Overview
Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells and immunoglobulin M (IgM) monoclonal gammopathy.1 This condition is defined as “lymphoplasmacytic lymphoma” (LPL) by the Revised European-American Lymphoma and WHO classification systems.2,3 WM is a rare disorder with approximately 1,000 to 1,500 new cases diagnosed annually in the United States.4
Literature Search Criteria and Guidelines Update Methodology
Prior to the update of this version of the NCCN Clinical Practice Guidelines (NCCN Guidelines) for WM, an electronic search of the PubMed database was performed to obtain key literature in WM/LPL using the following search terms: Waldenström macroglobulinemia OR lymphoplasmacytic lymphoma. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.5
The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Practice Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies.
The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the NCCN Guidelines update have been included in this version of the discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.
The complete details of the development and updates of the NCCN Guidelines are available at NCCN.org.
Diagnosis
Key to the diagnosis of WM/LPL is the demonstration of bone marrow infiltration by a lymphoplasmacytic cell population manifested by small lymphocytes with evidence of plasmacytoid/plasma cell differentiation. The bone marrow infiltration should be supported by immunophenotypic studies (flow cytometry and/or immunohistochemistry) showing the following profile: sIgM+, CD19+, CD20+, CD22+.1 According to the current WHO classification, the lymphocytes in WM are typically negative for CD5, CD10, and CD23.6 However, this should not exclude diagnosis because exceptions occur and approximately 10%–20% of cases may express CD5, CD10, or CD23.7,8 MYD88 (L265P) mutations are present in greater than 90% of patients with WM,9 and can help differentiate WM/LPL from IgM myeloma or marginal zone lymphoma.
Workup
Essential Tests
History and physical examination are essential components of initial evaluation. The essential laboratory studies include CBC with differential, peripheral blood smear examination, and comprehensive metabolic panel (CMP). CMP includes serum blood urea nitrogen/creatinine, electrolytes, albumin, calcium, and liver function tests to assess kidney and liver function.10
To establish the diagnosis of WM, it is necessary to demonstrate IgM monoclonal protein in the serum and histologic evidence of lymphoplasmacytic cells in the bone marrow.1 Serum protein electrophoresis, serum quantitative immunoglobulins, and serum immunofixation electrophoresis are used to identify and quantify the M-protein (IgM). Although detection of a monoclonal IgM protein in the serum is a diagnostic criterion for WM, this monoclonal IgM may be found clinically either in the setting of clinical WM, IgM monoclonal gammopathy of undetermined significance (IgM MGUS), or IgM multiple myeloma. It is important to make this distinction during diagnosis. Approximately 5% of patients with LPL can secrete non-IgM paraproteins (eg, IgG, IgA, kappa, lambda) or be nonsecretory and should be managed like WM.
The International Prognostic Scoring System for WM (IPSSWM) is useful for prognostication of WM at first-line treatment initiation.11,12 Its value in making treatment-related decisions remains to be clarified.11
Bone marrow is almost always involved in WM; therefore, a unilateral bone marrow aspirate and biopsy should be performed to document clonal lymphoplasmacytic cell population and confirmed by immunohistochemistry and/or flow cytometry.1,6 Multiparametric flow cytometry may provide additional data on the immunophenotypic characterization of WM.13
The bone marrow aspirate should be tested for MYD88 (L265P) mutation. Whole genome sequencing of bone marrow LPL cells has identified MYD88 (L265P) as a commonly recurring mutation in patients with WM.9,14,15 Absence of MYD88 mutations should not be used to exclude diagnosis of WM if other criteria are met.16 The NCCN Panel recommends allele-specific PCR for MYD88 (L265P) detection.
CT scans of the chest, abdomen, and pelvis with intravenous contrast and/or PET-CT at diagnosis are useful to properly stage the patient and can assess adenopathy, splenomegaly, and other extramedullary disease sites.
Tests Useful Under Certain Circumstances
IgM is a pentamer and a common cause of hyperviscosity. Therefore, evaluation for characteristic clinical signs and symptoms of serum viscosity should be done at diagnosis. Many patients with WM will exhibit an elevated serum viscosity level of over 1.8 centipoise. Patients typically become symptomatic at serum viscosity levels of over 4.0 centipoise. However, in some patients, lower levels of serum viscosity can cause retinal changes and hemorrhages that may necessitate intervention.17 Serum viscosity results should not be used as the sole criterion for intervention, in part due to long turnaround time and potential technical issues.
In fewer than 10% of patients with WM, monoclonal IgM may present with cold agglutinin activity, where the monoclonal IgM interact with specific red cell antigens below physiologic temperatures, producing chronic hemolytic anemia.18 The cold agglutinin titers are greater than 1:1,000 in most cases. In up to 20% of patients with WM, the monoclonal IgM may behave as a cryoglobulin (type I) but will be symptomatic in 5% or less of the cases. The presence of cold agglutinins or cryoglobulins may affect determination of IgM levels; therefore, testing for cold agglutinins and cryoglobulins should be performed at diagnosis.19
When suspected, cryocrit, a test for cryoglobulins, should be obtained. The presence of cryoglobulins may render falsely low serum IgM levels. In such situations, maintaining the serum sample in a warm bath will provide a more reliable serum IgM level measurement.20
Twenty-four–hour urine for total protein, creatinine clearance, urine protein electrophoresis, and urine immunofixation electrophoresis may be useful.
