Waldenström’s macroglobulinemia is a rare and incurable low-grade B-cell lymphoproliferative disease defined by specific genotypic subtypes that have implications for treatment response and long-term outcomes. Treatment—and there is no established standard—is mainly focused on controlling symptoms and preventing organ damage.
Ajay K. Nooka, MD, MPH
At the 2023 Debates and Didactics in Hematology and Oncology Conference, sponsored annually by Winship Cancer Institute, Ajay K. Nooka, MD, MPH, Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta, guided attendees through various approaches to managing this malignancy.1
Initial Presentation and Diagnosis
Patients at one end of the disease spectrum do not require treatment: those with IgM monoclonal gammopathy of unknown significance (MGUS) and those with smoldering Waldenström’s macroglobulinemia. IgM MGUS is determined by findings of < 3 g/dL serum IgM, < 10% marrow involvement, and no end-organ damage. Smoldering Waldenström’s macroglobulinemia is diagnosed by ≥ 3 g/dL serum IgM and/or ≥ 10% marrow involvement plus no end-organ damage.
Treatment is initiated when patients develop symptomatic Waldenström’s macroglobulinemia, which is defined as any-level serum IgM and ≥ 10% bone marrow involvement with the presence of end-organ damage related to the underlying IgM, he indicated.
A diagnosis requires the presence of IgM monoclonal gammopathy, the presence of bone marrow infiltration by lymphocytes with plasmacytic differentiation in an intertrabecular pattern, and an immunophenotype supportive of both a lymphocytic component and a plasmacytic component.
New patients should undergo a variety of laboratory tests and generally a bone marrow biopsy to identify mutations, which are informative for treatment selection. Dr. Nooka orders other tests on an individual basis, according to symptoms and/or intended treatment. In addition to the standard workup, these tests may include positron-emission tomography/computed tomography (PET/CT); neuropathy, anemia, and hepatitis panels; and an assessment for cryoglobulins.
Genotyping
Since certain mutations can be prognostic and predictive, genotyping is important in the patient with Waldenström’s macroglobulinemia. The MYD88 L265P variant is highly prevalent; it is associated with favorable overall survival and is unlikely to transform to diffuse large B-cell lymphoma. Almost one-third of patients with MYD88 mutations have somatic mutations in CXCR4, and although this may convey resistance to ibrutinib, overall survival is not impacted. TP53 mutations are generally rare but are seen in patients with CXCR4 WHIM mutations.
When to Initiate Treatment
Although observation is usually appropriate for patients with IgM MGUS and smoldering Waldenström’s macroglobulinemia, Dr. Nooka described scenarios that warrant the initiation of treatment:
- History: Fever > 101°F, drenching night sweats, weight loss, severe neuropathy, severe fatigue
- Physical Findings: Abnormal fundoscopic exam, lymphadenopathy, organomegaly, neuropathy
- Monoclonal Protein and Other Tests: Rising IgM by densitometry, hemoglobin ≤ 10 g/dL, platelets < 100 × 109/L from Waldenström’s macroglobulinemia, bulky lymph nodes, hyperviscosity
- Other Diseases and Signs: Amyloidosis, kidney impairment, cryoglobulinemia, transformation.
“If these findings can be tied to the underlying disease process, that’s a trigger for me to start treatment. You do not need a million-dollar workup,” Dr. Nooka said.
Recommended Primary Therapy
Primary therapy includes two Bruton’s tyrosine kinase (BTK)-based regimens given for an indefinite duration—ibrutinib with or without rituximab and single-agent zanubrutinib—and five fixed-duration regimens containing rituximab paired with either bendamustine, cyclophosphamide, or the proteasome inhibitors bortezomib, carfilzomib, or ixazomib, all with or without dexamethasone. The activity of these regimens is not affected by mutation status, but they are associated with certain treatment-related side effects; therefore, treatment should be individualized.
WHAT ARE CXCR4 WHIM MUTATIONS?
CXCR4 WHIM-like mutations are the second most common somatic mutations (after MYD88 L265P) in patients with Waldenström macroglobulinemia. About one-third of these patients harbor somatic mutations in the regulatory C-terminal domain of CXCR4. The location of these mutations in patients with Waldendstrom’s macroglulinemia is similar to germline mutations found in patients with WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), a congenital, rare primary immunodeficiency disorder characterized by chronic noncyclic neutropenia.
