RARE DISEASE
Waldenström macroglobulinemia
Waldenström macroglobulinemia
Waldenström macroglobulinemia
Drug discovery
20
drugs
With orphan designations
Overview
Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by bone marrow infiltration of lymphoplasmacytic cells and serum IgM monoclonal protein. Over 90% of patients harbor the MYD88 L265P mutation. Clinical manifestations include anemia, thrombocytopenia, hyperviscosity syndrome, neuropathy, and organomegaly. While incurable, survival has improved with therapies targeting B-cell pathways, such as Bruton tyrosine kinase (BTK) inhibitors and CD20 monoclonal antibodies [1][4][11].
Therapies
First-line: BTK inhibitors (ibrutinib, zanubrutinib) ± rituximab; bendamustine-rituximab (BR); or proteasome inhibitors (bortezomib) [1][3][13].
Asymptomatic: Active surveillance until symptom onset [3][16].
Emerging options: CAR-T therapy, BCL2 inhibitors (venetoclax), and CXCR4-targeted agents [3][13].
Categories: rare hematological diseases, rare neoplastic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
1,264 drug discovery papers about Waldenström macroglobulinemia, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,264 drug discovery papers about Waldenström macroglobulinemia, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-10 | IgM Pleural Amyloidosis Diagnosed by Pleural Effusion Cell Block: A Case Report.
Immunoglobulin light chain (AL) amyloidosis is characterized by the systemic deposition of light-chain-derived amyloids. Immunoglobulin M (IgM)-associated AL amyloidosis is extremely rare and clinically distinct. A 70-year-old man presented with dyspnea, bilateral pleural effusion, and mediastinal lymphadenopathy on computed tomography (CT). Amyloid was detected in a pleural effusion cell block and confirmed via an axillary lymph node biopsy. Serum studies and bone marrow findings supported IgM-λ AL amyloidosis associated with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. First-line therapy failed, but second-line therapy reduced pleural effusion, avoiding thoracentesis for one year. A pleural effusion cell block analysis enabled rapid diagnosis with minimally invasive exploration.
2026-07-09 | WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia.
WNK2 is a known tumor suppressor in a set of solid tumors, including glioblastoma multiforme and pancreatic ductal adenocarcinoma. WNK2 functions are largely unknown beyond the kinase domain (KD)-dependent inhibition of ERK1/2 signaling. Waldenström's Macroglobulinemia (WM) is an indolent, yet incurable, B cell lymphoma characterized by highly recurrent MYD88 (MYD88MUT) and CXCR4 (CXCR4MUT) mutations that trigger sustained NF-κB and ERK1/2 signaling. Although not expressed in healthy B cells, WNK2 is a top dysregulated gene in MYD88MUT WM. To study WNK2 regulation and signaling, we performed multi-omics analyses, including bulk and PacBio Iso-Seq RNA-Seq and methylome, in 264 untreated WM and functional studies in cell lines and primary WM cells. Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM. We identified novel isoforms that carried a shared aberrant splicing event, either contained or lacked the KD and were highly expressed by the tumor cells, unlike the canonical full-length isoforms. Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling. We observed a similar, cancer-specific upregulation of WNK2 in a set of solid tumors, including the highly aggressive cholangiocarcinoma. Our findings reveal an undocumented oncogenic function for WNK2 driven by novel, cancer-specific isoforms and provide a framework for its further investigation as a determinant of disease progression in MYD88MUT WM and a novel therapeutic target in hematological and solid tumor oncology.
2026-07-03 | Diagnostic challenge of occult ER-positive breast carcinoma within bone marrow indolent B-cell lymphoma and response to CDK4/6 inhibitor: a case report.
Bone marrow metastasis from hormone receptor-positive breast cancer can be challenging to detect, especially in patients with concurrent hematologic malignancies, where isolated epithelial cells may be hidden by a dominant lymphoid infiltrate. This situation requires careful histopathologic and immunophenotypic evaluation to prevent misdiagnosis. We report a 74-year-old White woman with Waldenström's macroglobulinemia carrying the MYD88 L265P mutation and bone marrow infiltration by indolent B-cell non-Hodgkin lymphoma. She was evaluated for suspected skeletal disease progression due to rising tumor markers and inconclusive PET findings. Bone marrow biopsy revealed small clusters of epithelial cells positive for estrogen receptor (ER), cytokeratin AE1/AE3, and GATA3, consistent with metastatic breast carcinoma within a lymphoid background. Notably, ER positivity was the only marker indicating epithelial origin. The patient had previously received empirical aromatase inhibitor therapy after the initial detection of scattered ER-positive epithelial cells in 2018. Following disease progression in December 2024, she was treated with palbociclib and fulvestrant, while the indolent lymphoma was managed with active surveillance. At 6-month follow-up, the patient showed clinical stability, a biochemical response, and radiologic evidence of stable disease. This case emphasizes the importance of maintaining a high level of clinical and pathological suspicion when assessing bone marrow infiltration, especially in patients with a history of malignancy. The presence of isolated ER-positive epithelial cells within a lymphoid marrow environment should raise suspicion of occult breast carcinoma metastasis. Due to the rarity of this coexistence, the underlying mechanisms and optimal management strategies are still unclear. To our knowledge, this is one of the few reported cases of occult ER-positive breast carcinoma presenting solely as bone marrow involvement in a patient with indolent B-cell lymphoma, with documented response to CDK4/6 inhibitor-based therapy. This case report was prepared in accordance with the CAse REport (CARE) guidelines.
2026-06-10 | Combined Immunoglobulin Heavy- and Light-Chain Amyloidosis Associated With Waldenström Macroglobulinaemia: A Case Report With Diagnostic Challenges and a Favourable Treatment Outcome.
Waldenström macroglobulinaemia (WM) is a rare lymphoplasmacytic lymphoma that produces monoclonal IgM, and renal amyloidosis is an uncommon complication. Light-chain amyloidosis occurs more frequently than heavy-chain or combined heavy- and light-chain (AHL) amyloidosis. This report describes a woman with proteinuria in the nephrotic range, elevated IgM, and IgM kappa monoclonal protein in serum and urine. Kidney biopsy revealed AHL amyloidosis with IgM and kappa deposition. Laser microdissection-liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS) confirmed the presence of peptides from heavy and light chains. WM with renal amyloidosis was diagnosed, and the patient was started on bendamustine and rituximab. She had a significant hematologic response, achieving a very good partial response according to the international criteria. A renal response characterized by a reduction in proteinuria and stabilization of renal function was also observed. The patient remains asymptomatic after 43 months of follow-up. This case of WM with renal AHL amyloidosis highlights the importance of keeping renal amyloidosis in mind in patients with proteinuria. The favourable hematologic and renal response to treatment with bendamustine and rituximab in this case adds valuable data for the management of WM complicated by renal amyloidosis.
2026-05-28 | Iopofosine I-131 after BTK inhibitors in Waldenström macroglobulinemia: CLOVER-WaM subgroup efficacy and safety.
7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .
cell therapies
2026-09-01 | [Therapeutic apheresis in first-line treatment of hematological disorders - an evidence-based review].
Therapeutic apheresis (TA) is an important treatment for certain conditions. TA refers to various procedures in which either plasma (plasmapheresis) or specific blood cell fractions (cyta-pheresis) are removed. These include, among others, extracorporeal photopheresis (EP), erythrocytapheresis (EA), therapeutic plasma exchange (TPE), and therapeutic erythrocyte exchange (TEE). The indications for these procedures in specific diseases are published by the American Society for Apheresis (ASFA) as well as by hematology societies such as the American Society of Hematology (ASH) and the British Society of Haematology (BSH). There are only a few indications for therapeutic apheresis as first-line therapy for hematologic diseases, either as primary treatment or in combination with other therapies, for which strong evidence (Grade 1A-1C) exists. These indications include TPE for symptomatic hyperviscosity syndrome, hyperviscosity syndrome prophylaxis during rituximab therapy for Waldenström's macroglobulinemia, TEE for acute complications of sickle cell disease such as stroke and for the prophylaxis of such events, as well as the use of TPE for thrombotic thrombocytopenic purpura. Less well-known indications with strong evidence include the treatment of erythrocytosis in polycythemia vera and the treatment of iron overload in hereditary hemochromatosis using EA. Similarly, EP is an established treatment option for mycosis fungoides and Sézary syndrome. The aim of this paper is to summarize these indications.
2025-05-18 | Report of Consensus Panel 6 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on Diagnosis and Management of Transformed Waldenstrom's Macroglobulinemia.
Histological transformation (HT) in Waldenström's macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström's Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise 18FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of TP53 abnormalities and CXCR4 mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.
2024-08-19 | Waldenström macroglobulinemia: a challenging case treated with anti-CD19 CAR-T cell therapy.
Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M (IgM) protein (Owen et al., 2003). Common signs and symptoms include fatigue due to anemia, lymph node enlargement, hepatosplenomegaly, thrombocytopenia, symptoms related to high viscosity, and peripheral neuropathy, among others. Despite significant advances in WM treatment, this type of indolent lymphoma remains incurable, with a wide array of patient outcomes (Ruan et al., 2020). In recent years, chimeric antigen receptor T (CAR-T) cell therapy targeting cluster of differentiation 19 (CD19) has shown unprecedented response rates and durability in the treatment of B-cell malignancies. In this report, we describe a challenging case of WM that involved multiple extramedullary sites, relapsed, and was refractory to chemotherapy, immunotherapy, and targeted therapy. After anti-CD19 CAR-T cell therapy, the tumor burden significantly decreased and the patient's condition remained stable at the writing of this report. 华氏巨球蛋白血症（WM）是一种罕见的小淋巴细胞、浆细胞样淋巴细胞和浆细胞肿瘤，会累及骨髓，甚至累及淋巴结和脾，通常与克隆性IgM球蛋白血症相关。尽管WM通常伴有惰性临床病程，但却无法治愈。本研究报告了一个具有挑战性的WM案例。该患者在化疗、免疫治疗和布鲁顿酪氨酸激酶（BTK）抑制剂治疗后出现复发/难治性病变，并累及髓外，但在CD19定向嵌合抗原受体T（CAR-T）细胞治疗后病情得到改善。此外，我们还回顾了文献中报道的CAR-T细胞治疗WM病例。本案例中的患者已接受一年多的随访，其病情仍保持良好的部分缓解状态，这表明CAR-T细胞疗法具有作为复发/难治性WM替代方案的潜力。人们迫切希望进行更大规模的临床研究来评估这种疗法的有效性和安全性。. 华氏巨球蛋白血症（WM）是一种罕见的小淋巴细胞、浆细胞样淋巴细胞和浆细胞肿瘤，会累及骨髓，甚至累及淋巴结和脾，通常与克隆性IgM球蛋白血症相关。尽管WM通常伴有惰性临床病程，但却无法治愈。本研究报告了一个具有挑战性的WM案例。该患者在化疗、免疫治疗和布鲁顿酪氨酸激酶（BTK）抑制剂治疗后出现复发/难治性病变，并累及髓外，但在CD19定向嵌合抗原受体T（CAR-T）细胞治疗后病情得到改善。此外，我们还回顾了文献中报道的CAR-T细胞治疗WM病例。本案例中的患者已接受一年多的随访，其病情仍保持良好的部分缓解状态，这表明CAR-T细胞疗法具有作为复发/难治性WM替代方案的潜力。人们迫切希望进行更大规模的临床研究来评估这种疗法的有效性和安全性。
2024-07-26 | Uveal effusion in Waldenstrom's macroglobulinemia.
To reastport a case of Waldenstrom macroglobulinemia-related choroidal detachments. Case report. A 80-year-old woman was referred for bilateral visual loss for few months. She was hospitalized for a Waldenstrom's disease. Both anterior chambers were deep and quiet. Fundus revealed bilateral choroidal detachment without serous retinal detachments. No vitritis, retinal tear or pigmented lesion were observed. After eliminating all other causes of uveal effusion, the patient was treated for her hemopathy with chemotherapy associated with corticosteroids and plasmapheresis. One month later, fundus showed a complete disappearance of choroidal detachments and vision improved. Uveal effusion is an extremely rare ocular damage of Waldenström disease. As choroidal vessels are porous, they may allow immunoglobulins, over produced, to leak toward supra-choroidal space triggering choroidal detachments.
2024-06-27 | High efficacy of CD19 CAR T cells in patients with transformed Waldenström macroglobulinemia.
Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.
proteins
2026-03-29 | Malignant transformation in patients with monoclonal gammopathy of undetermined significance treated with teriparatide for osteoporosis: a bicenter retrospective study and analysis of the French national pharmacovigilance database.
Malignant transformation in patients with monoclonal gammopathy of undetermined significance treated with teriparatide was evaluated. Among 29 patients, only two progressed to hematologic malignancy (one multiple myeloma, one Waldenström's macroglobulinemia). These findings are reassuring and suggest that TPT may remain an option for selected patients with severe osteoporosis and MGUS. Osteoporosis is a highly prevalent bone disease with limited therapeutic options, particularly in multimorbid patients. Monoclonal gammopathy of undetermined significance (MGUS), a frequent finding in osteoporosis and a recognized fracture risk factor, often leads to contraindication of teriparatide (TPT), further restricting treatment choices. This study aimed to assess hematologic malignant transformation in osteoporotic patients with MGUS treated with TPT. A retrospective bicenter observational study was conducted at Lille and Angers University Hospitals (2016-2022). Patients with osteoporosis and confirmed MGUS at TPT initiation were included. Demographic, hematologic, bone, and treatment parameters were collected. In parallel, hematologic malignancies reported with TPT were reviewed from the French national pharmacovigilance database (PVDB) over the same period. Twenty-nine patients (69% women; mean age 72.6 ± 12.6 years) were included. Most had major comorbidities (89.7% with Charlson Comorbidity Index ≥ 3). MGUS was IgG-type in 55.2% and IgM-type in 41.4%. The mean follow-up from TPT initiation was 60.2 ± 30.7 months (median 54.0; 95% CI 49.0-71.4). Two patients developed hematologic malignancy: one multiple myeloma (MM) 7 years after TPT and one Waldenström's macroglobulinemia 21 months after initiation, both with intermediate-risk MGUS. TPT was well tolerated with premature discontinuation in 17.2% of cases. Of the two hematologic malignancies identified in the PVDB, only one (MM) occurred in a patient with pre-existing MGUS. Malignant progression was rare, providing reassuring evidence regarding hematologic safety. TPT may be considered in selected patients with severe osteoporosis and MGUS, provided careful hematologic monitoring.
2025-02-11 | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom's Macroglobulinemia.
Waldenstrom's Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88-mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22/CD9-positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice.
2024-12-05 | Expression of MYD88 L265P Mutation in Subtypes of Diffuse Large B-Cell Lymphoma in the Pakistani Population.
MYD88 L265P mutation is a gain-of-function driver mutation. It is observed in a significant proportion of Waldenstrom macroglobulinemia and activated B-cell subtype of diffuse large B-cell lymphoma (DLBCL; non-germinal center subtype). The incidence of this mutation in the subtypes of DLBCL has not yet been documented in the Pakistani population. This study aimed to ascertain the frequency and association of MYD88 L265P mutation within 2 subtypes of DLBCL, germinal center B-cell-like (GCB) and non-GCB B-cell lymphoma (non-GCB), in the local population. This cross-sectional study was conducted at the Armed Forces Institute of Pathology, Punjab, Pakistan. All newly diagnosed cases of DLBCL were included in the study. We analyzed 82 biopsy-proven cases of DLBCL (28 cases of GCB subtype and 54 cases of non-GCB subtype). DNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and a conventional polymerase chain reaction was used to detect the MYD88 L265P mutation. The MYD88 L265P mutation was detected in 01 of 28 (3.6%) cases of the GCB subtype (95% CI: 0%-10%) and in 12 of 54 (22.2%) cases of the non-GCB subtype (95% CI: 11%-33%). Pearsos χ2 test revealed a statistically significant association of MYD88 L265P mutation with non-GCB subtype of DLBCL (P = 0.024). This association will assist in identifying a target population that may benefit from MYD88-specific treatment regimens. This may exponentially improve the outcome of patients with DLBCL harboring this mutation.
2024-03-23 | Use of Vonicog Alpha and Acquired von Willebrand Syndrome, a New Approach: A Case Report.
Therapeutic management of acquired von Willebrand syndrome (AVWS) can be challenging, particularly in cases of AVWS associated with monoclonal IgM such as Waldenström macroglobulinemia (WM) where several therapeutic options may be ineffective. Here, we describe the case of an 88-year-old patient who developed AVWS during follow-up for WM. The presence of a severe bleeding symptomatology not controlled by several therapies (plasma-derived von Willebrand factor, plasmapheresis) led us to introduce a supplementation with recombinant von Willebrand factor, vonicog α (Veyvondi, Takeda, Japan), starting at a dose of 50 IU/kg/d. This supplementation allowed clinical (no further bleeding) and biological (hemoglobin level, von Willebrand factor parameters) improvements. Because of the persistence of bleeding risk factors, the treatment was maintained at a prophylactic dose (20 UI/kg three times a week), without recurrence of bleeding events for a period of 9 months.
2023-08-18 | The oncogenic human B-cell lymphoma MYD88 L265P mutation genocopies activation by phosphorylation at the Toll/interleukin-1 receptor (TIR) domain
Abstract MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset of diffuse large B-cell lymphomas. MYD88-L265P strongly promotes NF-κB pathway activation, JAK-STAT signaling and lymphoma cell survival. Previous studies have identified other residues of the TIR-domain crucially involved in NF-κB activation, including serine 257 (S257), indicating a potentially important physiological role in the regulation of MYD88 activation. Here, we demonstrate that MYD88 S257 is phosphorylated in B-cell lymphoma cells and that this phosphorylation is required for optimal TLR-induced NF-κB activation. Furthermore, we demonstrate that a phosphomimetic MYD88-S257D mutant promotes MYD88 aggregation, IRAK1 phosphorylation, NF-κB activation and cell growth to a similar extent as the oncogenic L265P mutant. Lastly, we show that expression of MYD88-S257D can rescue cell growth upon silencing of endogenous MYD88-L265P expression in lymphoma cells addicted to oncogenic MYD88 signaling. Our data suggest that the L265P mutation promotes TIR domain homodimerization and NF-κB activation by copying the effect of MY88 phosphorylation at S257, thus providing novel insights into the molecular mechanism underlying the oncogenic activity of MYD88-L265P in B-cell malignancies.
antibodies
2026-07-13 | Characteristics and clinical course of younger patients with asymptomatic monoclonal gammopathies.
Monoclonal gammopathy of undetermined significance (MGUS), smouldering multiple myeloma (SMM) and asymptomatic Waldenström's macroglobulinaemia (aWM) are precursor conditions with variable risk of progression to symptomatic malignancy. We aimed to characterize the asymptomatic monoclonal gammopathies in younger patients among 1237 consecutive patients of which 12.1% were <50 years, while 2% were <40 years. Among patients <50 years, most had MGUS and a female predominance was seen. Of patients <40 years, 71% were females, 50% had SMM and 50% MGUS. Patients <50 progressed with either SLiM criteria (clonal bone marrow plasma cell percentage ≥60% involved:uninvolved serum free light chain ratio ≥100 <1 focal lesions on MRI studies) or bone lesions detected in regular follow-up imaging, without catastrophic complications. For SMM patients <50 years, progression rate to symptomatic disease at 2, 3 and 5 years was 4%, 6% and 12% while for older patients was 9%, 13% and 20%, respectively, but adjusted for baseline risk by 20/2/20, no significant difference emerged. No patient <50 years with MGUS or aWM has yet progressed. Among SMM patients <40 years none was at high risk per 20/2/20, while no progression event occurred after a median follow-up of 3 years. In conclusion, younger patients with asymptomatic monoclonal gammopathies exhibit similar biological features compared to older patients, with generally low progression rates, suggesting early detection and low risk of complications with protocolized follow-up.
