Zanubrutinib in AL Amyloidosis Associated With Waldenström Macroglobulinemia and Other B‐Cell Non‐Hodgkin Lymphoma

Immunoglobulin amyloid light-chain (AL) amyloidosis is a rare disorder in which misfolded monoclonal light chains deposit within organs, resulting in organ damage. Although the majority of AL amyloidosis is associated with an underlying plasma cell clone, approximately 5%–7% of cases are associated with IgM M-proteinemia and/or an underlying B-cell clone, such as IgM monoclonal gammopathy of undetermined significance (MGUS), lymphoplasmacytic lymphoma (LPL), Waldenström Macroglobulinemia (WM), or Marginal Zone Lymphoma (MZL) 1, 2. IgM-associated AL (IgM-AL) amyloidosis exhibits a different clinical phenotype compared to non-IgM AL amyloidosis, including lower involved free light chain (FLC) levels 3, 4. As in all AL amyloidosis, the goal of therapy is to obtain deep FLC responses by targeting the underlying clone 3, 5. However, these types of responses are difficult to achieve, contributing to a worse prognosis 3, 5. Rituximab-bendamustine ± autologous stem cell transplantation is considered a preferred treatment option, but it is often not feasible due to age and/or amyloid-related morbidities, or may not lead to the required deep response 3, 6. This leaves a significant proportion of patients without effective treatment options. Bruton's tyrosine kinase inhibitors (BTKi) are highly effective and well tolerated in LPL/WM, especially in the presence of a MYD88L265P mutation 7, 8. Therefore, BTKi might represent a useful treatment option in IgM-AL amyloidosis. However, data of ibrutinib in 8 IgM-AL amyloidosis patients demonstrated severe (cardio)toxicity and low responses resulting in very poor outcomes 9. Zanubrutinib, a second generation BTKi, was developed to improve specificity with less off-target activity 10. In the ASPEN study, zanubrutinib was associated with deeper responses and a more favorable toxicity profile (including less cardiotoxicity) compared to ibrutinib in WM. Thus, we hypothesized that zanubrutinib may be a more effective and feasible approach for IgM-AL amyloidosis 11. Hence, we aimed to describe clinical outcomes and evaluate safety and tolerability of zanubrutinib in AL amyloidosis associated with WM or other B-cell non-Hodgkin Lymphoma (B-NHL). We performed an international retrospective study of patients with AL amyloidosis with underlying WM or other B-NHL treated with zanubrutinib. Amyloid deposition was confirmed by Congo red staining on biopsy material followed by AL typing. Eleven centers in the United Kingdom, United States, Germany, Denmark and The Netherlands were asked to report all consecutive patients who received at least 1 dose of zanubrutinib. Hematologic and organ response parameters were collected every 3 and 6 months, respectively. AL amyloidosis consensus criteria were used to assess hematologic and organ responses 12, 13. Hematologic response was assessed based on baseline difference between involved and uninvolved FLC (dFLC) above 50 mg/L with abnormal FLC-ratio. For patients with baseline dFLC below 50 mg/L, adapted FLC response criteria defined as low-dFLC partial response (PR) and/or normalization of involved FLC (iFLC; when elevated at baseline) were used 14-16. In patients where these dFLC criteria were not met, hematologic response assessment was based on M-protein levels exceeding 5 g/L 12. If this was also not feasible, the patient was considered unevaluable for hematologic response (Figure S1). Patients not eligible for hematologic response assessment were evaluated for safety and tolerability only. Safety was assessed in accordance with Common Terminology Criteria (CTCAE), version 5.0 (2017). All patients signed informed consent. Twenty-one patients treated with zanubrutinib between November 2020 and December 2024 were identified. Table 1 shows baseline characteristics, prior treatment and AEs. Bone marrow pathology showed 13 (62%) WM, 3 (14%) IgG LPL and 5 (24%) MZL. There were no cases with underlying plasma cell dyscrasia. IgM M-protein was present in 14 (67%) patients, IgG M-protein