Waldenstrom Macroglobulinemia Treatment & Management

Updated: Aug 27, 2018
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

Patients who meet the diagnostic criteria for Waldenström macroglobulinemia (WM) on the basis of serum IgM monoclonal protein, bone marrow lymphoplasmacytic infiltration, or both but who do not have evidence of end-organ damage are considered to have indolent disease or smoldering Waldenström macroglobulinemia. No treatment is indicated for asymptomatic disease. [3] Patients can be observed carefully with periodic measurement of the M component, immunoglobulin, and serum viscosity.

For patients with clinical or laboratory indications for treatment, the major classes of effective agents include the following [2] :

  • Monoclonal antibodies (eg, rituximab)
  • Alkylating agents
  • Purine nucleoside analogs
  • Proteasome inhibitors
  • Immunomodulatory drugs
  • Mammalian target of rapamycin (mTOR) inhibitors

Because the paucity of high-quality data on WM treatment, Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) guidelines, issued in 2016, advocate participation in clinical trials. Outside of trials, mSMART guidelines recommend a single cycle of rituximab (with no maintenance therapy) for patients with any of the following [2] :

  • Hemoglobin < 11 g/dLor symptomatic
  • Platelet count < 120 x 10 9/L
  • IgM-related neuropathy
  • WM-associated hemolytic anemia
  • Symptomatic cryoglobulinemia

For patients with bulky disease, profound cytopenia (hemoglobin ≤ 10 g/dL, platelets < 100 x 109/L), constitutional symptoms, or hyperviscosity symptoms, mSMART guidelines recommend four to six cycles of bendamustine plus rituximab, preceded by plasmapheresis in patients with symptomatic hyperviscosity. An alternative, particularly for patients with nonbulky WM, is dexamethasone plus rituximab and cyclophosphamide. After entering remission, patients aged 70 years or younger who are potential candidates for autologous stem cell transplantation may be considered for stem cell harvest for future use.

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.

For relapsed disease, patients who achieved a durable response (3 years or longer) with initial treatment and tolerated it well can be retreated with the original regimen. The FDA approved an expanded indication for ibrutinib in WM beyond its use as a monotherapy to include combination use with rituximab. [22] In patients with relapsed or refractory disease harboring the MYD88 L265P mutation, ibrutinib is highly effective. A bortezomib-rituximab–based option is reasonable for patients with relapsed or refractory disease who do not have neuropathy.

Autologous stem cell transplantation should be considered at the first or second relapse in select patients with chemosensitive disease. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. [2]

Treatment recommendations from the International Workshops on Waldenström Macroglobulinemia are as follows [23] :

  • 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, bortezomib/dexamethasone, or ibrutinib provide durable responses and are indicated for most patients

  • New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), and mTOR inhibitors (eg, everolimus) 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

Paulus et al reported that the anti-CD38 monoclonal antibody daratumumab has in vitro and in vivo (mouse model) activity against Waldenström macroglobulinemia. The therapeutic effect was augmented by cotreatment with ibrutinib, even in ibrutinib-resistant Waldenström macroglobulinemia cell lines. [24]

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. [25] 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 monoclonal antibody, alkylating agents, nucleoside analogues, and combination therapy. Currently, no randomized data determine the best option. Therapy is decided on the basis of patient age, performance status, aggressiveness of disease, and paraprotein manifestations.

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. [21] 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 require plasmapheresis. [26]

Ibrutinib

In January 2015, ibrutinib (Imbruvica) became the first drug approved by the US Food and Drug Administration (FDA) for treatment of Waldenström macroglobulinemia. [27] 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. [28]

Single-agent ibrutinib demonstrated high efficacy in an open-label substudy of the larger iNNOVATE trial. In 31 adults with WM that was refractory to rituximab and who had received a median of four previous therapy regimens, 90% of patients had an overall response, of which 71% were major responses, after a median follow-up of 18.1 months. The estimated 18-month progression-free survival rate was 86% (95% confidence interval [CI], 66-94%) and the estimated 18-month overall survival rate was 97% (95% CI, 79-100%). [5, 6]

Response to ibrutinib is highest in patients with the MYD88 L265 mutation and wild-type CXCR4, less in patients with MYD88 L265P and the CXCR4 WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) mutation, and lowest in those with wild-type MYD88. Treon et al have reported major responses to ibrutinib in two patients in two patients with wild-type MYD88, on the basis of allele-specific polymerase chain reaction (AS-PCR) assays, in whom Sanger sequencing in tumor samples identified harbored MYD88 mutations that were not amenable to AS-PCR analysis for MYD88 L265P. [29]  