Patients with WM and peripheral neuropathy may harbor antibodies against myelin-associated glycoprotein (MAG) or other glycoproteins or lipids.19,21
Serum anti-MAG antibodies can be evaluated in patients with sensory peripheral neuropathies22; in those with motor neuropathy, antiganglioside M1 antibodies may also be evaluated. In patients with peripheral neuropathy, referral for neurologic consultation should be considered. Nerve conduction studies or electromyography may help determine if neuropathy is related to the monoclonal process or other causes.23
The median age at the time of WM diagnosis ranges from 60 to 75 years.19,24,25 Therefore, frailty assessment should be considered before treatment of older adults with WM as per NCCN Guidelines for Older Adult Oncology (available at NCCN.org).
The manifestation of neurologic deficits is ambiguous and could be the result of underlying comorbidities. If central nervous system (CNS) involvement is suspected in individuals with WM; imaging studies, cerebrospinal fluid (CSF) analysis, or tissue biopsy are needed to investigate Bing-Neel syndrome.
Asymptomatic or Minimally Symptomatic
WM may be preceded by asymptomatic disease states such as IgM MGUS or smoldering WM.26 Approximately 1.5% of patients with IgM MGUS and 12% of those with smoldering WM have disease progression to WM per year.9,27–29 The risk of disease progression is estimated using an asymptomatic risk score calculator, which takes the following diagnostic measurements into consideration: bone marrow involvement (percentage), serum IgM level (mg/dl), serum beta-2- microglobulin level (mg/dl), and serum albumin level (g/dl).3 Based on the risk score, the risk of disease progression is categorized into low risk, intermediate risk, and high risk, with a median time to progression to symptomatic disease of 9.2 years, 4.8 years, and 1.8 years, respectively. The frequency of follow-up varies based on the risk status. Follow-up includes monitoring with diagnostic testing, including CBC, CMP, serum protein electrophoresis, and serum immunoglobulins, every 12 months for low risk, every 6 months for intermediate risk, and every 3 months for high risk.
Primary Therapy Regimens for WM/LPL
According to the NCCN WM/LPL Panel, treatment should be initiated for patients with a diagnosis of WM/LPL only in those who are symptomatic. The indicative symptoms of treatment include hyperviscosity; neuropathy; symptomatic adenopathy or organomegaly; amyloidosis; cryoglobulinemia; cold agglutinin disease; anemia; B symptoms; and presence of cytopenia.11,30–32 Importantly, high IgM level per se should not be considered a criterion for initiation of therapy in the absence of other indications. The NCCN Panel notes that it is important to rule out symptoms related to comorbidities before treatment initiation and detection of cold agglutinins or cryoglobulins in the absence of symptoms does not represent a criterion to treat, whereas treatment should be considered in asymptomatic patients with serum IgM level >6,000 mg/dL.
Becaues WM is a rare disease, few randomized trials and limited data comparing different treatment approaches exist. Therefore, the treatment of WM has been primarily adopted from data derived from phase II or retrospective studies.
According to the NCCN Panel, for patients requiring immediate disease control, such as those with symptomatic hyperviscosity, initial plasmapheresis is recommended.33 After plasmapheresis, systemic treatment should be initiated as soon as possible.
Agents that limit future treatment options should be avoided during initial therapy. Exposure to continuous oral alkylator therapy or nucleoside analogues should be avoided before stem cell harvest if an autologous stem cell transplant (SCT) is being considered. Nucleoside analogues are associated with an increased risk of disease transformation, development of myelodysplastic syndromes, and secondary acute myeloid leukemia (AML).34,35 Exposure to nucleoside analogues should be limited, particularly in younger patients who may be potential SCT candidates.
The NCCN Panel recommends monitoring of serum IgG levels during therapy. Herpes zoster prophylaxis should be considered for patients receiving proteasome inhibitor-based regimens and nucleoside analogues.
Hepatitis B virus (HBV) reactivation is common in patients with hematologic malignancies. The NCCN Panel recommends screening for HBV infection by testing for hepatitis B surface antigen or antibody to hepatitis B core antigen before starting therapy with carfilzomib or anti-CD20 monoclonal antibodies. Prophylactic antiviral therapy with entecavir is recommended for those who have hepatitis B surface antigen to prevent HBV reactivation. In those with resolved HBV infection, who have antibodies to hepatitis B core antigen, the panel prefers prophylaxis with antiviral therapy. However, if there is a concurrent high-level hepatitis B surface antibody, monitoring serially for hepatitis B viral load and giving antiviral therapy as soon as HBV DNA is detectable is also an option.
All treatment options for WM/LPL are listed alphabetically in the NCCN Guidelines. The NCCN Panel has categorized WM therapy regimens as: “preferred regimens,” “other recommended regimens,” and regimens “useful under certain circumstances.” The purpose of classifying regimens is to provide guidance on treatment selection considering the relative efficacy, toxicity, and other factors that play into treatment selection, such as pre-existing comorbidities (eg, peripheral neuropathy, rituximab intolerance). The NCCN Panel members strongly encourage treatment in the context of a clinical trial when possible.