in 6 (28%) (of which 3 MZL), and light-chain only in 1 (5%) patient. Kappa isotype was present in 52% and lambda in 48% of patients. MYD88L265P was detected in 18/20 (90%) evaluable cases and CXCR4 mutations were identified in 1/5 (20%). At baseline, cardiac, renal, and liver involvement were identified in 10 (48%), 9 (43%), and 4 (19%) patients, respectively. Seven (33%) had soft tissue involvement, mainly lymphadenopathy (6/7), and 6 (29%) had peripheral neuropathy (Table 1). Of 18 (86%) evaluable patients, Mayo 2004 staging for cardiac involvement was stage I in 8 patients (44%), II in 3 (17%), IIIa in 4 (22%), and IIIb in 3 (17%). The median number of prior treatment lines for AL amyloidosis was 2 (range 0–3). Nineteen patients (90%) were previously treated for AL amyloidosis; 15 received rituximab-bendamustine and 4 had prior ibrutinib exposure. Of the two patients who received zanubrutinib as first-line for AL amyloidosis, one had not received any prior therapy, while the other had been treated with rituximab-bendamustine for WM. We summarized reasons for zanubrutinib initiation, prior lines of therapy and responses in Table S1. Reasons to switch from ibrutinib to zanubrutinib are listed in Table 1. zanu 01 (NL) 71 years, male WM (75%) MYD88—L265p CXCR4—WT Urinary tract infection (6 m),j Periodic diarrhea (15 m)i zanu 02 (NL) 80 years, male WM (20%) MYD88—L265p CXCR4—s341Hfs*2 zanu 03 (NL) 56 years, male WM (30%) MYD88—L265p CXCR4—NP zanu 04 (NL) 79 years, male WM (30%) MYD88—L265p CXCR4—NP zanu 05 (NL) 89 years, male WM (30%) MYD88—L265p CXCR4—NP Worsening heart failure (3-6 m), Renal insufficiency (6 m), Death (heart failure, 6 m)j zanu 06 (GB) 45 years, male WM (50%) MYD88—L265p CXCR4—NP zanu 07 (NL) 65 years, male WM (12.5%) MYD88—L265p CXCR4—NP zanu 08 (DE) 53 years, female WM (40%) MYD88—L265p CXCR4 – WT TP53 mutation zanu 09 (D) 80 years, female WM (29%) MYD88—NPd CXCR4—NP zanu 10b (US) 69 years, male WM (20%) MYD88—L265p CXCR4—WT zanu 11 (GB) 74 years, female WM (45%) MYD88 – L265p CXCR4—NP zanu 12 (D) 76 years, male WM (70%) MYD88—L265p CXCR4—WT zanu 13 (GB) 55 years, male WM (12.5%) MYD88—L265p CXCR4—NP zanu 14 (DE) 83 years, male IgG LPL (37.5%) MYD88—L265p CXCR4—NP zanu 15 (GB) 59 years, female IgG LPL (Unknown) MYD88—L265p CXCR4—NP zanu 16 (NL) 63 years, male IgG LPL (80%) MYD88—L265p CXCR4—NP Brady-tachy syndrome (3 m), Anemia (3 m), Death (heart failure, 3 m) zanu 17 (DE) 65 years, female MZL (NA) MYD88—L265p CXCR4—NP zanu 18 (DE) 59 years, male MZL (NA) MYD88—L273p CXCR4—NP Neutropenia (3 m), Acute hepatitis E infection (3 m)i, j zanu 19 (DE) 58 years, female MZL (40%) MYD88—L265p CXCR4—NP zanu 20 (DE) 71 years, female MZL (NA) MYD88 – negc CXCR4—NP zanu 21 (DE) 69 years, female MZL (NA) MYD88—L265p CXCR4—NP The median age was 69 years (range 45–89). Nineteen patients (90%) commenced with zanubrutinib at 320 mg daily, one at 240 mg and one at 80 mg. Zanubrutinib was combined with rituximab in one patient. The clinical course with longitudinal follow-up and hematologic response per patient are shown in Figure 1. At time of data-collection, median follow up was 14.2 months (range 2.5–43.1), calculated by reverse Kaplan–Meier (KM) method. Median time on zanubrutinib was 7.9 months (range 1.6–24.4) and in 9 (43%) patients, therapy was still ongoing. In total, 19 (90%) patients were evaluable for hematologic response as depicted in Figure S1. Of these, 11 (58%) had baseline dFLC above 50 mg/L with abnormal FLC-ratio, while the remaining 8 (42%) were assessed using the adapted criteria for low-dFLC burden. At best response, responses were observed in 8 of 19 (42%) patients, whereas the other 11 (58%) achieved no response (NR). Of the 8 responding patients, 4 (50%) achieved a very good partial response (VGPR), 1 (12.5%) a partial response (PR) and based on low-dFLC criteria 3 (38%) had normalization of iFLC of which 1 also achieved low-dFLC PR. None of the patients achieved a complete response (CR). Best achieved dFLC, iFLC, and total immunoglobulin levels are provided in Figure S2. Median time to best response was 3.0 months (range 2.1–6.7), with 