A  prospective study by Treon et al of ibrutinib as primary therapy in 30 symptomatic patients with untreated Waldenström macroglobulinemia found that ibrutinib monotherapy is highly active, produces durable responses, and is safe. In patients with wild-type CXCR4 versus those with mutated CXCR4, rates of major (94% vs 71%) and very good partial (31% vs 7%) responses were higher and time to major responses more rapid (1.8 vs 7.3 months; P = 0.01). [30]

In August 2018, the FDA approved an expanded indication for ibrutinib in WM beyond its use as a monotherapy to include combination use with rituximab. Approval is based on results from the iNNOVATE study which compared ibrutinib plus rituximab with placebo plus rituximab in 150 patients with either relapsed/refractory disease or previously untreated Waldenström's macroglobulinemia. At 30 months, PFS rate was 82% with ibrutinib-rituximab compared with 28% for placebo-rituximab (hazard ratio for progression or death, 0.20; P< 0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P< 0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P< 0.001). [22]

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. [31]

A phase III study that included 339 patients with Waldenström macroglobulinemia found that fludarabine was superior to chlorambucil.as initial therapy. Patients receiving fludarabine had significantly longer median progression-free survival than those receiving chlorambucil (37.8 versus 27.1 months, respectively; P = 0.015), and median overall survival was not reached with fludarabine but was 69.8 months with chlorambucil (P = 0.014). [32]

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. [33] The median overall [34] survival was 73 months.

Combination chemotherapy

Combination chemotherapy approaches have been explored, with response rates of more than 75%. Combinations include the following [35, 36] :

  • Fludarabine plus rituximab
  • Fludarabine plus cyclophosphamide
  • Cladribine plus cyclophosphamide
  • Cladribine plus cyclophosphamide and rituximab
  • Bortezomib, dexamethasone, and rituximab (BDR)
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)

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. [37]

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). [38] 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. [39]

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. [40]

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. [41]

There has been only 1 randomized trial in patients with relapsed or refractory disease. Leblond et al [42] 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.

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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 [43] :

  • 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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Peripheral Neuropathy Treatment

A consensus panel from the eighth International Workshop on Waldenström macroglobulinaemia (IWWM8) has proposed treatment recommendations for patients with Waldenström macroglobulinemia.The panel advised that patients with slowly progressing Waldenström macroglobulinemia and/or peripheral neuropathy do not require immediate therapy, but steady progression of neuropathy with accumulating disability should prompt action. Possible options for patients who require treatment are as follows [18] :

  • Rituximab alone
  • Dexamethasone, cyclophosphamide, and rituximab (DRC)
  • Bendamustine-rituximab (BR)
  • Carfilzomib, rituximab, dexamethasone (CARD) or purine analogue combinations
  • Ibrutinib, where available, could be considered in the setting of intolerance of chemotherapy-based therapies or failure of previous therapies

Further IWWM8 recommendations include the following [18]

  • When treatment is indicated, patients require treatment of sufficient intensity to remit both the systemic disease and the neurological component
  • Appropriate precautions should be taken in patients considered at high risk of a flare (IgM > 40 g/L), such as deferring rituximab until cycle 2 of combination chemotherapy or performing prior plasma exchange
  • Neurotoxic agents should be avoided; in particular, the vinca alkaloids have no place in the management of Waldenström macroglobulinemia, particularly in patients with peripheral neuropathy
  • Plasmapheresis, corticosteroids, and intravenous immunoglobulin (IVIg) are of little or no value in the treatment of Waldenström macroglobulinemia–associated neuropathy
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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. [44] Reduced-intensity allogeneic stem cell transplantion may be an option in very select patients.

Cornell et al evaluated long-term outcomes of allogeneic hematopoietic cell transplantation in 144 patients with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma and reported durable survival in select patients. [45] At 5 years, results were as follows:

  • Progression-free survival: 46%
  • Overall survival: 52%
  • Relapse: 24%
  • Nonrelapse mortality: 30%

Overall survival was significantly superior in patients with chemosensitive disease and better pretransplant disease status. Progression-free survival did not differ significantly in patients who received myeloablative conditioning and those who received reduced-intensity conditioning. [45]

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