Preferred Regimens for Primary Therapy
Bendamustine/Rituximab
Rituximab, a monoclonal antibody that targets the B-lymphocyte antigen CD20, has been used successfully in the treatment of WM, because CD20 is expressed on lymphoplasmacytic cells in patients with WM. The Study Group Indolent Lymphomas (StiL) examined the activity of bendamustine plus rituximab (BR) versus cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (RCHOP) in a large, randomized, multicenter phase III trial of previously untreated patients with indolent non-Hodgkin lymphoma (NHL).36 Included in this study were 41 patients with WM/LPL, 40 of whom were available for response assessment.36 After a median follow-up of 45 months, the median progression-free survival (PFS) was significantly longer with BR treatment, 69.5 versus 28.5 months with RCHOP.37 BR was associated with a lower incidence of grade 3 or 4 neutropenia, infectious complications, and alopecia in this study. These results suggest that BR may be a preferable option to RCHOP as primary therapy for WM.37 The results of the StiL NHL-2008 MAINTAIN trial demonstrate a median PFS of 65.3 months in those receiving bendamustine and rituximab, which is consistent with the results of the StiL NHL1-2003 trial (69.5 months).38
Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered for patients receiving bendamustine/rituximab. The NCCN Panel has included bendamustine/rituximab as a preferred regimen for primary therapy.
Bortezomib/Dexamethasone/Rituximab
Bortezomib has shown excellent activity in the management of WM as a single agent,39 in combination with rituximab,40 or in combination with rituximab and dexamethasone.41,42
The study by the Waldenström Macroglobulinemia Clinical Trials Group reported an overall response rate (ORR) of 96%, including 83% of patients experiencing a partial response (PR) with the combination of intravenous bortezomib (using a twice-a-week schedule), along with rituximab and dexamethasone (BDR) in newly diagnosed patients with WM.41 With a median follow-up of 2 years, 80% of patients remained free of disease progression, including all patients experiencing a very good PR (VGPR) or better. However, grade 3 peripheral neuropathy was observed in 30% of patients. The development of peripheral neuropathy led to premature discontinuation of bortezomib in 61% of patients in this study.
In another multicenter phase II trial, the activity of BDR (using once-weekly intravenous bortezomib) was evaluated in 59 patients with newly diagnosed symptomatic WM.43 The ORR was 85% (3% complete response [CR], 7% VGPR, and 58% PR). In 11% of patients, an increase of IgM (≥25%) was observed after administration of rituximab. After 32 months of follow-up, median PFS was 42 months and 3-year overall survival (OS) was 81%. Peripheral neuropathy was observed in 46% (grade ≥3 in 7%) of patients; 8% discontinued bortezomib due to neuropathy.43
Neuropathy is a primary toxicity observed with bortezomib-based regimens. Therefore, evaluation of patients for the development of bortezomib-related peripheral or autonomic neuropathy is important. Administering bortezomib subcutaneously and once weekly reduces the risk of peripheral neuropathy. Therefore, this is the preferred method of administration. Although both weekly and twice-weekly dosing schemas of bortezomib are appropriate, the weekly schema is preferred.
The NCCN Panel has included BDR as a preferred regimen for primary therapy.
Ibrutinib With or Without Rituximab
Signaling pathways from the B-cell antigen receptor and Bruton’s tyrosine kinase (BTK) are crucial in mediating the growth and survival of B-cell malignancies, including WM.44
A phase II trial of ibrutinib monotherapy in patients with symptomatic WM (n=63) who received at least one prior treatment reported an ORR of 90% (10 with a VGPR, 36 with a PR, 11 with a minor response, none with a CR) and a median time to response of 4 weeks.45 At 5 years, the PFS and OS rates were 54% and 87%, respectively.46 CXCR4 mutations impacted adversely time to response, depth of response, and PFS duration. Treatment-related toxic effects of grade 3 or higher included neutropenia (in 16% of patients) and thrombocytopenia (in 11% of patients).46 Similar results were observed in a phase II study on 30 patients with treatment-naïve WM treated with ibrutinib, with an ORR of 100%, a VGPR rate of 30%, and 48-month PFS rate of 76%.47 Other adverse events associated with ibrutinib include bleeding and arrhythmia. The US FDA has approved ibrutinib as single-agent therapy for patients with WM until disease progression or unacceptable toxicity.
The phase III iNNOVATE trial (n=150) compared both newly diagnosed and patients with relapsed/refractory WM treated with ibrutinib/rituximab or rituximab plus placebo.48 At 30 months of follow-up, the ibrutinib/rituximab treatment showed an ORR of 95% compared with 48% in those treated with rituximab/placebo. In newly diagnosed patients, treatment with ibrutinib/rituximab demonstrated an improved PFS at 24 months (84%) compared with the rituximab arm (59%) (hazard ratio [HR], 0.34; 95% CI, 0.12–0.95).48 The rituximab-induced infusion reactions were markedly reduced in the ibrutinib/rituximab arm.49 At 50 months of follow-up, improvements in PFS were seen with ibrutinib/rituximab (median not reached) over rituximab/placebo (median PFS, 20 months), demonstrating a significant reduction in disease progression or death (HR, 0.25; 95% CI, 0.15–0.42; P<.0001). The estimated 54-month PFS rates were 68% with ibrutinib/rituximab versus 25% with rituximab/placebo. Median OS was not reached in either treatment arm (HR, 0.81; 95% CI, 0.33–1.99; P=.64). The ORR was 92% with ibrutinib/rituximab versus 44% with rituximab/placebo. CXCR4 mutations affected VGPR rates (23% vs 44%) but did not impact PFS. The most common grade 3–4 adverse events with ibrutinib/rituximab over the 5-year study period were infections (29%), atrial fibrillation (16%), hypertension (15%), neutropenia (13%), anemia (12%), and pneumonia (11%).50
The NCCN Panel has included ibrutinib with or without rituximab as a preferred regimen for primary therapy (category 1).