4 of 8 (50%) achieving best response within 3.0 months. The median duration of response was 18.4 months (range 6.4–43.1). Table S2 summarizes best achieved WM response for patients with underlying WM 17. In 15 patients treated for at least 6 months with zanubrutinib, organ response was assessed. In 3 out of 10 (30%) patients, cardiac response was evaluable. Two achieved a response based on the cardiac biomarker NT-proBNP, while 1 had stable disease. Renal response was achieved in 2 out of 9 patients (22%). In the remaining 7 patients, renal response could not be assessed due to missing 24-h urinary protein measurements. Based on eGFR data in 7 out of 8 evaluable cases, eGFR improved in 1 patient, remained stable in 4 patients, and 2 patients had worsening of renal function. Of 3 (75%) patients evaluable for liver response based on alkaline phosphatase, 1 achieved a response, while 2 had stable disease. At time of evaluation, twelve (57%) patients had permanently stopped zanubrutinib (reasons provided in Figure 1). Three (14%) patients died while on therapy due to progression of AL amyloidosis, of which 2 related to heart failure in patients with Mayo stage II advisory board/consultancy fees from AbbVie, Novartis, BYONDIS (all to institution); K.C. has received the following: Speakers Fee: Sanofi, Advisory Board: Sanofi, Conference participation: Beigene; S.D. has received the following: BeiGene: congress support, advisory board, speaker, grant funding. Cellectar: advisory board. Sanius Health: consultant. Ouro Medicines: consultant; K.G. has received the following: BMS and Beigene: speakers bureau (no personal funding); T.H. has received the following: speaker fee from AbbVie, BMS, Beigene and J U.H. has received the following: Honorarium for talks: Janssen, Pfizer, Alnylam, Prothena, Astra Zeneca, Financial support of congress participation; Janssen, Prothena, Pfizer Advisory Boards: Pfizer, Prothena, Janssen, Alexion, Alnylam, Financial sponsoring of Amyloidosis Registry: Janssen; M.J.K. has received the following: honoraria from and consulting/advisory role for Adicet Bio, Beigene, Bristol Myers Squibb/Celgene, Kite, a Gilead Company, Miltenyi Biotec, Novartis, and Roche; travel support from Kite, a Gilead Company, BMS and Roche (all to institution); I.B.K. has received the following: Speaker fees from Johnsson and Johnsson, Beigene, Sanofi, Amgen, travel support from Johnsson and Johnsson and Beigene, advisory Board Johsson S.L. has received the following: honoraria from and consulting/advisory role for Bristol Myers Squibb/Celgene, Sanofi, Janssen, Regeneron, Pfizer and GSK; S.S. has received the following: Consultant/Adviser for and received travel grant, honoraria, and research funding from Janssen and Prothena; received honoraria from Pfizer and Takeda; and is an adviser for Telix; received travel grants from Binding Site, Celgene, and Jazz; A.W. has received the following: Consultancy/Honorarium from Alexion, Pfizer, GSK, Prothena, Attralus, Janssen. M.C.M. has received the following as institutional honoraria: Research grant Beigene, Janssen Speakers bureau Siemens, Sanofi, Janssen, Advisory Board Janssen, Hospitality Janssen, Beigene; J.M.I.V. has received the following as institutional honoraria: research support from Beigene and AbbVie/Genmab; advisory board/consultancy fees from Sanofi and Janssen; and speaker fees from BMS, Beigene, Sanofi, and Amgen; W.V., F.W., J.K., D.T., P.A.F.G., S.B.M., A.S., A.V., and P.E.W. declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1: Flowchart for assessing hematologic response in AL amyloidosis including overview of current study cohort with 21 patients. Figure S2: Best achieved dFLC, iFLC, and total IgM or IgG levels per patient with AL amyloidosis treated with zanubrutinib. Table S1: Prior therapies before zanubrutinib with best hematologic responses for AL amyloidosis and/or the underlying disease, and reason for start zanubrutinib. Table S2: Best hematologic response achieved based on AL and WM (IgM) criteria in patients with underlying WM. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.