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Waldenstrom Macroglobulinemia Treatment & Management

  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Jan 15, 2016
 

Approach Considerations

Patients who meet the criteria for Waldenström macroglobulinemia (serum IgM monoclonal protein, bone marrow lymphoplasmacytic infiltration, or both) without end-organ damage are considered to have indolent disease or smoldering Waldenström macroglobulinemia. No treatment is indicated for asymptomatic disease. Patients can be observed carefully with periodic measurement of the M component, immunoglobulin, and serum viscosity.

Indications for initiating active treatment include clinical evidence of adverse effects of the paraprotein (hyperviscosity with neurologic or ocular disturbance, peripheral neuropathy, amyloidosis, symptomatic cryoglobulinemia, cytopenias), disease progression (including progressive anemia), or development of constitutional symptoms.

Therapeutic intervention of Waldenström macroglobulinemia can be divided into treatment of IgM paraprotein complications and treatment of the disease per se. Current therapies include the use of the following[16] :

  • Plasmapheresis (for patients with symptomatic hyperviscosity)
  • Ibrutinib (BKT inhibitor)
  • Rituximab (anti-CD20 antibody)
  • Purine nucleoside analogues
  • Alkylating agents
  • Thalidomide
  • Bortezomib
  • Everolimus
  • Alemtuzumab
  • Interferon alfa
  • Combination therapies
  • High-dose chemotherapy
  • Bone marrow transplantation

Except for patients requiring emergency treatment of hyperviscosity syndrome, most patients can be treated as outpatients. Periodic physical examinations for organomegaly, routine chemistry evaluations, serum paraprotein level, serum viscosity, and coagulation tests should be performed to monitor for progression and to aid in treatment decisions. Patients requiring emergency plasmapheresis should be transferred to a center that offers this therapy.

Treatment recommendations from the International Workshops on Waldenström Macroglobulinemia are as follows[17] :

  • Treatment should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, neuropathy)
  • Combinations of rituximab with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provide durable responses and are indicated for most patients
  • New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options
  • Selection of a different regimen is typically recommended for relapsed or refractory disease, although reuse of a prior effective regimen may be appropriate in selected patients with relapsed disease after long-lasting remission
  • Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features

See also Waldenstrom Macroglobulinemia Treatment Protocols.

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Emergent Treatment

Hyperviscosity syndrome manifestations should be treated promptly, and emergent care is paramount. The treatment of choice for symptoms related to hyperviscosity is urgent plasmapheresis.[18] The principle behind management is that 80% of all IgM is confined to the intravascular space. Most often, half of the volume or more should be removed to significantly lower the serum viscosity.

Viscosity should be measured before and after plasmapheresis. Approximately 2-4U of plasma must be removed every 1-2 weeks because the effects produced are not permanent and plasma is replaced with albumin and saline.

Chemotherapy should be considered soon after stabilization to reduce the production of the paraprotein by the malignant lymphocytes.

Macroglobulinemia can cause complications similar to peripheral neuropathy; cryoglobulinemia or amyloidosis can occur in the absence of high IgM concentrations and manifestations of the lymphomatous process. These symptoms largely result from certain physicochemical properties of the monoclonal IgM protein and can be treated by repeated plasmapheresis followed by systemic therapy. However, evidence supporting plasma exchange for the treatment of peripheral neuropathy associated with IgM paraprotein is weak (grade of recommendation C).

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Pharmacologic Therapy

Front line therapy consists of alkylator agents, nucleoside analogues,[19] monoclonal antibody, and combination therapy. Currently, no randomized data determine the best option. Therapy is decided based on patient age, performance status, aggressiveness of disease, and paraprotein manifestations.

