Waldenstrom Macroglobulinemia Treatment Protocols
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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.
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.
Consider single-agent rituximab therapy.
Nonbulky symptomatic disease is characterized by WM-associated neuropathy, anemia or cytopenias, low-volume nodal disease, and asymptomatic splenomegaly. [2]
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. [3]
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
94 (9)
Ibrutinib
Ibrutinib 420 mg PO once daily until disease progression
Included both untreated and previously treated patients
63 [6]
62 (0)
Rituximab
Rituximab 375 mg/m2 IV once weekly x 4 weeks
Included both untreated and previously treated patients
69 [8]
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 [9]
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 [10]
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 [11]
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 [12]
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 [13]
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 [14]
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 [15]
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 [16]
83
Campath
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 [17]
36 (3)
Hyperviscosity syndrome should be suspected only in patients with WM/LPL who have a serum viscosity greater than 4. [18]
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. [19]
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. [20]
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. [21]
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. [22]
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. [23]
While allogeneic transplantation has resulted in some very durable remissions, transplant-related mortality remains very high. [23, 24, 25] Approaches that use reduced intensity conditioning regimens appear promising, with durable remissions and reduced transplant-related mortality. [23, 26] 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.
Morel P, Duhamel A, Gobbi P, Dimopoulos MA, Dhodapkar MV, McCoy J. International prognostic scoring system for Waldenstrom macroglobulinemia. Blood. 2009 Apr 30. 113(18):4163-70. [Medline].
Kastritis E, Dimopoulos MA. Current therapy guidelines for Waldenstrom’s macroglobulinaemia. Best Pract Res Clin Haematol. 2016 Jun. 29 (2):194-205. [Medline].
Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, et al. Lenalidomide and rituximab in Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2009 Jan 1. 15(1):355-60. [Medline].
Ioakimidis L, Patterson CJ, Hunter ZR, Soumerai JD, Manning RJ, Turnbull B. Comparative outcomes following CP-R, CVP-R, and CHOP-R in Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma. 2009 Mar. 9(1):62-6. [Medline].
Buske C, Hoster E, Dreyling M, Eimermacher H, Wandt H, Metzner B, et al. The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Leukemia. 2009 Jan. 23(1):153-61. [Medline].
Treon SP, Tripsas CK, Yang G, Cao Y, Xu L, Hunter Z, et al. A prospective multicenter study Of The Bruton’s tyrosine kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenström’s macroglobulinemia (abstract 251). Presented at the 55th American Society of Hematology Annual Meeting and Exposition. New Orleans, LA. December 7-10, 2013. [Full Text].
Dimopoulos MA, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, et al. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia. N Engl J Med. 2018 Jun 21. 378 (25):2399-2410. [Medline].
Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004 Oct. 45(10):2047-55. [Medline].
Peinert S, Tam CS, Prince HM, Scarlett J, Wolf MM, Januszewicz EH. Fludarabine based combinations are highly effective as first-line or salvage treatment in patients with Waldenström macroglobulinemia. Leuk Lymphoma. 2010 Dec. 51(12):2188-97. [Medline].
Tedeschi A, Benevolo G, Varettoni M, Battista ML, Zinzani PL, Visco C, et al. Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer. 2012 Jan 15. 118(2):434-43. [Medline].
Rummel MJ, Niederle N, von Grunhagen U. . Bendamustine plus rituximabversus CHOP plus rituximab as first-line-treatment in patients with indolentlymphomas and Waldenstro¨m’s macroglobulinemia [abstract]. The SixthInternational Workshop on Waldenstro¨m’s Macroglobulinemia.
Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009 Aug 10. 27(23):3830-5. [Medline].
Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007 Aug 1. 25(22):3344-9. [Medline].
Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, et al. Thalidomide and rituximab in Waldenstrom macroglobulinemia. Blood. 2008 Dec 1. 112(12):4452-7. [Medline]. [Full Text].