2026-03-20 | Waldenström Macroglobulinemia: A 15-Year Retrospective Study of Clinical Features, Biological Profile, and Therapeutic Outcomes
Waldenström Macroglobulinemia: A 15-Year Retrospective Study of Clinical Features, Biological Profile, and Therapeutic OutcomesH. Otsmane, L. Sahraoui, M.C. Rahali, F. Talbi, SE Belakehal, F.Z. ArdjounDepartment of Hematology, Central Hospital (HCA), Kouba, Algiers, Algeria
AbstractBackground:
Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoproliferative disorder characterized by bone marrow infiltration by lymphoplasmacytic cells and the production of a monoclonal immunoglobulin M (IgM). Clinical manifestations are related to both tumor burden and IgM-related complications, particularly hyperviscosity syndrome.Methods:
We conducted a retrospective, single-center study over a 15-year period (1995–2010) including patients diagnosed with WM at the Department of Hematology, Central Hospital (HCA), Algiers. Clinical presentation, laboratory findings, treatment modalities, and outcomes were analyzed.Results:
A total of 15 patients were included (male-to-female ratio 4:1), with a median age of 63 years. Constitutional symptoms were observed in 73% of cases. Anemia was the most common clinical feature (70%), followed by tumor syndrome (60%) and hemorrhagic manifestations (30%).Laboratory findings revealed anemia in 14 patients, neutropenia in 7, and thrombocytopenia in 3 cases. Bone marrow examination showed predominantly polymorphic lymphoplasmacytic infiltration. Serum protein electrophoresis demonstrated a monoclonal IgM peak, mainly of kappa light-chain type.Hyperviscosity-related complications were frequent, including hypertension and papilledema (33% each), as well as retinal hemorrhages.Treatment was initiated in 13 patients and included mono- or polychemotherapy regimens. The best responses were achieved with fludarabine-based therapy and CHOP regimens, leading to complete remission in a subset of patients.Conclusion:
WM predominantly affects elderly males and is frequently revealed by anemia and hyperviscosity syndrome. In our experience, treatment with purine analogs and combination chemotherapy yielded meaningful clinical responses. The integration of anti-CD20 monoclonal antibodies is expected to further improve patient outcomes.
KeywordsWaldenström Macroglobulinemia; Immunoglobulin M; Hyperviscosity Syndrome; Lymphoplasmacytic Lymphoma; Rituximab; Purine Analogues; Bone Marrow; Retrospective Studies
2026-03-18 | A real-world 10-year follow-up analysis of survival and safety of CD20-targeted therapy in patients with Waldenstrom macroglobulinemia.
To evaluate the long-term survival and safety outcomes of CD20-targeted chemoimmunotherapy regimens in patients with Waldenstrom macroglobulinemia (WM) in a real-world single-center cohort from China. We conducted a retrospective analysis of 128 patients with WM who received CD20-based regimens at a single center from 2014 to 2024. Baseline characteristics, treatment efficacy, survival outcomes (OS and PFS) and safety profiles were compared among the four treatment groups. Significant differences were found in age, disease burden, and bone marrow infiltration. Patients in the R-CHOP group had higher IgM levels and bone marrow infiltration rates. The FCR group achieved the longest OS (75.86 ± 22.05 months, P < 0.01). The RTX group showed the poorest outcomes, with a mortality rate of 75% within 12 months after relapse. ORR and consolidation therapy rates were similar across groups. The FCR group had the highest rate of grade ≥3 adverse events (60%), mainly leukopenia and thrombocytopenia. The R-CHOP group had a higher infection risk, while RTX was the safest. In this 10-year single-center real-world cohort from China, CD20-targeted chemoimmunotherapy achieved durable disease control with acceptable long-term safety in patients with WM. Differences in efficacy and toxicity profiles among FCR, BR, R-CHOP, and rituximab monotherapy support an individualized treatment approach that takes into account patient age, comorbidities, and tolerance. Because standardized quality-of-life instruments were not used in this retrospective study, our findings should be interpreted as reflecting survival and treatment-related toxicity rather than validated health-related quality of life.
2026-01-08 | Bruton tyrosine kinase inhibitors and invasive aspergillosis and mucormycosis: a case report and multi-center exploratory retrospective study.
Bruton tyrosine kinase inhibitors (BTKIs) are increasingly utilized for patients with certain malignant hematologic conditions. While cases of invasive fungal infections have been reported in patients on BTKIs, no multi-center epidemiological studies have been performed. The Epic Cosmos platform, a nationwide electronic health record data set, provides an opportunity to assess real-world epidemiologic data. A 69-year-old female with recently diagnosed Waldenström macroglobulinemia with associated autoimmune hemolytic anemia undergoing treatment with zanubrutinib and prednisone presented with fatigue and acute kidney injury. Imaging demonstrated a bladder mass with bilateral hydronephrosis leading to transurethral resection of the bladder mass with histopathology revealing both broad ribbon-like hyphae resembling Mucorales spp. and acute-angle branching resembling Aspergillus spp. with angioinvasion. Additional imaging revealed bilateral pulmonary cavitary lesions and renal and brain involvement. Bronchoalveolar lavage returned a positive galactomannan and culture growth of Aspergillus fumigatus. The patient was treated with liposomal amphotericin B with eventual transition to oral isavuconazole. Zanubrutinib and steroids were discontinued. To assess real-world occurrence of IFIs in patients on BTKIs, we performed an exploratory analysis using Epic Cosmos. IFIs continue to be described in patients undergoing treatment with BTKIs. Through exploratory analysis using Epic Cosmos, aspergillosis occurred not infrequently (0.5%-1.9%) in patients on various BTKIs. Of patients on ibrutinib with a diagnosis of chronic graft-versus-host disease, aspergillosis was identified in 32 (8.3%) patients. Patients on BTKIs who developed aspergillosis were frequently on corticosteroids. Mucormycosis in patients on BTKIs was rare (<0.1%).
2025-08-04 | Obinutuzumab induction and maintenance in patients with Waldenström macroglobulinaemia: an open-label, single-arm phase 2 study.
Despite progress in the treatment of Waldenström macroglobulinaemia, this disease still remains a therapeutic challenge, especially in older patients with multiple comorbidities. This study aimed to assess obinutuzumab single-agent induction and maintenance activity and safety in patients with relapsed or refractory Waldenström macroglobulinaemia. This open-label, single-arm phase 2 study enrolled patients with relapsed or refractory Waldenström macroglobulinaemia with confirmed CD20 expression and measurable disease. Patients received an infusion of obinutuzumab 1000 mg on days 1, 8, and 15 during first cycle, followed by five more cycles with infusions on day 1. Patients with a response defined as stable disease or better at the end of the induction phase entered 2-year maintenance treatment with obinutuzumab 1000 mg every eight weeks, followed by the observation phase. The primary endpoint was best overall response. This trial is registered at ClinicalTrials.gov, NCT03679455, and EudraCT, 2016-005053-20. Between September 04, 2018 and March 25, 2021, we enrolled 23 patients (median age 66 years, range 52-86 years). The median duration of follow-up was 3.8 years (range 0.1-6.0).The best overall response rate (BOR) was 65.2% (15 of 23 [95% CI 42.7-83.6]). In patients with baseline IgM level ≥40 g/L, BOR was reported in 75.0% (9 of 12 [95% CI 42.8-90.5]).Overall response rate (ORR) at the end of induction was reported in 12 (51%) of 23 patients. At the end of the study, ORR was reported in 15 (65%) of 23 patients. After the end of the study, the percentage of patients who achieved a very good partial response (VGPR) and complete remission (CR) has increased significantly compared to proportion of patients who achieved VGPR and CR after the 6-month induction phase (26% vs 4%, and 4% vs 0%, respectively). Progression-free survival was 65% (95% CI 43-84); overall survival was 74% (95% CI 52-90).Grade 3 or higher adverse events occurred in 15 (65.2%) patients, however, treatment-related grade 3 or higher adverse events occurred in 8 (34.8%) patients. One death that occurred during the induction phase was associated to disease progression, one death that occurred during maintenance phase was related to COVID-19, and one with disease progression. The remaining 3 deaths occurred during the follow-up phase, during subsequent lines of treatment. Obinutuzumab is active as single-agent induction and maintenance in patients with relapsed or refractory Waldenström macroglobulinaemia with manageable toxicity. Clinically significant is the fact that very good responses were deepened after the completion of the study with obinutuzumab. Roche Polska Ltd.
other
2026-08-08 | Peripheral neuropathies associated with immunoglobulin M monoclonal gammopathies and low-grade B-cell lymphomas: diagnostic and therapeutic approach.
Peripheral neuropathies associated with monoclonal gammopathies and low-grade B-cell lymphomas represent a clinically heterogeneous group of disorders encountered by both neurologists and hematologists. This review provides a practical and updated approach to their diagnosis and management, with a particular focus on IgM-associated neuropathies and anti-MAG neuropathy. IgM-related neuropathies encompass immune-mediated disorders - most commonly driven by antibodies against myelin-associated glycoprotein (MAG) - as well as infiltrative mechanisms (neurolymphomatosis, Bing-Neel syndrome) and protein deposition diseases (AL amyloidosis). Anti-MAG neuropathy remains the most common and best-characterized entity. Over the past decade, therapeutic strategies have evolved substantially with the emergence of clone-directed approaches, including anti-CD20-based regimens and covalent Bruton tyrosine kinase inhibitors (cBTKi). However, high-quality evidence remains limited. Establishing a causal relationship between neuropathy and IgM gammopathy is essential and requires a multidisciplinary approach. Treatment should be individualized and primarily reserved for progressive, functionally impairing disease. Despite therapeutic advances, many patients experience persistent disability, underscoring the need for novel strategies and prospective clinical trials using validated neurological endpoints.