Zanubrutinib
Zanubrutinib is a BTK inhibitor with a higher affinity to BTK than ibrutinib. In the phase III ASPEN trial, 201 patients with treatment-naïve or relapsed/refractory WM were randomized 1:1 to receive either zanubrutinib or ibrutinib. All patients had a MYD88 (L265P) mutation and 26% had a CXCR4 mutation. No statistical difference in VGPR was seen between the zanubrutinib and ibrutinib groups (28% vs 19%; P=.09).51 The 42-month PFS rate for zanubrutinib was 78% and for ibrutinib was 70% with a HR of 0.63 (95% CI, 0.36–1.12).52 Zanubrutinib induced higher VGPR (21% vs 10%) and 42-month PFS rates (73% vs 49%) than ibrutinib in patients with CXCR4 mutations.
The ASPEN safety data comparing zanubrutinib monotherapy showed a decrease in the incidence of atrial fibrillation (4% vs 17%) and a lower incidence in most nonhematologic adverse events compared with ibrutinib. The incidence of hematologic adverse events was similar except for neutropenia, for which zanubrutinib was associated with a 2-fold likelihood of any grade (29% vs 13%) and grade ≥3 (20% vs 8%) neutropenia compared with ibrutinib. A larger proportion of patients received granulocyte colony-stimulating factor with zanubrutinib compared with ibrutinib.51
The NCCN Panel has included zanubrutinib as a preferred regimen for primary therapy (category 1).
Other Recommended Regimens for Primary Therapy
Bendamustine
Based on the durable responses seen in previously treated WM, as monotherapy in rituximab-intolerant individuals,53 bendamustine has been included as an option for primary therapy for WM.
Carfilzomib/Rituximab/Dexamethasone
A prospective phase II study studied the combination of carfilzomib/rituximab/dexamethasone in newly diagnosed symptomatic patients (n=31) with WM/LPL.54 Long-term follow-up demonstrated an ORR of 87% and a median PFS of 46 months.55 The study found that the response to this regimen was not impacted by MYD88 (L265P) mutation status. Rituximab-associated IgM flare (increase of IgM ≥25%) was observed in 23% of patients. No significant peripheral neuropathy was observed in this study. IgA and IgG depletion were commonly observed and necessitated truncation of therapy and/or intravenous immunoglobulin use in several patients.54
The NCCN Panel has included carfilzomib/rituximab/dexamethasone as a treatment option under “Other Recommended Regimens” for primary therapy (see algorithm page WM/LPL-B 2 of 4) and noted under general considerations that it can potentially cause cardiac and pulmonary toxicity, especially in older patients.
Ixazomib/Rituximab/Dexamethasone
A prospective phase II study of patients (n=26) with symptomatic WM studied the combination of ixazomib/rituximab/dexamethasone and found this regimen to be safe and effective as a primary therapy option.56 All enrolled patients had the MYD88 (L265P) mutation, and 58% had a CXCR4 mutation. The median time to response was 8 weeks. The overall, major, and VGPR rates were 96%, 77%, and 19%, respectively, and the median time to response was 8 weeks.56 The median PFS was 40 months, median duration of response was 38 months, and the median time to next treatment was 40 months. PFS, duration of response, and time to next treatment were not affected by CXCR4 mutational profile.57
The NCCN Panel has included ixazomib/rituximab/dexamethasone as a treatment option under “Other Recommended Regimens” for primary therapy (see algorithm page WM/LPL-B 2 of 4).
Rituximab
Single-agent rituximab is active in patients with WM; however, the response rates for single-agent rituximab using either standard or extended dosing vary between 25% and 45%.35,58,59 Transient increases in IgM levels (also called the IgM flare) have been reported in 40%–50% of patients after initiation of rituximab therapy.60,61 The rituximab-related IgM flare may lead to symptomatic hyperviscosity, as well as worsening of IgM-related neuropathy, cryoglobulinemia, and other IgM-related complications. These levels may persist for months and do not indicate treatment failure but may necessitate plasmapheresis to reduce IgM levels. Prophylactic plasmapheresis can be considered in patients with high IgM levels (typically 4,000 mg/dL or higher)62 before rituximab exposure to minimize the risk of symptomatic IgM flare. The risk of IgM flare may be decreased in patients receiving rituximab in combination with other agents.41 Rituximab may be reasonable for treating patients with IgM anti-MAG antibody-related neuropathies.63
Rituximab/Cyclophosphamide/Dexamethasone
In a prospective study of people with untreated WM (n=72), treatment with rituximab/cyclophosphamide/dexamethasone (R-CD) resulted in an ORR of 83% that included a 7% CR and a 67% PR. The 2-year PFS was 67% for all evaluable individuals and 80% for responders. The R-CD regimen was well-tolerated, with 9% of those experiencing grade 3 or 4 neutropenia and approximately 20% of individuals experiencing some form of toxicity related to rituximab.64 The 8-year OS rates based on the IPSSWM risk status for WM were 100%, 55%, and 27% for low-, intermediate-, and high-risk disease, respectively (P=.005).65 In a retrospective analysis of outcomes after treatment with R-CD in 50 people with untreated WM, the ORR was 96% and the median PFS was 34 months. The response rate and duration of response were independent of MYD88 mutational status.66
The NCCN Panel has included rituximab/cyclophosphamide/dexamethasone as a treatment option under “Other Recommended Regimens” for primary therapy (see algorithm page WM/LPL-B 2 of 4).
