Treatment Protocols
Numerous single and multi-agent chemotherapeutic approaches are used in the treatment of Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL); however, none is considered the standard of care, as 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 the following;
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Age
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Comorbidities
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Cytopenias
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Hyperviscosity
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Neuropathy
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Organ dysfunction
Initial management of asymptomatic/smoldering disease
Asymptomatic/smoldering disease is defined by the following [2] :
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Hemoglobin level > 10 g/dL
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Platelet count > 100 × 10 9/L
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Absence of IgM-mediated or tumor-related manifestations
Observation is recommended for these patients.
Initial treatment of non-bulky symptomatic disease
Signs and symptoms in patients with non-bulky WM/LPL may be IgM mediated or tumor related. IgM-mediated manifestations include the following [3] :
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Cold agglutinin hemolytic disease
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AL (light chain) amyloidosis
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IgM POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome
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Peripheral neuropathy
Consider single-agent rituximab therapy for patients with non-bulky symptomatic WM/LPL:
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Rituximab 375 mg/m 2 IV once weekly x 4 weeks
Treatment of bulky symptomatic disease
Bulky symptomatic disease is characterized by one or more of the following:
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Bulky adenopathy
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Symptomatic hepatosplenomegaly
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Cytopenias
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Hyperviscosity
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Constitutional symptoms
See Table 1, below, for common regimens that have been used and outcome data. Bendamustine/rituximab is the preferred initial therapy for most patients, while ibrutinib/rituximab is an acceptable alternative for elderly patients who cannot tolerate chemotherapy. [4] Bortezomib should be avoided in patients with baseline neuropathy. Nucleoside analogs such as fludarabine or cladribine pose a risk of stem cell damage and leukemogenesis and should not be used as initial therapy in patients who are candidates for stem cell transplantation (SCT). [5]
Table 1. Common regimens used to treat bulky symptomatic Waldenstrom macroglobulinemia (Open Table in a new window)
Regimen |
Dose/Schedule |
Study Results |
BR |
Bendamustine 90 mg/m2 IV days 1-2 Rituximab 375 mg/m2 IV day 1 Repeat 28-day cycle for 4-6 cycles |
Rummel et al [6] : 41 treatment-naive patients; ORR 95% |
DRC |
Dexamethasone 20 mg IV day 1 Rituximab 375 mg/m2 IV day 1 Cyclophosphamide 100 mg/m2 PO BID days 1-5 Repeat 21-day cycle for 6 cycles |
Kastritis et al [7] : 72 treatment-naive patients; ORR 83%, CRR 7% |
BDR |
Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 during cycle 1 followed by 1.6 mg/m2 on days 1, 7, 15, and 22 for cycles 2-5 Dexamethasone 40 mg IV weekly starting day 1 of cycle 2 Rituximab 375 mg/m2 IV weekly starting day 1 of cycle 2 5 cycles total; 21 days for cycle 1; 35 days for cycles 2-5 |
Gavriatopoulou et al [8] : 59 treatment-naive patients; ORR 85%, CRR 3% |
Rituximab |
Rituximab 375 mg/m2 IV once weekly x 4 weeks |
Gertz et al [9] : 69 treatment-naive and previously treated patients; ORR 27.5%, CRR 0% |
| Zanubrutinib | Zanubrutinib 160 mg PO BID or 320 mg PO qDay | Tam et al (ASPEN phase 3 trial) [10] : Major response rates (MRR) were 77% and 78% for zanubrutinib and ibrutinib, respectively |
Ibrutinib |
Ibrutinib 420 mg PO once daily until disease progression |
Treon et al [11] : 30 treatment-naive patients; ORR 100%, CRR 0% Treon et al [12] : 63 previously treated patients; ORR 90.5% |
Ibrutinib/rituximab |
Ibrutinib 420 mg PO once daily until disease progression Rituximab 375 mg/m2 IV once weekly during weeks 1-4 and weeks 17-20 |
Dimopoulos et al [13] : 150 treatment-naive and previously treated patients; ORR 92%, CRR 3% |
Acalabrutinib |
Acalabrutinib 100 mg PO BID until disease progression |
Owen et al [14] : 106 treatment-naive and previously treated patients; ORR 93%, CRR 0% |
Cladribine/rituximab |
Cladribine 0.1 mg/kg SC days 1-5 Rituximab 375 mg/m2 IV day 1 Repeat 28-day cycle for 4 cycles |
Laszlo et al [15] : 29 treatment-naive and previously treated patients; ORR 90%, CRR 24% |
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 |
Peinert et al [16] : 27 treatment-naive and previously treated patients; ORR 90%, CRR 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 |
Tedeschi et al [17] : 43 treatment-naive and previously treated patients; ORR 79%, CRR 11.6% |
ORR = overall response rate; CRR = complete response rate |
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Treatment of symptomatic hyperviscosity
Hyperviscosity syndrome should be suspected in patients with WM/LPL who have a serum viscosity greater than 4 units (Centipoises [cp]). [18]
Urgent plasmapheresis followed by initiation of systemic chemotherapy (see Table 1, above) is an accepted treatment approach for symptomatic hyperviscosity. Two to three exchanges are required to reduce the IgM levels by 30%-60%. Rituximab is known to precipitate a flare reaction and should either be administered after plasmapheresis or omitted from the first cycle of therapy in at-risk patients. [19]
Maintenance therapy
The role of maintenance therapy in patients with WM/LPL remains controversial, as there are no prospective trials demonstrating a benefit. However, some centers extrapolate from the data on indolent lymphoma and consider rituximab maintenance in patients who respond to a rituximab-containing induction regimen. [20]
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 was well tolerated and resulted in a durable remission (lasting > 3 years). Other salvage approaches include the following
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Carfilzomib/rituximab/dexamethasone [21] : Induction: carfilzomib 20 mg/m 2 (cycle 1 only), then 36 mg/m 2 (for cycles 2 and beyond), with dexamethasone 20 mg on days 1, 2, 8, and 9 and rituximab 375 mg/m 2 on days 2 and 9 every 21 days for six cycles. Maintenance: carfilzomib 36 mg/m 2 and dexamethasone 20 mg on days 1 and 2, rituximab 375 mg/m 2 on day 2 every 8 weeks for eight cycles
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Thalidomide/rituximab [22] : Thalidomide 200 mg/day for 2 weeks, then 400 mg for 50 weeks; rituximab 375 mg/m 2 once weekly on weeks 2 to 5 and 13 to 16
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Alemtuzumab [23] : 30 mg IV 3 times weekly for up to 12 weeks
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Autologous SCT
In addition, therapies under investigation include ixazomib, ofatumumab, venetoclax, and pembrolizumab. [24, 25]
Autologous SCT should be considered in patients with good functional status and adequate organ function who have multi-relapsed or refractory and chemosensitive disease. A multi-center study from the European Bone Marrow Transplant Registry demonstrated 5-year progression-free survival (PFS) and overall survival of 40% and 69%, respectively, for patients with predominantly multi-relapsed or refractory disease who had received autologous SCT. [26] One-year nonrelapse mortality was low at 4%; factors that impacted survival included number of previous lines of therapy and the presence of chemo-refractory disease.
