Using Biology to Determine Type and Duration of Treatment in Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) is a non-Hodgkin lymphoma characterized by the accumulation of malignant IgM-secreting lymphoplasmacytic cells in the bone marrow and other organs.¹ The clinical features of WM are diverse and include anemia, hyperviscosity, extramedullary disease (eg, lymphadenopathy, splenomegaly, pleural effusions, kidney involvement), and peripheral neuropathy, among others (eg, amyloidosis, cryoglobulinemia, cold agglutinin disease).² In some cases, patients with WM can be asymptomatic at diagnosis and remain asymptomatic or minimally symptomatic for several years. The best course of action for asymptomatic patients is observation without intervention. A combination of bone marrow involvement and levels of serum albumin, β2-microglobulin, and IgM can be used to predict the median time to therapy initiation.³

Jorge J. Castillo, MD, clinical director of Bing Center for Waldenström Macroglobulinemia and senior physician at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, will explore the challenges of managing WM. He will present on September 30, 2022, at 11:04 am.

MYD88 and CXCR4 Mutations Are Common Recurrent Mutations in WM

From a biological perspective, recurrent somatic mutations in MYD88 and CXCR4 have been described in more than 90% and approximately 40% of patients with WM, respectively.^4,5 Most MYD88 mutations (>95%) occur in the locus 265 (L265P). More than 30 CXCR4 mutations have been described and can be nonsense or frameshift. Thus far, WM is the only malignancy associated with somatic CXCR4 mutations. Based on their genomic profile, patients with WM can be classified into 3 groups: MYD88 mutated and CXCR4 wild type, which comprises 50% to 60%; MYD88 and CXCR4 mutated, which comprises 30% to 35%; and MYD88 and CXCR4 wild type, which comprises 5% to 10% of all cases.

Patients Can Have Distinct Clinical Features Depending on Their Genomic Profile

Clinically, these 3 genomic categories are associated with distinct clinical features. Patients with MYD88/CXCR4-mutated disease present with higher burden of disease in the bone marrow, higher serum IgM levels, and higher rates of symptomatic hyperviscosity and acquired von Willebrand disease.6 On the other hand, patients with MYD88/CXCR4 wild-typedisease are more likely to present with extramedullary disease and have a higher risk of transformation to diffuse large B-cell lymphoma.⁴ Patients with MYD88/CXCR4-mutated or MYD88/CXCR4 wild-typedisease have also been associated with a shorter time from diagnosis to treatment initiation than patients with MYD88-mutated/CXCR4 wild-typedisease.^3,7

The Genomic Profile Can Help Tailor Treatment Options

The genomic profile of patients with WM can help tailor treatment options, especially when considering the use of Bruton tyrosine kinase (BTK) inhibitors. In the seminal phase 2 study that evaluated ibrutinib (Imbruvica) in patients with previously treated WM, patients with MYD88/CXCR4-mutated disease had lower rates of partial response or better (major response; 68% vs 97%, respectively) and very good partial response (VGPR; 9% vs 47%) than patients with MYD88-mutated/CXCR4 wild-typedisease.^8,9 In addition, the time to a major response was longer (4.7 vs 1.8 months), and the 5-year progression-free survival (PFS) rate was lower (38% vs 70%), suggesting a CXCR4 mutational status as a resistance mechanism to BTK inhibition. Furthermore, in patients with MYD88/CXCR4 wild-typedisease, the overall response rate was 60%, but the rates of major response and VGPR were 0%, with a median PFS of 24 months.

In a phase 2 study that included 30 patients with previously untreated WM, the 14 patients with MYD88/CXCR4-mutated disease had a longer time to response (7.3 vs 1.8 months), lower rates of major response (78% vs 94%) and VGPR (44% vs 14%), and lower 4-year PFS rates (59% vs 92%) to ibrutinib monotherapy than the 16 patients with MYD88-mutated/CXCR4 wild-type disease.^10,11 No patients with MYD88/CXCR4 wild-typedisease were enrolled in this study.

In the iNNOVATE study (NCT02165397), 150 patients with previously treated and treatment-naïve WM were randomly assigned 1:1 to ibrutinib plus rituximab (Rituxan) or placebo plus rituximab.12,13 The addition of rituximab to ibrutinib was associated with a time to response of 3 months vs 1 month, a major response rate of 77% vs 81%, a VGPR or better rate of 23% vs 44%, and a 54-month PFS rate of 63% vs 72% in patients with MYD88/CXCR4-mutated disease vs patients with MYD88-mutated/CXCR4 wild-type disease, respectively. Patients with MYD88/CXCR4 wild-typedisease had a 73% major response rate with a VGPR rate of 27% and a 54-month PFS rate of 70%, suggesting that the addition of rituximab to ibrutinib might improve outcomes in this genomic group, although a formal comparison between ibrutinib plus rituximab and ibrutinib monotherapy has not been made.

In the ASPEN study (NCT03053440), zanubrutinib (Brukinsa) was associated with a similar time to major response (3.1 vs 2.8 months, respectively) and lower rates of VGPR (18% vs 34%) in patients with MYD88/CXCR4-mutated disease vs patients with MYD88-mutated/CXCR4 wild-typedisease.¹⁴ The benefit of zanubrutinib was lower rates of atrial fibrillation, although with higher rates of neutropenia. Patients with MYD88/CXCR4 wild-typedisease had a major response rate of 50% and a VGPR rate of 27% to zanubrutinib, suggesting that novel covalent BTK inhibitors might induce deeper responses in this genomic group.15 However, one must be aware of the substantial differences in MYD88 and CXCR4 mutational status assessment techniques between these studies.