The proteasome-containing regimens have yielded comparable outcomes in clinical trials, with response rates of around 70% and median progression-free survival of more than 40 months. In a recent phase III trial, the addition of bortezomib to rituximab, cyclophosphamide, and dexamethasone was associated with a major response rate of 81% in treatment-naive patients, vs 70% in those given rituximab, cyclophosphamide, and dexamethasone, resulting in a 24-month progression-free survival of 81% vs 73%.2 Bortezomib, dexamethasone, and rituximab is listed as a preferred regimen for primary therapy by the National Comprehensive Cancer Network®, along with bendamustine plus rituximab, ibrutinib with or without rituximab, and zanubrutinib.
Ibrutinib proved to be a “game changer” in Waldenström’s macroglobulinemia, having yielded an overall response rate of 90% and a major response rate of 73% in the pivotal trial.3 By mutation status, the response rate was 100% in patients with mutated MYD88 and wild-type CXCR4 and was 86% in patients with both of these genes mutated but dropped to 60% in “double wild-type” patients. “The mutation status helps us understand which patients should be treated with a BTK inhibitor, vs fixed-duration chemotherapy, where the outcome is not affected by mutation status,” Dr. Nooka explained.
The iNNOVATE trial suggested that the addition of rituximab could boost the effect of ibrutinib.4 With the combination, 30-month progression-free survival was 82%, vs 28% with ibrutinib alone (hazard ratio [HR] = 0.20; P < .001), with benefit seen regardless of mutation status. Although the regimen was generally well tolerated, the combination was associated with more bleeding events (51% vs 21%).
Practical Considerations for Ibrutinib
Dr. Nooka described some of the practical considerations for using ibrutinib in Waldenström’s macroglobulinemia:
- Check MYD88 mutation status prior to starting ibrutinib.
- Recommend a pharmacy consult prior to treatment initiation, because of CYP3A interactions.
- Be aware of the 3% risk of major bleeding: avoid using ibrutinib in combination with warfarin; instruct the patient to avoid nonsteroidal anti-inflammatory drugs, fish oil, Seville oranges, grapefruit, and starfruit; stop the drug 3 days prior to minor surgery and 7 days prior to major surgery.
- Be aware of the 10% risk of atrial fibrillation and ~20% risk of hypertension.
- Do not stop ibrutinib unless disease progression is suspected or toxicity is unmanageable, as abrupt treatment discontinuation may trigger rapid relapse.
BTK Inhibitor–Based Therapy
The BTK inhibitor zanubrutinib has advanced the indefinite-duration approach. This drug is “a well-tolerated and viable option for front-line therapy in the right patient,” Dr. Nooka said, based on results of the ASPEN trial, which compared zanubrutinib with ibrutinib in patients with MYD88 L265P mutations.5 Although efficacy was similar by independent central review, zanubrutinib was considerably better tolerated. The incidence of atrial fibrillation or flutter, for example, was 15% with ibrutinib but 2% with zanubrutinib (P < .05).
There have been no randomized comparisons between the BTK inhibitor–based indefinite-duration regimens and the chemotherapy-based fixed-duration regimens, but an analysis of age-matched patient data has been conducted by an international team of collaborators.6 The patients, all with MYD88 mutations, were treated with bendamustine plus rituximab or single-agent ibrutinib as primary therapy for Waldenström’s macroglobulinemia. Although more patients receiving bendamustine/rituximab achieved at least a very good partial response (50% vs 33%; P = .009)—as would be expected with chemoimmunotherapy—survival was similar. At 4 years, the overall survival rate was 95% with bendamustine/rituximab and 86% with ibrutinib (P = .31), and the progression-free survival rate was 72% vs 78% (P = .015). Given the comparable outcomes with these approaches, the best treatment depends on the individual patient, stated Dr. Nooka.
Treatment of Relapsed Disease
Use of the newer highly selective BTK inhibitor pirtobrutinib could change the conventional practice of not prescribing another BTK inhibitor after patients experience disease progression on a first one. Before now, such retreatment was not shown to “recapture” previous responses to BTK inhibition, but pirtobrutinib may actually be effective in patients with prior treatment, according to the phase I/II BRUIN study.7 The use of pirtobrutinib resulted in a major response rate of 67% in patients previously treated with a BTK inhibitor; at 18 months, 57% of these patients were progression-free, and 82% were alive. Median progression-free survival was 14 months, and median overall survival was 16 months in this subset.
“There was good activity across the board, even among patients with prior BTK inhibition. Pirtobrutinib is a good regimen, very well tolerated, with impressive progression-free survival and overall survival, and it can be given to patients [whose disease is] progressing on a BTK inhibitor,” Dr. Nooka said.
Other Potential Options
The BCL2 inhibitor venetoclax may represent an additional option in this setting. In a phase II study of patients with relapsed or refractory disease, the overall response rate was 84%, with major responses achieved by 81% of patients.8 Median progression-free survival was 30 months, and at 2 years, 80% of patients were progression-free. CXCR4 mutation status did not affect response or progression-free survival. A trial evaluating the combination of venetoclax with ibrutinib, however, was stopped early because of cardiac toxicity (ClinicalTrials.gov identifier NCT04273139).