Ibrutinib

In January 2015, ibrutinib (Imbruvica) became the first drug approved by the US Food and Drug Administration (FDA) for treatment of Waldenström macroglobulinemia. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor; it forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The approval is based on results of a multicenter phase II study in which 63 patients with previously treated Waldenström macroglobulinemia demonstrated a response rate of 62% (very good partial responses of 11% and partial responses of 51%). These responses were maintained and the median duration of response (DOR) has not been reached, with a range of 2.8+ to 18.8+ months.[20]

Rituximab

Rituximab, an anti-CD20 monoclonal antibody, produces response rates of 20-50% irrespective of prior exposure to chemotherapy. Response to rituximab may be affected by polymorphisms in the Fc-gamma RIIIA (CD16) receptor gene.[14] Time to response is slow and exceeds 3 months on average. The flare phenomenon (abrupt increase of IgM paraprotein level) has been described, which may result in hyperviscosity syndrome and indication for plasmapheresis.[21]

Fludarabine and cladribine

The purine nucleoside analogues fludarabine and cladribine have demonstrated activity against Waldenström macroglobulinemia. They are effective therapy for patients who are primarily resistant or who relapse after alkylating agents.

Dhodapkar et al, in a study evaluating fludarabine response in previously untreated and previously treated patients, reported an overall response rate of 36%, with 3% of patients experiencing complete remission; the overall survival period was 84 months. Fludarabine has also demonstrated activity for patients resistant to cladribine.[22]

A phase III study of chlorambucil versus fludarabine as initial therapy is ongoing. Results from this trial will help to determine the best initial therapeutic approach and management of Waldenström macroglobulinemia.[23]

Cladribine is also used as initial therapy, and it provides excellent response rates with minimal treatment. The MD Anderson Cancer Center published data from 90 patients treated with either cladribine alone or in combination with prednisone, cyclophosphamide, or rituximab. The overall response was 94% for cladribine alone, 60% for cladribine and prednisone, 84% for cladribine and cyclophosphamide, and 94% for cladribine, cyclophosphamide, and rituximab.[24] The median overall survival was 73 months.

Chlorambucil

Single-agent alkylating drug therapy has been traditionally used for over 40 years. Oral chlorambucil with or without prednisone is frequently used as initial therapy for Waldenström macroglobulinemia, especially in elderly patients. The response rate is approximately 60%, and the median survival is 60 months. Kyle et al conducted a prospective study comparing daily with intermittent oral chlorambucil, and demonstrated no significant difference in response rate or survival.[25] The optimal duration of treatment is unknown.

Cyclophosphamide

Cyclophosphamide, alone or in combination, is also effective, but no comparative data with chlorambucil exist.

Combination chemotherapy

Combination chemotherapy approaches have been explored, with response rates of more than 75%. Combinations include fludarabine plus rituximab, fludarabine plus cyclophosphamide, cladribine plus cyclophosphamide, cladribine plus cyclophosphamide and rituximab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).[26, 27] The German Low Grade Lymphoma Study Group reported response rates of 69% and 94%, respectively, in 72 patients treated with either CHOP or R-CHOP.[28]

Salvage therapy

Salvage therapy for patients with resistant disease or relapse includes the reuse or alternative use of front-line agent, combination therapy, thalidomide (with or without steroids), bortezomib, everolimus, alemtuzumab, and stem cell transplantation.

Thalidomide

Thalidomide has demonstrated activity against Waldenström macroglobulinemia. Coleman et al, reporting on the use of clarithromycin, thalidomide, and dexamethasone in 12 patients previously treated with a purine analogue or alkylating agent, found that 10 patients responded (3 near-complete, 3 major, and 4 partial responses).[29] This combination can be useful in heavily pretreated patients.