Rituximab/Cyclophosphamide/Prednisone
The use of cyclophosphamide/prednisone/rituximab (CP-R) has been shown to be analogous to the more intense cyclophosphamide-based regimens with lesser treatment-related complications.67 A single institutional retrospective study examined the outcomes of symptomatic patients with WM who received CHOP-R (n=23), cyclophosphamide/vincristine/prednisone plus rituximab (CVP-R; n=16), or CP-R (n=19). Baseline characteristics were similar for all 3 cohorts except for serum IgM levels, which were higher in patients treated with CHOP-R (P≤.015). The ORR and CR to the 3 regimens were: CHOP-R (ORR, 96%; CR, 17%); CVP-R (ORR, 88%; CR, 12%); and CP-R (ORR, 95%; CR, 0%). A higher incidence for neutropenic fever and treatment-related neuropathy were reported for CHOP-R and CVP-R versus CP-R (P<.03).67
Maintenance Therapy
Retrospective data supported PFS and OS benefits with maintenance rituximab after a rituximab-containing regimen.68,69 However, a recent phase III study in WM patients who attained PR or better after 6 cycles of bendamustine/rituximab did not show PFS or OS benefit of maintenance rituximab over observation after induction therapy.38 In the subset analysis, patients older than 65 and patients with high IPSS risk for WM may have benefited from maintenance.38
Assessment of Response to Primary Treatment
Response to therapy in WM is defined by reduction in the IgM protein. According to the updated summary of response categories from the Eleventh International Workshop on WM,70 a minor response is an IgM reduction of at least 25%; a PR is defined as a ≥50% reduction in IgM immunoglobulin; a VGPR is a ≥90% reduction in IgM immunoglobulin; and a CR is immunofixation negativity in the serum along with resolution of extramedullary disease and clearance of the bone marrow. Stable disease is defined as a <25% reduction and <25% increase of serum IgM by electrophoresis without progression of adenopathy/organomegaly, cytopenias, or clinically significant symptoms due to disease and/or signs of WM. Progressive disease is defined as a 25% increase in serum IgM by protein electrophoresis confirmed by a second measurement. The updated summary of response categories and criteria from the Eleventh International Workshop on WM,70 has been included in the NCCN Guidelines (see Table 1 on page WM/LPL-C in the algorithm).
An important concern with the use of IgM as a surrogate marker of disease is that it can fluctuate independently of tumor cell killing. Rituximab induces a spike or flare in serum IgM levels that can occur when used as monotherapy and in combination with other agents and lasts for several weeks to months.19,60,61 Conversely, bortezomib and ibrutinib can suppress IgM levels independent of killing tumor cells in certain patients.71,72 One study showed that residual IgM-producing plasma cells are spared and persist in patients treated with selective B-cell–depleting agents such as rituximab, thus potentially skewing the relative response and assessment to treatment.73 Therefore, in circumstances where the serum IgM levels appear to be out of context with the patient's clinical progress, a bone marrow biopsy should be considered to clarify the patient's underlying disease burden.
Follow-up After Primary Treatment
After primary therapy, the NCCN Panel recommends assessing the response to treatment using consensus panel criteria outlined on page WM/LPL-C.
The goal of treatment is symptom relief and reducing the risk of organ damage. When assessing responses, it is important to recognize that with some agents, responses (reduction of IgM) to initial therapies are often delayed and may result in underestimation of response.
If the primary treatment was with a fixed duration chemoimmunotherapy regimen, patients should be observed for disease progression with tests including CBC, CMP, and IgM every 3 months for 2 years, then every 4–6 months for an additional 3 years, then every 6–12 months. Without symptoms, progression based on serum IgM levels alone should not be a reason to restart treatment.
If treatment is initiated with a BTK inhibitor regimen, treatment should be continued until disease progression or unacceptable toxicity. Rapid increases in IgM levels (IgM rebound) have been observed following discontinuation of BTK inhibitors. Consider continuing therapy with the BTK inhibitor until starting the next line of therapy or monitor for IgM rebound after discontinuing BTK inhibitors.
If symptoms persist or there is no response to primary treatment, an alternate therapy may be administered. If there is disease transformation to an aggressive lymphoma, see NCCN Guidelines for B-Cell Lymphomas (available at NCCN.org).
Therapy for Previously Treated WM
Many patients inevitably experience relapse after initial therapy and require further treatment.74 According to the NCCN Guidelines, administering the same regimen used for primary treatment is reasonable as therapy for relapsed disease, especially if the regimen was well-tolerated and the patient had a prolonged response. The panel notes that caution should be used when retreating with myelosuppressive regimens due to cumulative toxicities.