2025-11-03 | Characteristics, treatment outcomes, and prognostic analysis of 118 cases of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
Abstract Background : Lymphoplasmacytic Lymphoma/Waldenström macroglobulinemia (LPL/WM) is a rare B-cell lymphoma consist of lymphocytes,lymphoplasmacytic cells, and plasma cells. Although there is a general consensus on the diagnosis and treatment of LPL/WM, there is no standard first-line therapy due to the lack of prospective randomized clinical trials. Aims This study evaluated the efficacy and safety of different regimen in treatment-naïve (TN) LPL/WM patients through the real-world retrospective analysis. Methods:We retrospectively analysied LPL/WM patients were diagnosed during October, 2014 and October, 2024 in our hospital. These patients recived CHOP or CHOP like , FC chemotherapy. BR (Bendamustine, 70-90mg/m2, d1-2, Rituximab, 375mg/m2, d0), or VD (Bortezomib 1.3mg/m2,d1,8,15, Dexamethasone, 20mg, d1,2,8,9,15,16,22,23) or BTKi (Bruton Tyrosine kinase inhibitor, Ibrutinib 140mg QD, or Zanubrutinib 160mg BID), as the first line treatment. Then we evaluated the efficacy and survial of different treatments, analyzed PFS and OS of treatment-naïve LPL/WM patients Results There were 118 patients were diagnosed with LPL/WM from October , 2014 to October, 2024. 101 eligible patients were enrolled. The median age was 64 (range, 44-85) years,72.9% patients were over 60 years old. 58.5% patients were intermediate-high risk according to IPSSWM evaluation system. Hemoglobin decreased (median,78g/L, range 23-159), and Immunoglobulin M increased (median 35.6g/L,range 19-101) significantly. 35.0% patients with increased lymphocytes (more than 50%), 43.0% patients with increased plasma cell (more than 10%), 78% patients with MYD88 L265P mutation , only 12.82% patients with CXCR4 mutation from bone marrow detection. All the patients received median 4 cycles (range 2-6) treatment. The ORR and CRR were 85% and 5%, respectively. The VGPR, PR and MRR were 20%,30% and 30%, respectively. At a median follow-up of 38 months（range 4-108), the median PFS was 50 months. The median OS not reached. 5-year PFS and OS were 37.7% and 83.7%, respectively. The subgroup analysis results indicated that target therapy, BR, VD or BTKi with prolonged PFS （P=0.01）and OS （P=0.012）compared with traditional chemotherapy. BTKi , BR with increased MRR or VGPR than VD gruop (P＜0.05), and improved 5-years PFS, 100%, 58.3% and 30.9%, respectively (P＜0.05). The patients with increased lymphocytes or splenomegaly, BR group with better MRR or VGPR than VD regimen (P＜0.05). The patients with much more plasma cells or increased IgM , VD with increased MRR than BR regimen，and transformed to OS and PFS improvement (P＜0.05). Several independent prognostic factors affecting PFS, including high risk/very high risk (R-IPSS), non-targeted therapy, elevated LDH level, bone marrow plasma cells >10%. Non-targeted therapy is an independent prognostic factor affecting OS. Conclusions Targeted therapy has a significant effect, and individualized selection is recommended for LPL/WM patients. BR is mainly recommended for patients with increased lymphocyte and splenomegaly. VD is more suitable for patients with increased plasma cell, which can reduce IgM and relieve related symptoms.
2024-11-28 | Efficacy and safety of bendamustine, rituximab and bortezomib treatment in relapsed/refractory Waldenstrom Macroglobulinaemia: results of phase 2 single-arm FIL-BRB trial.
This multicentre phase II study Fondazione Italiana Linfomi (FIL)-bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90 mg/m2 on days 1-2), rituximab (375 mg/m2 intravenously on day 1) and bortezomib (1.3 mg/m2 sc on days 1, 8, 15, 22) every 28 days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinaemia (RR-WM). Moreover, MYD88L265P and CXCR4S338X mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30 months, progression-free survival was 84.2% (95% CI 68.2%-92.6%), 81.5% (95%CI 65.1-90.7) and 78.8% (95%CI 62.0-88.8) respectively. At 18 months, the Overall survival was 92.1% (95%CI 77.5%-97.4%). Overall, 19 patients (50%) experienced grade 3-4 haematological toxicity, mainly thrombocytopenia, and grade 1-3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia patients. MRD monitoring showed promising efficacy in clearing the residual disease.
2024-11-05 | Characterization of Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma Using Single Cell Transcriptomic Analysis
Background: Single cell (sc) RNA and B-cell receptor (BCR) sequencing can be used to characterize and enhance our understanding of intra-tumoral heterogeneity and gene expression profiles versus bulk approaches. Moreover, neoplastic cells can be compared to the patient's own comparable normal cell counterparts, facilitating identification of dysregulated genes and pathways. We applied these techniques to lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) patient samples to better understand the cellular make-up and gene expression profiles of tumor cells. Methods: Paired scRNA-seq and scBCR-seq were performed on fresh bone marrow (BM) aspirate samples from patients with symptomatic (N=26) and smoldering (N=3) WM, as well as a peripheral blood (PBMC) sample from 1 patient with smoldering LPL. All samples were subjected to CD138+ and CD19+ selection. cDNA libraries were prepared from these enriched samples, followed by simultaneous 5' gene expression (scRNA-seq) and scBCR-seq. Single-cell data were processed as previously described (Dang et al., Cancer Cell, 2023). The mutation status of MYD88, CXCR4, TP53, DNMT3A, TET2, and ASXL1 for each patient was determined by clinical molecular diagnostics. Results: We profiled 247,916 high-quality cells including 111,848 B-cells (21,382 progenitor/precursor/immature B-cells and 90,466 mature B-cells) and 136,068 plasma cells (PCs). We also obtained scBCR-seq data on 223,062 cells, of which 198,403 had paired scRNA-seq data. Clonotype was defined as monoclonal (frequency ≥5), polyclonal (frequency <5), and undetected. Unsupervised clustering analysis revealed 10 neoplastic clusters in B cells, including 4 precursor, 2 naïve, 3 memory and 1 atypical B-cell cluster. Additionally, 3 neoplastic clusters were identified in PCs. More than half of the naïve/germinal center (GC) B, unswitched memory B, IgE memory B, and PCs were monoclonal, while immature B, naïve B, S100A10+ memory B, and atypical B-cells were polyclonal. Monoclonal cells within a single patient displayed multiple phenotypes despite sharing the same clonotype. MYD88-mutated patients (N=25) had higher proportions of naïve and unswitched memory B-cells, but lower proportions of precursor B, switched memory B, and CXCR4+ PCs compared to MYD88 wild-type patients (N=4). MYD88mutCXCR4mut patients (N=10) had more PCs, but fewer naïve/GC B-cells than MYD88mutCXCR4wt patients (N=15). Smoldering WM patients (N=3) had higher proportions of proliferating pro/pre-B, naïve B, and unswitched memory B-cells than symptomatic WM patients (N=25). Patients with prior covalent BTK inhibitor treatment (N=12) had more plasmablasts but fewer naïve/GC B-cells compared to those without prior treatment (N=17). Differential gene expression analysis between monoclonal and polyclonal B-cells showed high expression of JCHAIN, BCL2, XBP1, ZNF804A, CDKN1A, and HSPA5, among others, in monoclonal B-cells. Pathway analysis revealed up-regulated apoptotic signaling, B-cell activation, response to endoplasmic reticulum stress, and glucose starvation, with down-regulated B-cell-mediated immunity and actin filament-based processes in monoclonal B-cells. Comparing monoclonal and polyclonal PCs, we observed elevated expression of JCHAIN, IGHM, CD79A, CXCR4, ZNF804A, among others, and a variety of ribosome genes, et al., with downregulated activity in B-cell activation, phagocytosis, humoral immune response, and complement activation in monoclonal PCs. Conclusions: These data highlight the intra-tumoral heterogeneity among WM patients and suggest that differences in gene expression between monoclonal and polyclonal cells may help inform new therapeutic strategies and sequences for pre-clinical and clinical investigation.
2019-08-16 | Dimerization of an aptamer generated from Ligand-guided selection (LIGS) yields a high affinity scaffold against B-cells.
Nucleic Acid Aptamers (NAAs) are a class of synthetic DNA or RNA molecules that bind specifically to their target. We recently introduced an aptamer termed R1.2 against membrane Immunoglobulin M (mIgM) expressing B-cell neoplasms using Ligand Guided Selection (LIGS). While LIGS-generated aptamers are highly specific, their lower affinity prevents aptamers from being used for translational applications. Highly specific aptamers with higher affinity can increase targetability, boosting the application of aptamers as diagnostic and therapeutic molecules. Herein, we report that dimerization of R1.2, an aptamer generated from LIGS, leads to high affinity variants without compromising the specificity. Three dimeric aptamer analogues with variable linker lengths were designed to evaluate the effect of linker length in affinity. The optimized dimeric R1.2 against cultured B-cell neoplasms, four donor B-cell samples and mIgM-positive Waldenström's Macroglobulinemia (WM) showed specificity. Furthermore, confocal imaging of dimeric aptamer and anti-IgM antibody in purified B-cells suggests co-localization. Binding assays against IgM knockout Burkitt's Lymphoma cells utilizing CRISPR/Cas9 further validated specificity of dimeric R1.2. Collectively, our findings show that LIGS-generated aptamers can be re-engineered into dimeric aptamers with high specificity and affinity, demonstrating wide-range of applicability of LIGS in developing clinically practical diagnostic and therapeutic aptamers.
small molecules
2026-08-10 | IgM Pleural Amyloidosis Diagnosed by Pleural Effusion Cell Block: A Case Report.
Immunoglobulin light chain (AL) amyloidosis is characterized by the systemic deposition of light-chain-derived amyloids. Immunoglobulin M (IgM)-associated AL amyloidosis is extremely rare and clinically distinct. A 70-year-old man presented with dyspnea, bilateral pleural effusion, and mediastinal lymphadenopathy on computed tomography (CT). Amyloid was detected in a pleural effusion cell block and confirmed via an axillary lymph node biopsy. Serum studies and bone marrow findings supported IgM-λ AL amyloidosis associated with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. First-line therapy failed, but second-line therapy reduced pleural effusion, avoiding thoracentesis for one year. A pleural effusion cell block analysis enabled rapid diagnosis with minimally invasive exploration.
2026-07-09 | WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia.