When selecting initial and salvage therapies for patients who may eventually be considered for autologous SCT, 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 SCT. [27]
Allogeneic SCT has resulted in some very durable remissions, with the largest study reporting a 5-year PFS of 46% in heavily pretreated patients. [28] However, transplant-related mortality remains significant, with a 5-year nonrelapse mortality of 30%, so this approach should only be utilized in younger patients in whom standard treatment options have failed and optimally as part of a clinical trial. [29]
Questions & Answers
Overview
What is the standard of care for chemotherapy to treat Waldenstrom macroglobulinemia (WM)?
How is asymptomatic/smoldering Waldenstrom macroglobulinemia (WM) treated?
How is nonbulky symptomatic Waldenstrom macroglobulinemia treated?
How is bulky symptomatic Waldenstrom macroglobulinemia (WM) treated?
How is hyperviscosity syndrome treated in Waldenstrom macroglobulinemia (WM)?
What is the role of maintenance chemotherapy in the treatment of Waldenstrom macroglobulinemia (WM)?
What are the regimens used in salvage therapy for Waldenstrom macroglobulinemia (WM)?
Tables
Regimen |
Dose/Schedule |
Study Results |
BR |
Bendamustine 90 mg/m2 IV days 1-2 Rituximab 375 mg/m2 IV day 1 Repeat 28-day cycle for 4-6 cycles |
Rummel et al [6] : 41 treatment-naive patients; ORR 95% |
DRC |
Dexamethasone 20 mg IV day 1 Rituximab 375 mg/m2 IV day 1 Cyclophosphamide 100 mg/m2 PO BID days 1-5 Repeat 21-day cycle for 6 cycles |
Kastritis et al [7] : 72 treatment-naive patients; ORR 83%, CRR 7% |
BDR |
Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 during cycle 1 followed by 1.6 mg/m2 on days 1, 7, 15, and 22 for cycles 2-5 Dexamethasone 40 mg IV weekly starting day 1 of cycle 2 Rituximab 375 mg/m2 IV weekly starting day 1 of cycle 2 5 cycles total; 21 days for cycle 1; 35 days for cycles 2-5 |
Gavriatopoulou et al [8] : 59 treatment-naive patients; ORR 85%, CRR 3% |
Rituximab |
Rituximab 375 mg/m2 IV once weekly x 4 weeks |
Gertz et al [9] : 69 treatment-naive and previously treated patients; ORR 27.5%, CRR 0% |
| Zanubrutinib | Zanubrutinib 160 mg PO BID or 320 mg PO qDay | Tam et al (ASPEN phase 3 trial) [10] : Major response rates (MRR) were 77% and 78% for zanubrutinib and ibrutinib, respectively |
Ibrutinib |
Ibrutinib 420 mg PO once daily until disease progression |
Treon et al [11] : 30 treatment-naive patients; ORR 100%, CRR 0% Treon et al [12] : 63 previously treated patients; ORR 90.5% |
Ibrutinib/rituximab |
Ibrutinib 420 mg PO once daily until disease progression Rituximab 375 mg/m2 IV once weekly during weeks 1-4 and weeks 17-20 |
Dimopoulos et al [13] : 150 treatment-naive and previously treated patients; ORR 92%, CRR 3% |
Acalabrutinib |
Acalabrutinib 100 mg PO BID until disease progression |
Owen et al [14] : 106 treatment-naive and previously treated patients; ORR 93%, CRR 0% |
Cladribine/rituximab |
Cladribine 0.1 mg/kg SC days 1-5 Rituximab 375 mg/m2 IV day 1 Repeat 28-day cycle for 4 cycles |
Laszlo et al [15] : 29 treatment-naive and previously treated patients; ORR 90%, CRR 24% |
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 |
Peinert et al [16] : 27 treatment-naive and previously treated patients; ORR 90%, CRR 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 |
Tedeschi et al [17] : 43 treatment-naive and previously treated patients; ORR 79%, CRR 11.6% |
ORR = overall response rate; CRR = complete response rate |
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