Laszlo D. Rituximab and subcutaneous 2-chloro-20-deoxyadenosine as therapy in untreated and relapsed Waldenstrom’s macroglobulinemia. Clin Lymph Myeloma Leuk. 2011. 11:133-135.
Treon SP, Hanzis C, Tripsas C, Ioakimidis L, Patterson CJ, Manning RJ. Bendamustine therapy in patients with relapsed or refractory Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011 Feb. 11(1):133-5. [Medline].
Treon SP, Soumerai JD, Hunter ZR, Patterson CJ, Ioakimidis L, Kahl B. Long-term follow-up of symptomatic patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia treated with the anti-CD52 monoclonal antibody alemtuzumab. Blood. 2011 Jul 14. 118(2):276-81. [Medline].
Castillo JJ, Garcia-Sanz R, Hatjiharissi E, Kyle RA, Leleu X, McMaster M, et al. Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia. Br J Haematol. 2016 Oct. 175 (1):77-86. [Medline]. [Full Text].
NCCN Guidelines. Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma. Version 2.2013. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf. Accessed: September 10, 2013.
Ghobrial IM, Fonseca R, Greipp PR, Blood E, Rue M, Vesole DH. Initial immunoglobulin M ‘flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an Eastern Cooperative Oncology Group Study. Cancer. 2004 Dec 1. 101(11):2593-8. [Medline].
Treon SP, Hanzis C, Manning RJ, Ioakimidis L, Patterson CJ, Hunter ZR. Maintenance Rituximab is associated with improved clinical outcome in rituximab naïve patients with Waldenstrom Macroglobulinaemia who respond to a rituximab-containing regimen. Br J Haematol. 2011 Aug. 154(3):357-62. [Medline].
Cornell RF, Bachanova V, D’Souza A, Woo-Ahn K, Martens M, et al. Allogeneic Transplantation for Relapsed Waldenström Macroglobulinemia and Lymphoplasmacytic Lymphoma. Biol Blood Marrow Transplant. 2017 Jan. 23 (1):60-66. [Medline]. [Full Text].
Gertz MA, Reeder CB, Kyle RA, Ansell SM. Stem cell transplant for Waldenström macroglobulinemia: an underutilized technique. Bone Marrow Transplant. 2011 Aug 29. [Medline].
Anagnostopoulos A, Hari PN, Pérez WS, Ballen K, Bashey A, Bredeson CN. Autologous or allogeneic stem cell transplantation in patients with Waldenstrom’s macroglobulinemia. Biol Blood Marrow Transplant. 2006 Aug. 12(8):845-54. [Medline].
Garnier A, Robin M, Larosa F, Golmard JL, Le Gouill S, Coiteux V. Allogeneic hematopoietic stem cell transplantation allows long-term complete remission and curability in high-risk Waldenström’s macroglobulinemia. Results of a retrospective analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Haematologica. 2010 Jun. 95(6):950-5. [Medline].
Kyriakou C. Autologous stem cell transplantation (ASCT) for patients with Waldenstrom’s macroglobulinaemia: an analysis of 201 cases from the European Bone Marrow Transplant Registry (EBMT). Haematologica. 2007. 92.
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
94 (9)
Ibrutinib
Ibrutinib 420 mg PO once daily until disease progression
Included both untreated and previously treated patients
63 [6]
62 (0)
Rituximab
Rituximab 375 mg/m2 IV once weekly x 4 weeks
Included both untreated and previously treated patients
69 [8]
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 [9]
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 [10]
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 [11]
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 [12]
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 [13]
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 [14]
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 [15]
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 [16]
83
Campath
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 [17]
36 (3)
Joseph M Tuscano, MD Associate Chief, Department of Hematology/Oncology/Internal Medicine, Veterans Administration Northern California System of Clinics; Professor, Department of Internal Medicine, Division of Hematology/Oncology, University of California at Davis School of Medicine
Joseph M Tuscano, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation
Disclosure: Received honoraria from Genentech for speaking and teaching.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee
Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology
Disclosure: Nothing to disclose.
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences
Disclosure: Nothing to disclose.
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