WNK2 is a known tumor suppressor in a set of solid tumors, including glioblastoma multiforme and pancreatic ductal adenocarcinoma. WNK2 functions are largely unknown beyond the kinase domain (KD)-dependent inhibition of ERK1/2 signaling. Waldenström's Macroglobulinemia (WM) is an indolent, yet incurable, B cell lymphoma characterized by highly recurrent MYD88 (MYD88MUT) and CXCR4 (CXCR4MUT) mutations that trigger sustained NF-κB and ERK1/2 signaling. Although not expressed in healthy B cells, WNK2 is a top dysregulated gene in MYD88MUT WM. To study WNK2 regulation and signaling, we performed multi-omics analyses, including bulk and PacBio Iso-Seq RNA-Seq and methylome, in 264 untreated WM and functional studies in cell lines and primary WM cells. Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM. We identified novel isoforms that carried a shared aberrant splicing event, either contained or lacked the KD and were highly expressed by the tumor cells, unlike the canonical full-length isoforms. Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling. We observed a similar, cancer-specific upregulation of WNK2 in a set of solid tumors, including the highly aggressive cholangiocarcinoma. Our findings reveal an undocumented oncogenic function for WNK2 driven by novel, cancer-specific isoforms and provide a framework for its further investigation as a determinant of disease progression in MYD88MUT WM and a novel therapeutic target in hematological and solid tumor oncology.
2026-07-03 | Diagnostic challenge of occult ER-positive breast carcinoma within bone marrow indolent B-cell lymphoma and response to CDK4/6 inhibitor: a case report.
Bone marrow metastasis from hormone receptor-positive breast cancer can be challenging to detect, especially in patients with concurrent hematologic malignancies, where isolated epithelial cells may be hidden by a dominant lymphoid infiltrate. This situation requires careful histopathologic and immunophenotypic evaluation to prevent misdiagnosis. We report a 74-year-old White woman with Waldenström's macroglobulinemia carrying the MYD88 L265P mutation and bone marrow infiltration by indolent B-cell non-Hodgkin lymphoma. She was evaluated for suspected skeletal disease progression due to rising tumor markers and inconclusive PET findings. Bone marrow biopsy revealed small clusters of epithelial cells positive for estrogen receptor (ER), cytokeratin AE1/AE3, and GATA3, consistent with metastatic breast carcinoma within a lymphoid background. Notably, ER positivity was the only marker indicating epithelial origin. The patient had previously received empirical aromatase inhibitor therapy after the initial detection of scattered ER-positive epithelial cells in 2018. Following disease progression in December 2024, she was treated with palbociclib and fulvestrant, while the indolent lymphoma was managed with active surveillance. At 6-month follow-up, the patient showed clinical stability, a biochemical response, and radiologic evidence of stable disease. This case emphasizes the importance of maintaining a high level of clinical and pathological suspicion when assessing bone marrow infiltration, especially in patients with a history of malignancy. The presence of isolated ER-positive epithelial cells within a lymphoid marrow environment should raise suspicion of occult breast carcinoma metastasis. Due to the rarity of this coexistence, the underlying mechanisms and optimal management strategies are still unclear. To our knowledge, this is one of the few reported cases of occult ER-positive breast carcinoma presenting solely as bone marrow involvement in a patient with indolent B-cell lymphoma, with documented response to CDK4/6 inhibitor-based therapy. This case report was prepared in accordance with the CAse REport (CARE) guidelines.
2026-06-10 | Combined Immunoglobulin Heavy- and Light-Chain Amyloidosis Associated With Waldenström Macroglobulinaemia: A Case Report With Diagnostic Challenges and a Favourable Treatment Outcome.
Waldenström macroglobulinaemia (WM) is a rare lymphoplasmacytic lymphoma that produces monoclonal IgM, and renal amyloidosis is an uncommon complication. Light-chain amyloidosis occurs more frequently than heavy-chain or combined heavy- and light-chain (AHL) amyloidosis. This report describes a woman with proteinuria in the nephrotic range, elevated IgM, and IgM kappa monoclonal protein in serum and urine. Kidney biopsy revealed AHL amyloidosis with IgM and kappa deposition. Laser microdissection-liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS) confirmed the presence of peptides from heavy and light chains. WM with renal amyloidosis was diagnosed, and the patient was started on bendamustine and rituximab. She had a significant hematologic response, achieving a very good partial response according to the international criteria. A renal response characterized by a reduction in proteinuria and stabilization of renal function was also observed. The patient remains asymptomatic after 43 months of follow-up. This case of WM with renal AHL amyloidosis highlights the importance of keeping renal amyloidosis in mind in patients with proteinuria. The favourable hematologic and renal response to treatment with bendamustine and rituximab in this case adds valuable data for the management of WM complicated by renal amyloidosis.
2026-05-28 | Iopofosine I-131 after BTK inhibitors in Waldenström macroglobulinemia: CLOVER-WaM subgroup efficacy and safety.
7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .
cell therapies
2026-09-01 | [Therapeutic apheresis in first-line treatment of hematological disorders - an evidence-based review].
Therapeutic apheresis (TA) is an important treatment for certain conditions. TA refers to various procedures in which either plasma (plasmapheresis) or specific blood cell fractions (cyta-pheresis) are removed. These include, among others, extracorporeal photopheresis (EP), erythrocytapheresis (EA), therapeutic plasma exchange (TPE), and therapeutic erythrocyte exchange (TEE). The indications for these procedures in specific diseases are published by the American Society for Apheresis (ASFA) as well as by hematology societies such as the American Society of Hematology (ASH) and the British Society of Haematology (BSH). There are only a few indications for therapeutic apheresis as first-line therapy for hematologic diseases, either as primary treatment or in combination with other therapies, for which strong evidence (Grade 1A-1C) exists. These indications include TPE for symptomatic hyperviscosity syndrome, hyperviscosity syndrome prophylaxis during rituximab therapy for Waldenström's macroglobulinemia, TEE for acute complications of sickle cell disease such as stroke and for the prophylaxis of such events, as well as the use of TPE for thrombotic thrombocytopenic purpura. Less well-known indications with strong evidence include the treatment of erythrocytosis in polycythemia vera and the treatment of iron overload in hereditary hemochromatosis using EA. Similarly, EP is an established treatment option for mycosis fungoides and Sézary syndrome. The aim of this paper is to summarize these indications.
2025-05-18 | Report of Consensus Panel 6 from the 12th International Workshop on Waldenstrom's Macroglobulinemia on Diagnosis and Management of Transformed Waldenstrom's Macroglobulinemia.
Histological transformation (HT) in Waldenström's macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström's Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise 18FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of TP53 abnormalities and CXCR4 mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.
2024-08-19 | Waldenström macroglobulinemia: a challenging case treated with anti-CD19 CAR-T cell therapy.
Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M (IgM) protein (Owen et al., 2003). Common signs and symptoms include fatigue due to anemia, lymph node enlargement, hepatosplenomegaly, thrombocytopenia, symptoms related to high viscosity, and peripheral neuropathy, among others. Despite significant advances in WM treatment, this type of indolent lymphoma remains incurable, with a wide array of patient outcomes (Ruan et al., 2020). In recent years, chimeric antigen receptor T (CAR-T) cell therapy targeting cluster of differentiation 19 (CD19) has shown unprecedented response rates and durability in the treatment of B-cell malignancies. In this report, we describe a challenging case of WM that involved multiple extramedullary sites, relapsed, and was refractory to chemotherapy, immunotherapy, and targeted therapy. After anti-CD19 CAR-T cell therapy, the tumor burden significantly decreased and the patient's condition remained stable at the writing of this report. 华氏巨球蛋白血症（WM）是一种罕见的小淋巴细胞、浆细胞样淋巴细胞和浆细胞肿瘤，会累及骨髓，甚至累及淋巴结和脾，通常与克隆性IgM球蛋白血症相关。尽管WM通常伴有惰性临床病程，但却无法治愈。本研究报告了一个具有挑战性的WM案例。该患者在化疗、免疫治疗和布鲁顿酪氨酸激酶（BTK）抑制剂治疗后出现复发/难治性病变，并累及髓外，但在CD19定向嵌合抗原受体T（CAR-T）细胞治疗后病情得到改善。此外，我们还回顾了文献中报道的CAR-T细胞治疗WM病例。本案例中的患者已接受一年多的随访，其病情仍保持良好的部分缓解状态，这表明CAR-T细胞疗法具有作为复发/难治性WM替代方案的潜力。人们迫切希望进行更大规模的临床研究来评估这种疗法的有效性和安全性。. 华氏巨球蛋白血症（WM）是一种罕见的小淋巴细胞、浆细胞样淋巴细胞和浆细胞肿瘤，会累及骨髓，甚至累及淋巴结和脾，通常与克隆性IgM球蛋白血症相关。尽管WM通常伴有惰性临床病程，但却无法治愈。本研究报告了一个具有挑战性的WM案例。该患者在化疗、免疫治疗和布鲁顿酪氨酸激酶（BTK）抑制剂治疗后出现复发/难治性病变，并累及髓外，但在CD19定向嵌合抗原受体T（CAR-T）细胞治疗后病情得到改善。此外，我们还回顾了文献中报道的CAR-T细胞治疗WM病例。本案例中的患者已接受一年多的随访，其病情仍保持良好的部分缓解状态，这表明CAR-T细胞疗法具有作为复发/难治性WM替代方案的潜力。人们迫切希望进行更大规模的临床研究来评估这种疗法的有效性和安全性。
2024-07-26 | Uveal effusion in Waldenstrom's macroglobulinemia.
To reastport a case of Waldenstrom macroglobulinemia-related choroidal detachments. Case report. A 80-year-old woman was referred for bilateral visual loss for few months. She was hospitalized for a Waldenstrom's disease. Both anterior chambers were deep and quiet. Fundus revealed bilateral choroidal detachment without serous retinal detachments. No vitritis, retinal tear or pigmented lesion were observed. After eliminating all other causes of uveal effusion, the patient was treated for her hemopathy with chemotherapy associated with corticosteroids and plasmapheresis. One month later, fundus showed a complete disappearance of choroidal detachments and vision improved. Uveal effusion is an extremely rare ocular damage of Waldenström disease. As choroidal vessels are porous, they may allow immunoglobulins, over produced, to leak toward supra-choroidal space triggering choroidal detachments.