For patients with remissions lasting less than 24 months or who show progressive disease/resistance to a first-line regimen, second-line treatment may include agents of a different class of drugs, either alone or in combination. In addition, it is important to avoid exposure to stem cell-damaging agents, such as an alkylator or nucleoside analogues, in patients who are candidates for autologous SCT. Regimens that are not toxic to stem cells must be offered, especially if stem cells have not previously been harvested. All regimens listed under primary treatment options are effective options for consideration in patients with previously treated WM.
Preferred Regimens for Previously Treated WM/LPL
Bendamustine/Rituximab
Bendamustine-based therapy is effective in relapsed/refractory WM because it produces high and durable response rates. A phase II study of patients with relapsed/refractory WM who received bendamustine-based therapy reported an ORR of 83.3%.53 The median PFS in patients with refractory WM/LPL was 13.2 months.53 A phase I–II study analyzed the outcome of bendamustine plus rituximab in patients with relapsed/refractory WM. Patients had previously received a median number of 2 lines of treatment (range, 1–5). The ORR reported was 80.2%.75 Another study evaluated the efficacy of BR and R-CD. Of the 160 patients, 60 received BR (43 with relapsed/refractory WM), and 100 received R-CD (50 had relapsed/refractory WM). In patients with relapsed/refractory WM, ORR with BR was 95% versus 87% with R-CD, P = 0.45; median PFS with BR was 58 versus 32 months with R-CD (2-year PFS was 66% vs 53%; P = 0.08).76
Bendamustine combined with rituximab is listed as one of the preferred options for relapsed/refractory disease and single agent bendamustine is listed under “Other Recommended Regimens” in the algorithm (see algorithm page WM/LPL-B 3 of 4).
Bortezomib/Dexamethasone/Rituximab
The use of bortezomib as therapy for relapsed disease is associated with an ORR of 60% when administered as a single agent, and of 70%–80% when in combination with rituximab39,71,72,77–79 with or without dexamethasone.80 Grade 3 peripheral neuropathy may occur in 30% of patients using the twice-a-week dosing schedule of bortezomib and in 10% of patients receiving once-a-week dosing. Bortezomib/dexamethasone/rituximab is listed as one of the preferred options for primary therapy as well as for previously treated WM/LPL.
Ibrutinib/Rituximab
Based on the results of the phase III iNNOVATE trial that included patients with relapsed/refractory WM (trial details listed under “Primary Therapy for WM/LPL,” page 5), the NCCN Panel has added it as one of the preferred regimens for therapy for previously treated WM/LPL (category 1).
Rituximab/Cyclophosphamide/Dexamethasone
A phase II study investigated symptomatic patients with WM (n=100), of whom 50 patients received at least one cycle of therapy for relapsed/refractory WM and 50 patients received at least one cycle of the same regimen for newly diagnosed WM.66 In the relapsed/refractory setting, the median PFS reported was 32 months (95% CI: 15–51) with a 2- and 4-year PFS rates of 54% and 34%, respectively.66
The NCCN Panel has included rituximab/cyclophosphamide/dexamethasone as one of the preferred regimens for therapy for previously treated WM/LPL
Zanubrutinib
Based on the phase III ASPEN trial results that included relapsed/refractory WM (trial details listed under Primary Therapy for WM/LPL), the NCCN Panel has included zanabrutinib as one of the preferred regimens for therapy for previously treated WM/LPL (category 1).
Other Recommended Regimens for Previously Treated WM/LPL
Acalabrutinib
Acalabrutinib is another BTK inhibitor that may be considered. A single-arm phase II trial analyzed the usage of acalabrutinib in 106 patients with treatment-naïve or relapsed/refractory WM. Of the total 106 enrolled, 14 patients (13%) were treatment-naïve, 41 patients (39%) had received 3 or more prior therapies, and 33 patients (31%) had refractory disease. In treatment-naïve patients, the 24-month OS was 92% and the 24-month PFS was 90%. In patients with relapsed/refractory disease, the 24-month OS was 89% and the 24-month PFS was 82%. The most common grade 3–4 adverse events were neutropenia (16%), pneumonia (7%), anemia (5%), and lower respiratory tract infection (5%).81 The NCCN Panel has included acalabrutinib as a treatment option under “Other Recommended Regimens” for previously treated WM/LPL (see algorithm page WM/LPL-B 3 of 4).
Ixazomib/Rituximab/Dexamethasone
The results of a phase I–II study involving patients (n=59) who had received a median of 2 prior therapies treated with ixazomib/rituximab/dexamethasone showed an ORR of 71% (14% VGPR, 37% PR, and 20% minor response) after 8 cycles.82 The median duration of response reported was 36 months. The PFS and OS were 56% and 88%, respectively, after a median follow-up of 24 months.82
Based on these data, the NCCN Panel has included ixazomib/rituximab/dexamethasone as a treatment option under “Other Recommended Regimens” for previously treated WM/LPL (see algorithm page WM/LPL-B 3 of 4).
Rituximab
Treatment with single-agent rituximab has been reported to produce 40%–50% response rates.58,61,83 The NCCN Panel has included single-agent rituximab as a treatment option under “Other Recommended Regimens” for previously treated WM/LPL.