Autologous stem cell transplantation remains an option for good-performance patients, especially those with limited treatment exposure who remain chemosensitive. Although there has been no randomized controlled trial documenting benefit, a study from the European Working Group for Blood and Marrow Transplant in 163 patients treated 20 months after diagnosis found that 70% of patients achieved at least a very good partial response.9 At 5 years, 40% were progression-free, and 70% were alive, with these rates influenced by the number of lines of therapy and chemorefractoriness.
On the horizon, results appear promising for the phospholipid drug conjugate CLR 131 (iopofosine iodine-131), which exploits cancer cells’ need for lipids. In four doses over a 2-month period, CLR 131 delivers the therapeutic isotope I-131, which kills tumor cells by creating double-stranded DNA breaks, explained Dr. Nooka.
In the phase II CLOVER-1 study of six patients with Waldenström’s macroglobulinemia of various genotypes, the response rate to CLR 131 was 100%, and 83% were major responses. The ongoing mean duration of response was 335 days.10 In patients with MYD88 wild-type disease, the response rate was 100%, with 17% complete responses, and mean treatment-free remission was 18 months.
In May 2020, the U.S. Food and Drug Administration granted CLR 131 Fast Track designation for patients with relapsed or refractory Waldenström’s macroglobulinemia or lymphoplasmacytic lymphoma. “This is a good option for patients who have had one prior line of therapy that includes a BTK inhibitor,” he commented.
Summary of Recommendations
Dr. Nooka concluded by summarizing his preferred options for treatment in various settings:
- Newly Diagnosed Disease: Bendamustine/rituximab, ibrutinib/rituximab, or zanubrutinib
- First Relapse: For relapse on a covalent BTK inhibitor (ibrutinib, zanubrutinib, acalabrutinib, orelabrutinib, tirabrutinib)—bendamustine/rituximab; for relapse off therapy, after bendamustine/rituximab or other chemoimmunotherapy, or in a covalent BTK inhibitor–naive patient—bendamustine/rituximab, ibrutinib/rituximab, zanubrutinib
- Salvage Therapy: Venetoclax, pirtobrutinib, proteasome inhibitor combinations, autologous stem cell transplantation in select patients, or repeat previously used fixed-duration therapy.
DISCLOSURE: Dr. Nooka has served on advisory boards and received honoraria from Adaptive Biotechnologies, Amgen, BeyondSpring, Bristol Myers Squibb, Cellectar Biosciences, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, Oncopeptides, ONK Therapeutics, Pfizer, Sanofi, Secura Bio, and Takeda; and has received grant or research support for investigator-initiated studies from Amgen, GlaxoSmithKline, Janssen, Merck, and Takeda.
REFERENCES
2. Buske C, Dimopoulos MA, Grunenberg A, et al: Bortezomib-dexamethasone, rituximab, and cyclophosphamide as first-line treatment for Waldenström’s macroglobulinemia. J Clin Oncol 41:2607-2616, 2023.
3. Treon SP, Xu L, Hunter Z: MYD88 mutations and response to ibrutinib in Waldenström’s macroglobulinemia. N Engl J Med 373:584-586, 2015.
4. Dimopoulos MA, Tedeschi A, Trotman J, et al: Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med 378:2399-2410, 2018.
5. Tam CS, Opat S, D’Sa S, et al: A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: The ASPEN study. Blood 136:2038-2050, 2020.
6. Abeykoon JP, Kumar S, Castillo JJ, et al: Bendamustine rituximab versus ibrutinib as primary therapy for Waldenström macroglobulinemia: An international collaborative study. 2022 ASCO Annual Meeting. Abstract 7566.
7. Mato AR, Shah NN, Jurczak W, et al: Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): A phase 1/2 study. Lancet 397:892-901, 2021.
8. Castillo JJ, Allan JN, Siddiqi T, et al: Venetoclax in previously treated Waldenström macroglobulinemia. J Clin Oncol 40:63-71, 2022.
9. Kyriakou C, Canals C, Sibon D, et al: High-dose therapy and autologous stem-cell transplantation in Waldenström macroglobulinemia: The Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 28: 2227-2232, 2010.
10. Ailawadhi S, Chanan-Khan AAA, Peterson JL, et al: Treatment free remission and overall response rate results in patients with relapsed/refractory Waldenstrom’s macroglobulinemia treated with CLR 131. 2021 ASCO Annual Meeting. Abstract 7561.