2024-06-27 | High efficacy of CD19 CAR T cells in patients with transformed Waldenström macroglobulinemia.
Histologic transformation of Waldenström macroglobulinemia (HT-WM) carries a poor prognosis with standard treatments. Here, we report the first series of HT-WM treated with chimeric antigen receptor T cells showing a high efficacy and no unexpected toxicity.
proteins
2026-03-29 | Malignant transformation in patients with monoclonal gammopathy of undetermined significance treated with teriparatide for osteoporosis: a bicenter retrospective study and analysis of the French national pharmacovigilance database.
Malignant transformation in patients with monoclonal gammopathy of undetermined significance treated with teriparatide was evaluated. Among 29 patients, only two progressed to hematologic malignancy (one multiple myeloma, one Waldenström's macroglobulinemia). These findings are reassuring and suggest that TPT may remain an option for selected patients with severe osteoporosis and MGUS. Osteoporosis is a highly prevalent bone disease with limited therapeutic options, particularly in multimorbid patients. Monoclonal gammopathy of undetermined significance (MGUS), a frequent finding in osteoporosis and a recognized fracture risk factor, often leads to contraindication of teriparatide (TPT), further restricting treatment choices. This study aimed to assess hematologic malignant transformation in osteoporotic patients with MGUS treated with TPT. A retrospective bicenter observational study was conducted at Lille and Angers University Hospitals (2016-2022). Patients with osteoporosis and confirmed MGUS at TPT initiation were included. Demographic, hematologic, bone, and treatment parameters were collected. In parallel, hematologic malignancies reported with TPT were reviewed from the French national pharmacovigilance database (PVDB) over the same period. Twenty-nine patients (69% women; mean age 72.6 ± 12.6 years) were included. Most had major comorbidities (89.7% with Charlson Comorbidity Index ≥ 3). MGUS was IgG-type in 55.2% and IgM-type in 41.4%. The mean follow-up from TPT initiation was 60.2 ± 30.7 months (median 54.0; 95% CI 49.0-71.4). Two patients developed hematologic malignancy: one multiple myeloma (MM) 7 years after TPT and one Waldenström's macroglobulinemia 21 months after initiation, both with intermediate-risk MGUS. TPT was well tolerated with premature discontinuation in 17.2% of cases. Of the two hematologic malignancies identified in the PVDB, only one (MM) occurred in a patient with pre-existing MGUS. Malignant progression was rare, providing reassuring evidence regarding hematologic safety. TPT may be considered in selected patients with severe osteoporosis and MGUS, provided careful hematologic monitoring.
2025-02-11 | Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom's Macroglobulinemia.
Waldenstrom's Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88-mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22/CD9-positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice.
2024-12-05 | Expression of MYD88 L265P Mutation in Subtypes of Diffuse Large B-Cell Lymphoma in the Pakistani Population.
MYD88 L265P mutation is a gain-of-function driver mutation. It is observed in a significant proportion of Waldenstrom macroglobulinemia and activated B-cell subtype of diffuse large B-cell lymphoma (DLBCL; non-germinal center subtype). The incidence of this mutation in the subtypes of DLBCL has not yet been documented in the Pakistani population. This study aimed to ascertain the frequency and association of MYD88 L265P mutation within 2 subtypes of DLBCL, germinal center B-cell-like (GCB) and non-GCB B-cell lymphoma (non-GCB), in the local population. This cross-sectional study was conducted at the Armed Forces Institute of Pathology, Punjab, Pakistan. All newly diagnosed cases of DLBCL were included in the study. We analyzed 82 biopsy-proven cases of DLBCL (28 cases of GCB subtype and 54 cases of non-GCB subtype). DNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and a conventional polymerase chain reaction was used to detect the MYD88 L265P mutation. The MYD88 L265P mutation was detected in 01 of 28 (3.6%) cases of the GCB subtype (95% CI: 0%-10%) and in 12 of 54 (22.2%) cases of the non-GCB subtype (95% CI: 11%-33%). Pearsos χ2 test revealed a statistically significant association of MYD88 L265P mutation with non-GCB subtype of DLBCL (P = 0.024). This association will assist in identifying a target population that may benefit from MYD88-specific treatment regimens. This may exponentially improve the outcome of patients with DLBCL harboring this mutation.
2024-03-23 | Use of Vonicog Alpha and Acquired von Willebrand Syndrome, a New Approach: A Case Report.
Therapeutic management of acquired von Willebrand syndrome (AVWS) can be challenging, particularly in cases of AVWS associated with monoclonal IgM such as Waldenström macroglobulinemia (WM) where several therapeutic options may be ineffective. Here, we describe the case of an 88-year-old patient who developed AVWS during follow-up for WM. The presence of a severe bleeding symptomatology not controlled by several therapies (plasma-derived von Willebrand factor, plasmapheresis) led us to introduce a supplementation with recombinant von Willebrand factor, vonicog α (Veyvondi, Takeda, Japan), starting at a dose of 50 IU/kg/d. This supplementation allowed clinical (no further bleeding) and biological (hemoglobin level, von Willebrand factor parameters) improvements. Because of the persistence of bleeding risk factors, the treatment was maintained at a prophylactic dose (20 UI/kg three times a week), without recurrence of bleeding events for a period of 9 months.
2023-08-18 | The oncogenic human B-cell lymphoma MYD88 L265P mutation genocopies activation by phosphorylation at the Toll/interleukin-1 receptor (TIR) domain
Abstract MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset of diffuse large B-cell lymphomas. MYD88-L265P strongly promotes NF-κB pathway activation, JAK-STAT signaling and lymphoma cell survival. Previous studies have identified other residues of the TIR-domain crucially involved in NF-κB activation, including serine 257 (S257), indicating a potentially important physiological role in the regulation of MYD88 activation. Here, we demonstrate that MYD88 S257 is phosphorylated in B-cell lymphoma cells and that this phosphorylation is required for optimal TLR-induced NF-κB activation. Furthermore, we demonstrate that a phosphomimetic MYD88-S257D mutant promotes MYD88 aggregation, IRAK1 phosphorylation, NF-κB activation and cell growth to a similar extent as the oncogenic L265P mutant. Lastly, we show that expression of MYD88-S257D can rescue cell growth upon silencing of endogenous MYD88-L265P expression in lymphoma cells addicted to oncogenic MYD88 signaling. Our data suggest that the L265P mutation promotes TIR domain homodimerization and NF-κB activation by copying the effect of MY88 phosphorylation at S257, thus providing novel insights into the molecular mechanism underlying the oncogenic activity of MYD88-L265P in B-cell malignancies.
antibodies
2026-07-13 | Characteristics and clinical course of younger patients with asymptomatic monoclonal gammopathies.
Monoclonal gammopathy of undetermined significance (MGUS), smouldering multiple myeloma (SMM) and asymptomatic Waldenström's macroglobulinaemia (aWM) are precursor conditions with variable risk of progression to symptomatic malignancy. We aimed to characterize the asymptomatic monoclonal gammopathies in younger patients among 1237 consecutive patients of which 12.1% were <50 years, while 2% were <40 years. Among patients <50 years, most had MGUS and a female predominance was seen. Of patients <40 years, 71% were females, 50% had SMM and 50% MGUS. Patients <50 progressed with either SLiM criteria (clonal bone marrow plasma cell percentage ≥60% involved:uninvolved serum free light chain ratio ≥100 <1 focal lesions on MRI studies) or bone lesions detected in regular follow-up imaging, without catastrophic complications. For SMM patients <50 years, progression rate to symptomatic disease at 2, 3 and 5 years was 4%, 6% and 12% while for older patients was 9%, 13% and 20%, respectively, but adjusted for baseline risk by 20/2/20, no significant difference emerged. No patient <50 years with MGUS or aWM has yet progressed. Among SMM patients <40 years none was at high risk per 20/2/20, while no progression event occurred after a median follow-up of 3 years. In conclusion, younger patients with asymptomatic monoclonal gammopathies exhibit similar biological features compared to older patients, with generally low progression rates, suggesting early detection and low risk of complications with protocolized follow-up.
2026-03-20 | Waldenström Macroglobulinemia: A 15-Year Retrospective Study of Clinical Features, Biological Profile, and Therapeutic Outcomes
Waldenström Macroglobulinemia: A 15-Year Retrospective Study of Clinical Features, Biological Profile, and Therapeutic OutcomesH. Otsmane, L. Sahraoui, M.C. Rahali, F. Talbi, SE Belakehal, F.Z. ArdjounDepartment of Hematology, Central Hospital (HCA), Kouba, Algiers, Algeria
AbstractBackground:
Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoproliferative disorder characterized by bone marrow infiltration by lymphoplasmacytic cells and the production of a monoclonal immunoglobulin M (IgM). Clinical manifestations are related to both tumor burden and IgM-related complications, particularly hyperviscosity syndrome.Methods:
We conducted a retrospective, single-center study over a 15-year period (1995–2010) including patients diagnosed with WM at the Department of Hematology, Central Hospital (HCA), Algiers. Clinical presentation, laboratory findings, treatment modalities, and outcomes were analyzed.Results:
A total of 15 patients were included (male-to-female ratio 4:1), with a median age of 63 years. Constitutional symptoms were observed in 73% of cases. Anemia was the most common clinical feature (70%), followed by tumor syndrome (60%) and hemorrhagic manifestations (30%).Laboratory findings revealed anemia in 14 patients, neutropenia in 7, and thrombocytopenia in 3 cases. Bone marrow examination showed predominantly polymorphic lymphoplasmacytic infiltration. Serum protein electrophoresis demonstrated a monoclonal IgM peak, mainly of kappa light-chain type.Hyperviscosity-related complications were frequent, including hypertension and papilledema (33% each), as well as retinal hemorrhages.Treatment was initiated in 13 patients and included mono- or polychemotherapy regimens. The best responses were achieved with fludarabine-based therapy and CHOP regimens, leading to complete remission in a subset of patients.Conclusion:
WM predominantly affects elderly males and is frequently revealed by anemia and hyperviscosity syndrome. In our experience, treatment with purine analogs and combination chemotherapy yielded meaningful clinical responses. The integration of anti-CD20 monoclonal antibodies is expected to further improve patient outcomes.