Choosing Therapy Based on Genomic Profile

Based on the previous information, BTK inhibitor monotherapy is preferred in patients with MYD88-mutated/CXCR4 wild-typedisease, whereas the addition of rituximab to ibrutinib or zanubrutinib can be considered in patients with MYD88/CXCR4-mutated disease or MYD88-mutated/CXCR4 wild-typedisease. Rituximab-containing regimens such as bendamustine (Bendeka) and rituximab or bortezomib, dexamethasone, and rituximab are safe and highly effective options in patients with WM regardless of MYD88 or CXCR4 mutational status.^16,17 The BCL2 antagonist venetoclax (Venclexta) is another option in the relapsed setting. In 32 patients treated with venetoclax monotherapy, MYD88/CXCR4-mutated disease was associated with a lower VGPR rate (12% vs 29%), but major response (76% vs 86%) and median PFS (~30 months) were similar to MYD88-mutated/CXCR4 wild-typedisease18 Rituximab monotherapy can be used in patients with WM regardless of genomic profile. However, [rituximab monotherapy] is associated with lower rates of major response (31%) and VGPR or better (5%), as well as shorter PFS (median 20 months) than chemoimmunotherapy or BTK inhibitors.¹²

Future Directions

Ongoing clinical trials are investigating triple, fixed-duration BTK inhibitor–containing regimens as well as noncovalent BTK inhibitors and immunotherapeutic agents such as the phospholipid-drug conjugate CLR 131, the anti-CD19 antibody-drug conjugate loncastuximab tesirine (Zynlonta) and chimeric antigen receptor T cells. It would be of great interest to investigate the impact of the genomic profile of patients with WM on these novel agents. Also, additional research is needed to standardize MYD88 and CXCR4 mutational testing to further optimize the applicability of genomic profile in the management of patients with WM.

References:

1. Swerdlow SH, Cook JR, Sohani AR, et al. Lymphoplasmacytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. World Health Organization; 2017:232-235.

2. Derman B, Castillo JJ, Sarosiek S, Beksac M. When a monoclonal gammopathy is not multiple myeloma. Am Soc Clin Oncol Educ Book. 2022;42:1-10. doi:10.1200/EDBK_349643

3. Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression risk stratification of asymptomatic Waldenström macroglobulinemia. J Clin Oncol. 2019;37(16):1403-1411. doi:10.1200/JCO.19.00394

4. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med. 2012;367(9):826-833. doi:10.1056/NEJMoa1200710

5. Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123(11):1637-46.doi:10.1182/blood-2013-09-525808

6. Castillo JJ, Moreno DF, Arbelaez MI, Hunter ZR, Treon SP. CXCR4 mutations affect presentation and outcomes in patients with Waldenstrom macroglobulinemia:a systematic review. Expert Rev Hematol. 2019;12(10):873-881. doi:10.1080/17474086.2019.1649132

7. Varettoni M, Zibellini S, Defrancesco I, et al. Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance. Haematologica. 2017;102(12):2077-2085. doi:10.3324/haematol.2017.172718

8. Treon SP, Meid K, Gustine J, et al. Long-Term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol. 2021;39(6):565-575. doi:10.1200/JCO.20.00555

9. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015;372(15):1430-1440. doi:10.1056/NEJMoa1501548

10. Castillo JJ, Meid K, Gustine JN, et al. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. Leukemia. 2022;36(2):532-539. doi:10.1038/s41375-021-01417-9

11. Treon SP, Gustine J, Meid K, et al. Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol. 2018;36(27):2755-2761. doi:10.1200/JCO.2018.78.6426

12. Buske C, Tedeschi A, Trotman J, et al. Ibrutinib plus rituximab versus placebo plus rituximab for Waldenström's macroglobulinemia: final analysis from the randomized phase III iNNOVATE study. J Clin Oncol. 2022;40(1):52-62. doi:10.1200/JCO.21.00838

13. Dimopoulos MA, Tedeschi A, Trotman J, et al; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström's macroglobulinemia. N Engl J Med. 2018;378(25):2399-2410. doi:10.1056/NEJMoa1802917

14.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. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844

15.Dimopoulos M, Sanz RG, Lee HP, et al. Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv. 2020;4(23):6009-6018. doi:10.1182/bloodadvances.2020003010

16.Laribi K, Poulain S, Willems L, et al. Bendamustine plus rituximab in newly-diagnosed Waldenström macroglobulinaemia patients. a study on behalf of the French Innovative Leukaemia Organization (FILO). Br J Haematol. 2019;186(1):146-149. doi:10.1111/bjh.15718

17.Castillo JJ, Gustine JN, Meid K, et al. CXCR4 mutational status does not impact outcomes in patients with Waldenström macroglobulinemia treated with proteasome inhibitors. Am J Hematol. 2020;95(4):E95-E98. doi:10.1002/ajh.25730

18.Castillo JJ, Allan JN, Siddiqi T, et al. Venetoclax in previously treated Waldenström macroglobulinemia. J Clin Oncol. 2022;40(1):63-71. doi:10.1200/JCO.21.01194