Rituximab/Cyclophosphamide/Prednisone
A retrospective study examined the outcomes of patients with WM who received 3 separate rituximab-based regimens. Rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (RCHOP; n=23), rituximab/cyclophosphamide/vincristine/prednisone (RCVP; n=16), or rituximab/cyclophosphamide/prednisone (RCP; n=19).67 The results reported the following ORR and CR rates to the regimens: RCHOP (ORR, 96%; CR, 17%); RCVP (ORR 88%; CR 12%); RCP (ORR, 95%; CR, 0%). Therapy-related adverse events such as neutropenic fever and treatment-related neuropathy were higher for RCHOP and RCVP compared with RCP (P<.03).67
The NCCN Panel has included RCP as a treatment option under “Other Recommended Regimens” for previously treated WM/LPL (see algorithm page WM/LPL-B 3 of 4).
Venetoclax
Venetoclax is an oral BCL2 antagonist approved for the treatment of chronic lymphocytic leukemia and AML. BCL2 is an antiapoptotic protein that is shown to be overexpressed in primary WM cells.84 A phase II trial analyzed venetoclax monotherapy in 33 patients with previously treated WM. All patients had a MYD88 (L265P) mutation, and 17 patients (53%) had a CXCR4 mutation. At median follow-up of 33 months, the median PFS was 30 months. At time of data cutoff, the 30-month OS was 100% and the ORR was 84%. There was no difference in major response rate nor PFS on the basis of CXCR4 mutational status. The most common grade 3–4 adverse event was neutropenia (42%).85 The NCCN Panel has included venetoclax as a treatment option under “Other Recommended Regimens” for previously treated WM/LPL (see algorithm page WM/LPL-B 3 of 4).
Regimens Useful in Certain Circumstances for Previously Treated WM/LPL
Cladribine Alone or With Rituximab
Cladribine, a nucleoside analogue, has been studied alone or in combination with rituximab and found to induce good ORRs with prolonged survivals.86–88 In a phase II trial of cladribine with rituximab in 29 patients with newly diagnosed or previously treated WM, reported ORRs and CR rates were 90% and 24%, respectively. Cladribine alone or with rituximab is listed under “Useful in Certain Circumstances” for “Therapy for Previously Treated WM/LPL” (see page WM/LPL-B 3 of 4 in the algorithm).
Everolimus
Everolimus, an inhibitor of mTOR, is a potentially effective drug in treating WM, with high single-agent activity but substantial toxicity. With a different mechanism of action, it offers an alternate therapeutic strategy for patients with relapsed/refractory WM. A phase II trial of single-agent everolimus was initiated in 60 patients with relapsed or relapsed/refractory WM.89 The response rate (minor response or better) was 73% with a PR rate of 50% and a minor response rate of 23%.90 The median PFS was 21 months. Grade 3- or 4-related toxicities were reported in 67% of patients. Dose reductions due to toxicity were made in 62% of patients. The most commonly reported hematologic toxicities were cytopenias. Pulmonary toxicity was seen in 5% of patients.90 The study reported that the patients who experienced a PR responded after a median of 2 months of treatment. Everolimus is listed in the algorithm under “Useful in Certain Circumstances” for “Therapy for Previously Treated WM/LPL”.
Fludarabine Alone or With Rituximab
Like cladribine, fludarabine is a nucleoside analogue and has been studied alone or in combination with rituximab and/or cyclophosphamide in patients with newly diagnosed WM. A recent phase III trial showed that monotherapy with fludarabine was more effective than chlorambucil in terms of PFS (36.3 vs 27.1 months; P=.012), duration of response (38.3 vs 19.9 months; P<.001), and OS (not reached in the fludarabine arm vs 69.8 months [95% CI, 61.6–79.8 months; P=.014] in the chlorambucil arm).91
A prospective, multicenter trial evaluated treatment with fludarabine with rituximab in patients with WM (n=43) who had received fewer than 2 prior therapies, of whom 63% had received no prior therapy. The ORR was 95%. The reported median time to progression for all patients was 51.2 months and was longer for untreated patients (P=.017) and those experiencing at least a VGPR (P=.049). After a median follow-up of 40.3 months, 3 cases with transformation to aggressive lymphoma and 3 cases with myelodysplastic syndromes/AML were reported.92 Fludarabine used alone or in combination with rituximab is listed in the algorithm under “Useful in Certain Circumstances” for “Therapy for Previously Treated WM/LPL.”
Fludarabine/Cyclophosphamide/Rituximab
A retrospective study of patients with relapsed/refractory WM reported an ORR of 80% after treatment with fludarabine, cyclophosphamide, and rituximab (FCR), with 32.5% (n=13) of patients reaching at least a VGPR.93 Another multicenter, prospective trial used the FCR regimen for patients with WM who were previously untreated or pretreated with chemotherapy (n=43).94 Most of the participants in this study (65%) received FCR as first-line treatment, 28% had relapsed disease, and 7% had disease that was refractory to a previous line of treatment. The results showed that FCR produces rapid response rates of 79%, with high rates of CR and VGPR. There is a risk of PJP associated with FCR treatment, including late onset of PJP.95 Therefore, the NCCN Panel recommends PJP prophylaxis for those treated with the FCR regimen.
Nucleoside analogues have shown efficacy in relapsed/refractory WM/LPL either alone or in combination with rituximab.88,92,94 All cladribine- and fludarabine-containing regimens have been listed in the algorithm under “Useful in Certain Circumstances” for “Therapy for Previously Treated WM/LPL” (see page WM/LPL-B 3 of 4).