KeywordsWaldenström Macroglobulinemia; Immunoglobulin M; Hyperviscosity Syndrome; Lymphoplasmacytic Lymphoma; Rituximab; Purine Analogues; Bone Marrow; Retrospective Studies
2026-03-18 | A real-world 10-year follow-up analysis of survival and safety of CD20-targeted therapy in patients with Waldenstrom macroglobulinemia.
To evaluate the long-term survival and safety outcomes of CD20-targeted chemoimmunotherapy regimens in patients with Waldenstrom macroglobulinemia (WM) in a real-world single-center cohort from China. We conducted a retrospective analysis of 128 patients with WM who received CD20-based regimens at a single center from 2014 to 2024. Baseline characteristics, treatment efficacy, survival outcomes (OS and PFS) and safety profiles were compared among the four treatment groups. Significant differences were found in age, disease burden, and bone marrow infiltration. Patients in the R-CHOP group had higher IgM levels and bone marrow infiltration rates. The FCR group achieved the longest OS (75.86 ± 22.05 months, P < 0.01). The RTX group showed the poorest outcomes, with a mortality rate of 75% within 12 months after relapse. ORR and consolidation therapy rates were similar across groups. The FCR group had the highest rate of grade ≥3 adverse events (60%), mainly leukopenia and thrombocytopenia. The R-CHOP group had a higher infection risk, while RTX was the safest. In this 10-year single-center real-world cohort from China, CD20-targeted chemoimmunotherapy achieved durable disease control with acceptable long-term safety in patients with WM. Differences in efficacy and toxicity profiles among FCR, BR, R-CHOP, and rituximab monotherapy support an individualized treatment approach that takes into account patient age, comorbidities, and tolerance. Because standardized quality-of-life instruments were not used in this retrospective study, our findings should be interpreted as reflecting survival and treatment-related toxicity rather than validated health-related quality of life.
2026-01-08 | Bruton tyrosine kinase inhibitors and invasive aspergillosis and mucormycosis: a case report and multi-center exploratory retrospective study.
Bruton tyrosine kinase inhibitors (BTKIs) are increasingly utilized for patients with certain malignant hematologic conditions. While cases of invasive fungal infections have been reported in patients on BTKIs, no multi-center epidemiological studies have been performed. The Epic Cosmos platform, a nationwide electronic health record data set, provides an opportunity to assess real-world epidemiologic data. A 69-year-old female with recently diagnosed Waldenström macroglobulinemia with associated autoimmune hemolytic anemia undergoing treatment with zanubrutinib and prednisone presented with fatigue and acute kidney injury. Imaging demonstrated a bladder mass with bilateral hydronephrosis leading to transurethral resection of the bladder mass with histopathology revealing both broad ribbon-like hyphae resembling Mucorales spp. and acute-angle branching resembling Aspergillus spp. with angioinvasion. Additional imaging revealed bilateral pulmonary cavitary lesions and renal and brain involvement. Bronchoalveolar lavage returned a positive galactomannan and culture growth of Aspergillus fumigatus. The patient was treated with liposomal amphotericin B with eventual transition to oral isavuconazole. Zanubrutinib and steroids were discontinued. To assess real-world occurrence of IFIs in patients on BTKIs, we performed an exploratory analysis using Epic Cosmos. IFIs continue to be described in patients undergoing treatment with BTKIs. Through exploratory analysis using Epic Cosmos, aspergillosis occurred not infrequently (0.5%-1.9%) in patients on various BTKIs. Of patients on ibrutinib with a diagnosis of chronic graft-versus-host disease, aspergillosis was identified in 32 (8.3%) patients. Patients on BTKIs who developed aspergillosis were frequently on corticosteroids. Mucormycosis in patients on BTKIs was rare (<0.1%).
2025-08-04 | Obinutuzumab induction and maintenance in patients with Waldenström macroglobulinaemia: an open-label, single-arm phase 2 study.
Despite progress in the treatment of Waldenström macroglobulinaemia, this disease still remains a therapeutic challenge, especially in older patients with multiple comorbidities. This study aimed to assess obinutuzumab single-agent induction and maintenance activity and safety in patients with relapsed or refractory Waldenström macroglobulinaemia. This open-label, single-arm phase 2 study enrolled patients with relapsed or refractory Waldenström macroglobulinaemia with confirmed CD20 expression and measurable disease. Patients received an infusion of obinutuzumab 1000 mg on days 1, 8, and 15 during first cycle, followed by five more cycles with infusions on day 1. Patients with a response defined as stable disease or better at the end of the induction phase entered 2-year maintenance treatment with obinutuzumab 1000 mg every eight weeks, followed by the observation phase. The primary endpoint was best overall response. This trial is registered at ClinicalTrials.gov, NCT03679455, and EudraCT, 2016-005053-20. Between September 04, 2018 and March 25, 2021, we enrolled 23 patients (median age 66 years, range 52-86 years). The median duration of follow-up was 3.8 years (range 0.1-6.0).The best overall response rate (BOR) was 65.2% (15 of 23 [95% CI 42.7-83.6]). In patients with baseline IgM level ≥40 g/L, BOR was reported in 75.0% (9 of 12 [95% CI 42.8-90.5]).Overall response rate (ORR) at the end of induction was reported in 12 (51%) of 23 patients. At the end of the study, ORR was reported in 15 (65%) of 23 patients. After the end of the study, the percentage of patients who achieved a very good partial response (VGPR) and complete remission (CR) has increased significantly compared to proportion of patients who achieved VGPR and CR after the 6-month induction phase (26% vs 4%, and 4% vs 0%, respectively). Progression-free survival was 65% (95% CI 43-84); overall survival was 74% (95% CI 52-90).Grade 3 or higher adverse events occurred in 15 (65.2%) patients, however, treatment-related grade 3 or higher adverse events occurred in 8 (34.8%) patients. One death that occurred during the induction phase was associated to disease progression, one death that occurred during maintenance phase was related to COVID-19, and one with disease progression. The remaining 3 deaths occurred during the follow-up phase, during subsequent lines of treatment. Obinutuzumab is active as single-agent induction and maintenance in patients with relapsed or refractory Waldenström macroglobulinaemia with manageable toxicity. Clinically significant is the fact that very good responses were deepened after the completion of the study with obinutuzumab. Roche Polska Ltd.
other
2026-08-08 | Peripheral neuropathies associated with immunoglobulin M monoclonal gammopathies and low-grade B-cell lymphomas: diagnostic and therapeutic approach.
Peripheral neuropathies associated with monoclonal gammopathies and low-grade B-cell lymphomas represent a clinically heterogeneous group of disorders encountered by both neurologists and hematologists. This review provides a practical and updated approach to their diagnosis and management, with a particular focus on IgM-associated neuropathies and anti-MAG neuropathy. IgM-related neuropathies encompass immune-mediated disorders - most commonly driven by antibodies against myelin-associated glycoprotein (MAG) - as well as infiltrative mechanisms (neurolymphomatosis, Bing-Neel syndrome) and protein deposition diseases (AL amyloidosis). Anti-MAG neuropathy remains the most common and best-characterized entity. Over the past decade, therapeutic strategies have evolved substantially with the emergence of clone-directed approaches, including anti-CD20-based regimens and covalent Bruton tyrosine kinase inhibitors (cBTKi). However, high-quality evidence remains limited. Establishing a causal relationship between neuropathy and IgM gammopathy is essential and requires a multidisciplinary approach. Treatment should be individualized and primarily reserved for progressive, functionally impairing disease. Despite therapeutic advances, many patients experience persistent disability, underscoring the need for novel strategies and prospective clinical trials using validated neurological endpoints.
2025-11-03 | Characteristics, treatment outcomes, and prognostic analysis of 118 cases of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
Abstract Background : Lymphoplasmacytic Lymphoma/Waldenström macroglobulinemia (LPL/WM) is a rare B-cell lymphoma consist of lymphocytes,lymphoplasmacytic cells, and plasma cells. Although there is a general consensus on the diagnosis and treatment of LPL/WM, there is no standard first-line therapy due to the lack of prospective randomized clinical trials. Aims This study evaluated the efficacy and safety of different regimen in treatment-naïve (TN) LPL/WM patients through the real-world retrospective analysis. Methods:We retrospectively analysied LPL/WM patients were diagnosed during October, 2014 and October, 2024 in our hospital. These patients recived CHOP or CHOP like , FC chemotherapy. BR (Bendamustine, 70-90mg/m2, d1-2, Rituximab, 375mg/m2, d0), or VD (Bortezomib 1.3mg/m2,d1,8,15, Dexamethasone, 20mg, d1,2,8,9,15,16,22,23) or BTKi (Bruton Tyrosine kinase inhibitor, Ibrutinib 140mg QD, or Zanubrutinib 160mg BID), as the first line treatment. Then we evaluated the efficacy and survial of different treatments, analyzed PFS and OS of treatment-naïve LPL/WM patients Results There were 118 patients were diagnosed with LPL/WM from October , 2014 to October, 2024. 101 eligible patients were enrolled. The median age was 64 (range, 44-85) years,72.9% patients were over 60 years old. 58.5% patients were intermediate-high risk according to IPSSWM evaluation system. Hemoglobin decreased (median,78g/L, range 23-159), and Immunoglobulin M increased (median 35.6g/L,range 19-101) significantly. 35.0% patients with increased lymphocytes (more than 50%), 43.0% patients with increased plasma cell (more than 10%), 78% patients with MYD88 L265P mutation , only 12.82% patients with CXCR4 mutation from bone marrow detection. All the patients received median 4 cycles (range 2-6) treatment. The ORR and CRR were 85% and 5%, respectively. The VGPR, PR and MRR were 20%,30% and 30%, respectively. At a median follow-up of 38 months（range 4-108), the median PFS was 50 months. The median OS not reached. 5-year PFS and OS were 37.7% and 83.7%, respectively. The subgroup analysis results indicated that target therapy, BR, VD or BTKi with prolonged PFS （P=0.01）and OS （P=0.012）compared with traditional chemotherapy. BTKi , BR with increased MRR or VGPR than VD gruop (P＜0.05), and improved 5-years PFS, 100%, 58.3% and 30.9%, respectively (P＜0.05). The patients with increased lymphocytes or splenomegaly, BR group with better MRR or VGPR than VD regimen (P＜0.05). The patients with much more plasma cells or increased IgM , VD with increased MRR than BR regimen，and transformed to OS and PFS improvement (P＜0.05). Several independent prognostic factors affecting PFS, including high risk/very high risk (R-IPSS), non-targeted therapy, elevated LDH level, bone marrow plasma cells >10%. Non-targeted therapy is an independent prognostic factor affecting OS. Conclusions Targeted therapy has a significant effect, and individualized selection is recommended for LPL/WM patients. BR is mainly recommended for patients with increased lymphocyte and splenomegaly. VD is more suitable for patients with increased plasma cell, which can reduce IgM and relieve related symptoms.
