over 11 g/dL, a platelet count of more than 100 X 109/L, and an absence of neuropathy, hyperviscosity, or WM-associated hemolytic anemia or constitutional symptoms.

Initial treatment of nonbulky symptomatic disease

Consider single-agent rituximab therapy.

Nonbulky symptomatic disease is characterized by WM-associated neuropathy, anemia or cytopenias, low-volume nodal disease, and asymptomatic splenomegaly.

Treatment of bulky symptomatic disease

See Table 1 for chemotherapy regimens that have been used and outcome data. Lenalidomide may lead to abrupt declines in hematocrit in patients with WM and should be avoided. [11]

Bulky symptomatic disease is characterized by bulky adenopathy, symptomatic splenomegaly, cytopenias, hyperviscosity, neuropathy, or constitutional symptoms.

Table 1. Regimens Used to Treat Bulky Symptomatic Disease, Patient Factors, and Response Rates (Open Table in a new window)

Regimen Dose/Schedule Treatment Status Number of Patients Enrolled Overall Response Rate, %



(Complete Response Rate)



CHOP-R Cyclophosphamide 750 mg/m2 IV day 1



Doxorubicin 50 mg/m2



Vincristine 1.4 mg/m2 IV (max 2 mg) day 1



Prednisone 50 mg/m2 PO days 1-5



Rituximab 375 mg/m2 IV day 1



Primary: Repeat 21 day cycle for 6-8 cycles



Untreated 66 [2, 3] 94 (9)
Ibrutinib Ibrutinib 420 mg PO once daily until disease progression Included both untreated and previously treated patients 63 [22] 62 (0)
Rituximab Rituximab 375 mg/m2 IV once weekly x 4 weeks Included both untreated and previously treated patients 69 [4] 27.5 (0)
Fludarabine/rituximab Fludarabine 25 mg/m2 IV days 1-5



Rituximab 375 mg/m2 IV day 1



Repeat 28 day cycle for 4-6 cycles



Included both untreated and previously treated patients 27 [5] 90 (3)
FCR Fludarabine 25 mg/m2 IV days 1-3



Cyclophosphamide 250 mg/m2 IV days 1-3



Rituximab 375 mg/m2 IV day 1



Primary: Repeat 28 day cycle for 4-6 cycles



May also be given with mitoxantrone 10 mg/m2 on day 1



Included both untreated and previously treated patients 43 [6] 79 (11.6)
BR Bendamustine 90 mg/m2 IV days 1-2



Rituximab 375 mg/m2 IV day 1



Primary: Repeat 21 day cycle for 6 cycles



Untreated 41 [7] 95
BDR Bortezomib 1.3 mg/m2plus



Dexamethasone 40 mg IV days 1, 4, 8, and 11



Rituximab 375 mg/m2 IV day 11



Primary: Repeat 21 day cycle for 4 cycles



Untreated 23 [8] 96 (22)
DRC Dexamethasone 20 mg IV day 1



Rituximab 375 mg/m2 IV day 1



Cyclophosphamide 100 mg/m2 PO BID days 1-5



Primary: Repeat 21 day cycle for 6 cycles



Untreated 72 [9] 83 (7)
TR Thalidomide 50-200 mg/d PO days 1-28



Rituximab 375 mg/m2 IV once weekly during weeks 2-5 and 13-16



Primary: Repeat 28 day cycle for 12 cycles



Included both untreated and previously treated patients 25 [10] 64 (4)
CR Cladribine 0.1 mg/kg SC days 1-5



Rituximab 375 mg/m2 IV day 1



Primary: Repeat 28 day cycle for 4 cycles



Included both untreated and previously treated patients 29 [12] 89.6 (24)
BR/A Bendamustine 90 mg/m2 IV days 1-2



Rituximab 375 mg/m2 IV or ofatumumab 300 mg IV day 1 of week 1, THEN 1000 mg IV day 1 of weeks 2, 3, and 4



Ofatumumab used for rituximab-intolerant patients



Previously treated 30 [13] 83
Campath Alemtuzumab



Initial dose escalation given on consecutive days if tolerated; complete within 2 weeks before initiating therapy



Titration: 3 mg/d IV over 2 h for first dose, if tolerated, increase to 10 mg/d, then if tolerated increase to 30 mg/d



Maintenance: 30 mg IV 3 times/week (alternate days) weeks for maintenance for 6-12 weeks



Previously treated 28 [14] 36 (3)

Treatment of symptomatic hyperviscosity

Hyperviscosity syndrome should be suspected only in patients with WM/LPL who have a serum viscosity greater than 4.

Plasma exchange is an accepted treatment approach for hyperviscosity but should be considered a temporizing measure until systemic chemotherapy can be started and successfully lowers the tumor mass and the IgM level. [15]

Long-term plasma exchange is rarely required and is used only in patients who have relapsed refractory disease, in whom few systemic treatment approaches exist. Patients with WM/LPL and associated hyperviscosity may need emergent paraprotein reduction using plasmapheresis. Two to three exchanges are required to reduce the IgM levels by 30%-60%. This is absolutely necessary, particularly before starting a rituximab-containing regimen, as rituximab is known to cause a flare reaction in patients with WM-associated hyperviscosity. [16]

Maintenance therapy

The role of maintenance therapy in patients with WM/LPL remains controversial, as there are no prospective trials demonstrating a benefit. However, many centers extrapolate from the data on indolent lymphoma and consider rituximab maintenance in patients who respond to a rituximab-containing induction regimen. [17]

Salvage therapy

Many of the regimens listed above that were not used as initial therapy can be considered as a salvage approach. In addition, many centers recommend retreating with the initial regimen if it demonstrated a durable remission (lasting >2 years) that was well tolerated. Other salvage approaches include alemtuzumab (Campath), bortezomib/rituximab, everolimus, ofatumumab (see Table 1), and autologous and allogeneic transplantation.

When selecting initial and salvage therapies for patients who may eventually be considered for autologous transplant, exposure to stem cell–damaging agents such as alkylating agents and purine analogs should be avoided. Because many of the standard regimens do contain alkylating agents and purine analogs, many centers recommend either collecting stems cells early to be sequestered for a later transplant or not waiting later than the second or third chemosensitive salvage before considering autologous transplantation. [18]

While allogeneic transplantation has resulted in some very durable remissions, transplant-related mortality remains very high. [18, 19, 20] Approaches that use reduced intensity conditioning regimens appear promising, with durable remissions and reduced transplant-related mortality. [18, 21] Allogeneic transplantation has demonstrated durable remissions with much lower transplant-related mortality but should be considered only in younger patients with highly refractory disease or as part of a clinical trial.