Ofatumumab
Ofatumumab is a human monoclonal antibody (immunoglobulin G1) that binds specifically to a distinct epitope encompassing both the small and large extracellular loops of the CD20 molecule.96,97 In cells expressing low levels of CD20, it induces complement-dependent cytotoxicity in vitro that is more potent compared with rituximab.74,94 Studies demonstrated that ofatumumab could be successfully administered, either as a single agent or as combination therapy with meaningful responses in patients with WM.98 According to the NCCN Panel, ofatumumab may be considered in patients who are intolerant to rituximab, either as single-agent or combination therapy. Therefore, it is listed in the algorithm under “Useful in Certain Circumstances” for “Therapy for Previously Treated WM/LPL.”
There is a risk of IgM flare with ofatumumab, as with rituximab. Therefore, similar precautions as with rituximab should be considered when using ofatumumab in those patients who show evidence of hyperviscosity or who have elevated IgM levels.
RCHOP (Rituximab/Cyclophosphamide/ Doxorubicin/Vincristine/Prednisone)
RCHOP is a stem cell–sparing regimen reported to be active in and well-tolerated by patients with WM.67,99,100 It has been reported as having at least a 90% response rate in patients with WM.67,100,101 In a randomized study involving 69 patients, most of whom had WM, the addition of rituximab to CHOP resulted in a higher ORR (94% vs 67%) and median time to progression (63 vs 22 months) in comparison with CHOP alone.100 The addition of vincristine to cyclophosphamide-containing regimens is associated with risk of neuropathy in patients with WM.41 According to the NCCN Panel, since vincristine is associated with a high risk of peripheral neuropathy in patients with WM/LPL, regimens without vincristine (eg, cyclophosphamide/dexamethasone/rituximab), may be considered if cyclophosphamide-based therapy is being considered.
Hematopoietic Cell Transplant
Hematopoietic cell transplantation (HCT) is also an option for relapsed WM in selected patients.102,103 HCT options listed in the NCCN Guidelines for WM/LPL are for high-dose therapy with autologous stem cell rescue.102,103 According to the NCCN Panel, myeloablative or nonmyeloablative allogeneic HCT may be considered,102 but in the context of a clinical trial.
Management of Bing-Neel Syndrome
Bing-Neel syndrome (BNS) is a rare manifestation of WM that results in the migration of lymphoplasmacytic cells to the CNS.104,105 Neurologic deficits concerning BNS include but are not limited to headaches, seizures, cranial nerve palsies, weakness in limbs, and atypical neuropathy. Differential diagnosis of BNS includes hyperviscosity syndrome with CNS manifestation which can present as new-onset of neurologic symptoms such as headaches, visual impairment, and nose bleeds.106 Hyperviscosity syndrome with CNS involvement can be differentiated from BNS by confirming an appropriate increase in serum IgM consistent with levels detected in those with WM, in conjunction with abnormal imaging and/or the presence of clonal B-cells in CSF or cerebral tissue.107 Diagnostic criteria and workup of BNS includes histology, CSF analysis, molecular testing, radiology, and blood analysis.106 Neuroimaging is encouraged to exclude differential diagnosis and aid in the selection of an appropriate site for biopsy.106 Two forms of CNS involvement (diffuse and tumoral) can be best evaluated after gadolinium administration and MRI.106 The diffuse form is associated with infiltration of lymphoid cells in the leptomeningeal sheath and perivascular space. This form presents as an enhancement or thickening of the meningeal sheath. Conversely, the tumoral form can be multifocal or unifocal and is found deep in the subcortical hemisphere.106 CNS lymphoma histology cannot be detected on an MRI, and thus BNS cannot be excluded in the absence of MRI findings. Diagnostic criteria for BNS include histologic biopsy of the cerebrum or meninges positive for clonal B cells with morphologic evidence of lymphoplasmacytic lymphoma. Analysis of the CSF should include cell count and differentiation, morphologic analysis, flow cytometry, and molecular testing to increase the sensitivity for detecting the presence of malignant B cells in the CSF. Analysis of CSF should be done routinely and should not precede the MRI to eliminate CSF sampling–induced meningeal enhancement.106 Immunoglobulin gene rearrangement assays can also be performed to determine clonal characteristics of a B cell population. In addition, mutations in MYD88 with an amino acid point mutation L265P have been detected in 93%–97% of individuals with WM, using highly sensitive diagnostic techniques such as allele-specific PCR.106 Definitive diagnosis of BNS includes presence of clonal B-cells in CSF or within a tissue biopsy with a typical manifestation and presentation of systemic disease. Diagnosis can be confirmed with or without leptomeningeal enhancement or masses detected with an MRI. A probable diagnosis is made with abnormal MRI findings without evidence of clonal B cells in CSF or tissue biopsy.
If a person has abnormal test results but remains asymptomatic, their treatment will continue with routine observation. If a person is symptomatic, various systemic therapy options are recommended; preferred regimens include BTK inhibitors such as ibrutinib108 and zanubrutinib. Other recommended regimens include chemotherapy agents such as bendamustine, cytarabine, fludarabine, and methotrexate. Regimens useful in certain circumstances include intrathecal methotrexate and radiotherapy. BNS is a rare and usually a late manifestation in those with WM. It can develop when a person is in remission or less typically at the beginning of disease manifestation.109 When BNS develops later in the disease, it is usually associated with a worse prognosis.106,110
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© 2024, National Comprehensive Cancer Network® (NCCN®). All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma Panel members can be found on page 19. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