Bortezomib

Ghobrial et al treated 37 patients with relapsed/refractory Waldenstrom macroglobulinemia with weekly bortezomib and rituximab. A minimal response or better was observed in 81% of patients treated, with 2 patients (5%) obtaining a complete remission/near–complete remission, 17 patients (46%) obtaining a partial response, and 11 patients (30%) obtaining a minor response. The median time to progression was 16.4 months.[30]

Everolimus

Ghobrial et al also studied the mTOR inhibitor everolimus in patients with relapsed/refractory Waldenström macroglobulinemia. Fifty patients were treated. The overall response rate (complete response plus partial remission plus minimal response) was 70%, with a partial response of 42% and minimal response of 28%. The median duration of response and median progression-free survival had not been reached at the time of the publication. The estimated progression-free survival at 6 and 12 months were 75% and 62%, respectively. Grade 3 or higher related toxicities were observed in 56% of patients. The most common were hematologic toxicities with cytopenias. Pulmonary toxicity occurred in 10% of patients.[31]

Alemtuzumab

A study by Treon et al determined that alemtuzumab is an active therapy, but short-term and long-term toxicities need to be weighed against other options. Late-onset autoimmune thrombocytopenia is a complication of alemtuzumab.[32]

There has been only 1 randomized trial in patients with relapsed or refractory disease. Leblond et al[33] found better patient response to fludarabine than to the combination of cyclophosphamide, doxorubicin, and prednisone (CAP), in a study of 92 patients with Waldenström macroglobulinemia who had previously received alkylating agent ̶ based therapy. Partial responses were seen in 30% of patients receiving fludarabine, compared with 11% of those receiving CAP. Responses were more durable in patients receiving fludarabine when compared with CAP (19 mo vs 3 mo, respectively). However, there was no difference in overall survival between the 2 patient groups.

Stem cell transplantation

High-dose chemotherapy with autologous peripheral blood cell transplantation is reserved for selected younger patients with primary refractory or relapsed disease. In a study of 6 patients who received autologous transplant, Desikan et al reported that long-term control can be achieved even in patients with refractory disease.[34] Reduced-intensity allogeneic stem cell transplantion may be an option in very select patients.

Additional therapeutic agents

Other agents are under investigation to evaluate their efficacy and tolerability. Interferon alpha, administered for 6 months in untreated and pretreated patients, showed a response rate of 50%, with a median duration of response of 27 months.

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Treatment Response Classification

The effectiveness of chemotherapy is monitored with serum monoclonal IgM concentration on protein electrophoresis, along with evaluation for signs or symptoms of active disease. Response criteria from the Third International Workshop on Waldenström's Macroglobulinemia include the following[35] :

  • Complete response - Disappearance of monoclonal protein by serum electrophoresis, no histologic evidence of bone marrow involvement, resolution of any adenopathy/organomegaly, or signs no symptoms attributable to Waldenström macroglobulinemia
  • Partial response - At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly; no new symptoms or signs of active disease
  • Minor response - At least 25%, but less than 50%, reduction of serum monoclonal IgM by protein electrophoresis; no new symptoms or signs of active disease
  • Stable disease - A less than 25% reduction and a less than 25% increase of serum monoclonal IgM by electrophoresis, without progression of adenopathy/organomegaly, cytopenias, or clinically significant symptoms due to disease and/or signs of Waldenström macroglobulinemia
  • Progressive disease - At least 25% increase in serum monoclonal IgM by protein electrophoresis, confirmed by second measurement or progression of clinically significant findings due to disease or symptoms attributable to Waldenström macroglobulinemia
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Contributor Information and Disclosures
Author

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Coauthor(s)

Doris Ponce, MD Fellow, Department of Hematology/Oncology, New York Medical College

Doris Ponce, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chief Editor

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.

Acknowledgements

Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center

Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Koyamangalath Krishnan, MD, FRCP, FACP Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Vijay Ramu, MBBS Staff Physician, Department of Internal Medicine, East Tennessee State University

Vijay Ramu, MBBS is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Harsha Vyas, MD Fellow, Section of Hematology and Oncology, Wake Forest University School of Medicine

Harsha Vyas, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.

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Purpura from Waldenström macroglobulinemia is evident in the forearm of a 65-year-old man who presented with a purpuric rash on all of his extremities. Although the patient had a history of hepatitis C, the possibility of hepatitis C cryoglobulinemia was excluded because the rash extended well beyond the hands and feet, and blood testing identified a type I cryoglobulinemia. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
 
 
 
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