2024-11-28 | Efficacy and safety of bendamustine, rituximab and bortezomib treatment in relapsed/refractory Waldenstrom Macroglobulinaemia: results of phase 2 single-arm FIL-BRB trial.
This multicentre phase II study Fondazione Italiana Linfomi (FIL)-bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90 mg/m2 on days 1-2), rituximab (375 mg/m2 intravenously on day 1) and bortezomib (1.3 mg/m2 sc on days 1, 8, 15, 22) every 28 days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinaemia (RR-WM). Moreover, MYD88L265P and CXCR4S338X mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30 months, progression-free survival was 84.2% (95% CI 68.2%-92.6%), 81.5% (95%CI 65.1-90.7) and 78.8% (95%CI 62.0-88.8) respectively. At 18 months, the Overall survival was 92.1% (95%CI 77.5%-97.4%). Overall, 19 patients (50%) experienced grade 3-4 haematological toxicity, mainly thrombocytopenia, and grade 1-3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia patients. MRD monitoring showed promising efficacy in clearing the residual disease.
2024-11-05 | Characterization of Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma Using Single Cell Transcriptomic Analysis
Background: Single cell (sc) RNA and B-cell receptor (BCR) sequencing can be used to characterize and enhance our understanding of intra-tumoral heterogeneity and gene expression profiles versus bulk approaches. Moreover, neoplastic cells can be compared to the patient's own comparable normal cell counterparts, facilitating identification of dysregulated genes and pathways. We applied these techniques to lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) patient samples to better understand the cellular make-up and gene expression profiles of tumor cells. Methods: Paired scRNA-seq and scBCR-seq were performed on fresh bone marrow (BM) aspirate samples from patients with symptomatic (N=26) and smoldering (N=3) WM, as well as a peripheral blood (PBMC) sample from 1 patient with smoldering LPL. All samples were subjected to CD138+ and CD19+ selection. cDNA libraries were prepared from these enriched samples, followed by simultaneous 5' gene expression (scRNA-seq) and scBCR-seq. Single-cell data were processed as previously described (Dang et al., Cancer Cell, 2023). The mutation status of MYD88, CXCR4, TP53, DNMT3A, TET2, and ASXL1 for each patient was determined by clinical molecular diagnostics. Results: We profiled 247,916 high-quality cells including 111,848 B-cells (21,382 progenitor/precursor/immature B-cells and 90,466 mature B-cells) and 136,068 plasma cells (PCs). We also obtained scBCR-seq data on 223,062 cells, of which 198,403 had paired scRNA-seq data. Clonotype was defined as monoclonal (frequency ≥5), polyclonal (frequency <5), and undetected. Unsupervised clustering analysis revealed 10 neoplastic clusters in B cells, including 4 precursor, 2 naïve, 3 memory and 1 atypical B-cell cluster. Additionally, 3 neoplastic clusters were identified in PCs. More than half of the naïve/germinal center (GC) B, unswitched memory B, IgE memory B, and PCs were monoclonal, while immature B, naïve B, S100A10+ memory B, and atypical B-cells were polyclonal. Monoclonal cells within a single patient displayed multiple phenotypes despite sharing the same clonotype. MYD88-mutated patients (N=25) had higher proportions of naïve and unswitched memory B-cells, but lower proportions of precursor B, switched memory B, and CXCR4+ PCs compared to MYD88 wild-type patients (N=4). MYD88mutCXCR4mut patients (N=10) had more PCs, but fewer naïve/GC B-cells than MYD88mutCXCR4wt patients (N=15). Smoldering WM patients (N=3) had higher proportions of proliferating pro/pre-B, naïve B, and unswitched memory B-cells than symptomatic WM patients (N=25). Patients with prior covalent BTK inhibitor treatment (N=12) had more plasmablasts but fewer naïve/GC B-cells compared to those without prior treatment (N=17). Differential gene expression analysis between monoclonal and polyclonal B-cells showed high expression of JCHAIN, BCL2, XBP1, ZNF804A, CDKN1A, and HSPA5, among others, in monoclonal B-cells. Pathway analysis revealed up-regulated apoptotic signaling, B-cell activation, response to endoplasmic reticulum stress, and glucose starvation, with down-regulated B-cell-mediated immunity and actin filament-based processes in monoclonal B-cells. Comparing monoclonal and polyclonal PCs, we observed elevated expression of JCHAIN, IGHM, CD79A, CXCR4, ZNF804A, among others, and a variety of ribosome genes, et al., with downregulated activity in B-cell activation, phagocytosis, humoral immune response, and complement activation in monoclonal PCs. Conclusions: These data highlight the intra-tumoral heterogeneity among WM patients and suggest that differences in gene expression between monoclonal and polyclonal cells may help inform new therapeutic strategies and sequences for pre-clinical and clinical investigation.
2019-08-16 | Dimerization of an aptamer generated from Ligand-guided selection (LIGS) yields a high affinity scaffold against B-cells.
Nucleic Acid Aptamers (NAAs) are a class of synthetic DNA or RNA molecules that bind specifically to their target. We recently introduced an aptamer termed R1.2 against membrane Immunoglobulin M (mIgM) expressing B-cell neoplasms using Ligand Guided Selection (LIGS). While LIGS-generated aptamers are highly specific, their lower affinity prevents aptamers from being used for translational applications. Highly specific aptamers with higher affinity can increase targetability, boosting the application of aptamers as diagnostic and therapeutic molecules. Herein, we report that dimerization of R1.2, an aptamer generated from LIGS, leads to high affinity variants without compromising the specificity. Three dimeric aptamer analogues with variable linker lengths were designed to evaluate the effect of linker length in affinity. The optimized dimeric R1.2 against cultured B-cell neoplasms, four donor B-cell samples and mIgM-positive Waldenström's Macroglobulinemia (WM) showed specificity. Furthermore, confocal imaging of dimeric aptamer and anti-IgM antibody in purified B-cells suggests co-localization. Binding assays against IgM knockout Burkitt's Lymphoma cells utilizing CRISPR/Cas9 further validated specificity of dimeric R1.2. Collectively, our findings show that LIGS-generated aptamers can be re-engineered into dimeric aptamers with high specificity and affinity, demonstrating wide-range of applicability of LIGS in developing clinically practical diagnostic and therapeutic aptamers.
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Drug Discovery Landscape
20 orphan drug designations for Waldenström macroglobulinemia, including 2 approved therapies.
20 orphan drug designations for Waldenström macroglobulinemia, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) | small molecules | FDA | Schrödinger, Inc. | |
3-((4-(1-((1-(6-(((S)-2,6-Dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide | small molecules | EMA | — | Eliquent Life Sciences Limited |
a bifunctional molecule consisting of a Bruton's tyrosine kinase (BTK)-binding hook and cereblon (CRBN)-binding harness, bridged by a chemical linker | small molecules | FDA | Nurix Therapeutics | |
tacabrutideg | small molecules | FDA | BeOne Medicines USA, Inc. | |
Sonrotoclax | small molecules | FDA | BeOne Medicines USA, Inc. | |
mavorixafor | small molecules | FDA | X4 Pharmaceuticals, Inc. | |
Autologous T-Cells transduced with a lentiviral vector (LVV) expressing CD20-specific chimeric antigen receptor (CAR) gene (CD20 CAR-T Cells) | cell therapies | FDA | Mustang Bio, Inc. | |
copanlisib | small molecules | FDA | — | Bayer HealthCare Pharmaceuticals Inc. |
18-(p-[131I]-iodophenyl)octadecyl phosphocholine | other | EMA | Scendea (NL) B.V. | |
[6-(4-Chlorophenyl)-spiro[3.5]non-6-en-7-yl]methyl}-piperazin-1-yl}-N-{{3-nitro-4-[((2S)-1,4-dioxan-2-ylmethyl)amino]phenyl}sulfonyl}-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide | small molecules | FDA | Ascentage Pharma Group Inc. | |
18-(p-[131I]-iodophenyl)octadecyl phosphocholine | small molecules | FDA | Cellectar Biosciences, Inc. | |
zanubrutinib [Brukinsa] | small molecules | FDA | Approved | BeOne Medicines USA, Inc. |
Acalabrutinib | small molecules | EMA | Acerta Pharma, BV | |
acalabrutinib | small molecules | FDA | Acerta Pharma, LLC (a member of the AstraZeneca Group) | |
antagonist of the endosomal Toll-like receptors (TLRs) 7, 8, and 9 | oligonucleotides | FDA | Idera Pharmaceuticals, Inc. | |
oprozomib | small molecules | FDA | Onyx Therapeutics, Inc. | |
ibrutinib [Imbruvica] | small molecules | FDA | Approved | Pharmacyclics, LLC |
idelalisib | small molecules | FDA | Gilead Sciences, Inc. | |
Autologous lymphoma-derived immunoglobulin idiotype antigen vaccine conjugated to keyhole limpet hemocyanin | vaccines | FDA | — | Biovest International, Inc. |
everolimus | small molecules | FDA | Novartis Pharmaceuticals Corp. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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