Sections

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.^[5]Patients can be observed carefully with periodic measurement of the M component, immunoglobulin, and serum viscosity.

Clinical indications for initiation of therapy include the following^[30]:

Recurrent fever, night sweats, weight loss, fatigue
Hyperviscosity
Lymphadenopathy, symptomatic or bulky (≥5 cm in maximum diameter)
Symptomatic hepatomegaly and/or splenomegaly
Symptomatic organomegaly and/or organ or tissue infiltration
Peripheral neuropathy from WM

Laboratory indications for initiation of therapy include the following^[30]:

Symptomatic cryoglobulinemia
Symptomatic cold agglutinin anemia
Autoimmune hemolytic anemia and/or thrombocytopenia
WM-related nephropathy
WM-related amyloidosis
Hemoglobin ≤10 g/dL
Platelet count < 100 × 10 ⁹/L

For patients with clinical or laboratory indications for treatment, the major classes of effective agents include the following^[4]:

Monoclonal antibodies (eg, rituximab)
Alkylating agents
Purine nucleoside analogs
Proteasome inhibitors
Immunomodulatory drugs
Mechanistic (mammalian) target of rapamycin (mTOR) inhibitors
Bruton’s tyrosine kinase (BTK) 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^[4]:

Hemoglobin < 11 g/dL or 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 tolerated initial treatment well and achieved a durable response (3 years or longer) with it can be retreated with the original regimen. For relapse after shorter responses, mSMART consensus recommendations are as follows^[4]:

Ibrutinib monotherapy, for patients with MYD88 mutation (irrespective of CXCR4 mutation) in their first or second relapse
A bortezomib-based combination (eg, bortezomib-dexamethasone-rituximab), if underlying peripheral neuropathy, if present, is grade 2 or less
Everolimus or purine analogs, in select patients with refractory or multiply relapsed disease
Dexamethasone-rituximab-cyclophosphamide
Bendamustine + rituximab

The US Food and Drug Administration (FDA) has approved an expanded indication for ibrutinib in WM beyond its use as a monotherapy to include combination use with rituximab.^[31] In 2021, the FDA approved another BTK inhibitor, zanubrutinib (Brukinsa), for the treatment of adult patients with WM.^[32]

Autologous stem cell transplantation should be considered at the first or second relapse in select patients with chemosensitive disease, especially if the first remission duration is short (< 2 years). Transplantation should not be offered to patients with refractory WM.^[4]

Treatment recommendations from the 10th International Workshop on Waldenström Macroglobulinemia are as follows^[33]:

Alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib, zanubrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients. MYD88 and L265P mutation testing should be performed before selection of ibrutinib.
In previously treated patients who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options.
Novel BTK inhibitors (acalabrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging treatment options.
The choice of therapy should be guided by the patient’s clinical profile, genomic features, and drug availability
Autologous stem cell transplantation may be considered following second or subsequent relapses despite treatment with chemoimmunotherapy and BTK inhibitors, in high-risk patients with chemosensitive disease.

In addition, clinical trials are currently exploring the following for treatment of WM^[33]:

Proteasome inhibitors - Ixazomib, dexamethasone, and rituximab
BTK inhibitors - Tirabrutinib; second generation, non-covalent BTK inhibitors (eg, vecabrutinib, LOXO-305) are being investigated for use in WM refractory to ibrutinib
The anti-CD38 monoclonal antibody daratumumab ^[34]

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.^[35]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).

Pharmacologic Therapy

Front-line therapy for Waldenström macroglobulinemia (WM) 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.^[29]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.^[36]

Ibrutinib

In 2015, ibrutinib (Imbruvica) became the first drug approved by the US Food and Drug Administration (FDA) for treatment of WM.^[37]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 was based on results of a multicenter phase II study in which 63 patients with previously treated WM 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) had not been reached, with a range of 2.8+ to 18.8+ months.^[38]

Long-term follow-up of patients in that study (median, 59 months) showed overall and major response rates of 90.5% and 79.4%, respectively. MYD88 and CXCR4 mutation status affected response rates: In patients with mutated MYD88, those with wild-type (WT) CXCR4 had a 97.2% major response rate, compared with a 68.2% rate in those with mutated CXCR4 status; in contrast, four patients who had WT MYD88 disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% for those with mutated MYD88 and WTCXCR4^WT and 38% for those with both MYD88and CXCR4 mutations.^[39]

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%).^[7]

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.^[40]

A prospective study by Treon et al of ibrutinib as primary therapy in 30 symptomatic patients with untreated WM 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).^[41]

In 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 WM. 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).^[31]

In the final analysis of iNNOVATE, with a median follow-up of 50 months, ibrutinib plus rituximab showed ongoing superiority across clinical outcomes in patients with WM, regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics. Median PFS was not reached with ibrutinib-rituximab, versus 20.3 months with placebo-rituximab (P< 0.0001).^[42]

Zanubrutinib

In August 2021, zanubrutinib (Brukinsa) became the second BTK inhibitor approved for Waldenström macroglobulinemia. Zanubrutinib is a novel potent BTK inhibitor that exhibits less off-target inhibition than ibrutinib.

FDA approval was based on the results of a randomized open-label phase 3 comparative study (ASPEN) with ibrutinib. Among 201 patients who were randomized 1:1 to receive either zanubrutinib or ibrutinib, 199 patients received at least 1 dose. The primary endpoint was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR). No patients achieved CR. Twenty-nine patients who received zanubrutinib achieved very good partial response (VGPR) vs 19 patients in the ibrutinib arm, which did not reach statistical significance (p = 0.09). Major response rates (MRR) were 77% and 78% for zanubrutinib and ibrutinib, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months.^[43]

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.^[44]

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).^[45]

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.^[46]The median overall^[47]survival was 73 months.

Combination chemotherapy

Combination chemotherapy approaches have been explored, with response rates of more than 75%. Combinations include the following^{[48, 49]}:

Fludarabine plus rituximab
Fludarabine plus cyclophosphamide
Cladribine plus cyclophosphamide
Cladribine plus cyclophosphamide and rituximab
Bortezomib, dexamethasone, and rituximab (BDR)
R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], 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.^[50]

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).^[51]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.^[52]

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.^[53]

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.^[54]

There has been only 1 randomized trial in patients with relapsed or refractory disease. Leblond et al^[55]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.

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^[56]:

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

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^[25]:

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^[25]

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

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.^[57]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.^[58]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.^[58]

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Media Gallery

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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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