Waldenstrom's Macroglobulinemia Research Articles

A phase 2, open-label study of ibrutinib plus rituximab in Japanese patients with Waldenstrom's macroglobulinemia.

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420mg orally once daily plus weekly rituximab 375mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4months, median follow-up: 35.0months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.

Abstract CT144: Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma

Abstract Background: HMPL-523, a selective oral Syk inhibitor, demonstrated encouraging benefit-risk profile in 2 Phase 1 (P1) studies in relapsed/refractory (R/R) lymphoma patients (pts) in USA/Europe (NCT03779113) and China (NCT02857998). In the 16 response-evaluable pts in the dose-escalation portion (Part 1) of study NCT03779113, 4 responses were noted, including complete responses (CRs) in R/R hodgkin lymphoma (HL) and follicular lymphoma (FL) pts (Strati et al. Blood 2021). Here, we report the results from the dose expansion portion (Part 2) of the study NCT03779113. Methods: Safety and efficacy of HMPL-523, at the recommended phase 2 dose (RP2D) of 700 mg QD, was evaluated in lymphoma pts who have exhausted all approved therapy options. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were assessed by investigators at weeks 8, 16, and 24, and then every 12 weeks. Results: As of 14 July 2023, 47 pts were enrolled in the Part 2 [25 HL, 9 Peripheral T cell lymphoma (PTCL), 7 Chronic lymphocytic leukemia (CLL), 2 each of FL and Mantle cell lymphoma (MCL), and 1 each with Marginal zone lymphoma (MZL) and Waldenström's macroglobulinemia (WM)]. Median age was 57 (Range:21-93) years, 55% were males, 85% were Caucasian, 47% had ECOG status of 1, 81% were disease stage ≥3 and 17% had B-symptoms at study entry. Median prior lines of therapy was 4 (range 1 - 12); 86% of CLL pts were prior BTK treated and 88% of HL pts had both a PD-1 inhibitor and Brentuximab vedotin. With a median drug exposure of 2.9 months, the overall response rate (ORR) among 41 efficacy evaluable pts was 26.8% and disease control rate (DCR) was 65.9% [4 CR (9.8%), 7 PR (17.1%) and 16 SD (39.0%)]. The median time-to-response was 1.9 months. Among HL pts (N=24), ORR was 25.0% and DCR was 66.7% [2 CR (8.3%), 4 PR (16.7%) and 10 SD (41.7%)]. Among PTCL pts (N=7), ORR and DCR were 42.9% [2 CR (28.6%) and 1 PR (14.3%)]. The median duration of response (DOR) was not reached for HL pts and was 5.7 months (2.0 - NR) in PTCL. Two pts (one each with HL and PTCL) with disease control were taken off treatment to be consolidated with allogenic stem cell transplant. At cut-off, 1 pt each with CLL (N=5 ) and WM (N=1) demonstrated a PR. Serious TEAEs occurred in 18 pts (38.3%), of which 4 (8.5%) were considered treatment-related (TRAE). Grade≥3 TRAEs were noted in 15 pts (31.9%); the most common Grade≥3 TRAEs (&amp;gt;5%) were alanine aminotransferase increase 4 (8.5%) and febrile neutropenia 3 (6.4%). Dose interruption due to TEAEs occurred in 23 pts (48.9%) and dose reduction in 4 pts (8.5%). Two pts (4.3%), 1 each with TEAE of thrombocytopenia and pruritis had drug discontinued. Conclusion: HMPL-523 was well tolerated at the RP2D of 700 mg QD in R/R lymphoma pts. Encouraging proof of activity was demonstrated in heavily pre-treated HL and PTCL pts. Additional studies are needed to evaluate the value of SYK-inhibitor as either monotherapy or combination in these high unmet-need population. Citation Format: Paolo Strati, Eva Gonzalez-Barca, Daniel Morillo, Sairah Ahmed, Dominik Chraniuk, Sirpa Leppa, Fatima de la Cruz Vicente, Piotr Centkowski, Rathi N. Pillai, Shivani Nanda, Alisha Khullar, Marjo Hahka-Kemppinen, Vijayvel Jayaprakash, Giuseppe Gritti. Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT144.

Abstract CT156: A Phase I study evaluating AC676, an innovative BTK chimeric degrader, in patients with relapsed and refractory B-cell malignancies

Abstract Study Background Bruton tyrosine kinase (BTK) is a key signaling molecule that plays a central role in B-cell receptor transduction. The development of drugs that inhibit BTK has transformed the management of patients with B-cell malignancies. However, therapy using covalent BTK inhibitors such as ibrutinib, and non-covalent inhibitors such as pirtobrutinib, can still result in resistance, primarily due to the development of mutations in BTK including residues C481 and L528. AC676 was designed as a chimeric degrader to target and degrade BTK using Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform. By effectively linking a BTK ligand to the cereblon E3-ligase recruiting ligand, AC676 brings BTK in proximity to cereblon, thereby inducing subsequent ubiquitination and degradation of BTK. AC676 degrades BTK proteins irrespective of mutations; including C481, kinase dead L528 and others, and thus may be effective for the treatment of patients who progress on both covalent and non-covalent BTK inhibitors. Notably, it is also effective in cell lines expressing gain of function PLCG2 mutants, suggesting that it removes BTK’s scaffolding function. AC676 does not degrade cereblon neo-substrates, so neutropenia is not expected to be an on-target effect. This abstract describes an ongoing first in human Phase 1 trial of AC676. Study Description AC676-001 is a Phase 1 dose-escalation study of AC676 administered orally once daily as monotherapy in patients with relapsed and refractory B-cell malignancies. Approximately 60 patients may be enrolled. Eligible patients must be ≥ 18 years, and have one of the following histologically confirmed relapsed or refractory disease types: Chronic lymphocytic leukemia and small lymphocytic lymphoma, Diffuse large B cell lymphoma - non-GCB subtype, Follicular lymphoma, Mantle cell lymphoma, Marginal zone lymphoma, Lymphoplasmacytic lymphoma including Waldenstrom macroglobulinemia. Patients must have received at least two prior systemic therapies or have no other standard of care therapies to provide significant clinical benefit. Patients must have measurable disease per disease-specific response criteria and Eastern Cooperative Oncology Group performance status≤ 1. Dose-escalation will begin with an accelerated titration phase, followed by a standard 3+3 phase. AC676 is administered orally once daily on a 28 day per cycle schedule at doses ranging from 50mg to 600mg. The primary objective of the study is to evaluate the safety and tolerability of AC676. Secondary objectives include the evaluation of anti-tumor activity and the pharmacokinetic profile following single and multiple doses. Study enrollment began in April 2023 with three sites currently open in the United States (NCT05780034). Citation Format: Jennifer Woyach, Michael Tees, Nancy Mota, Gladys Brown, Su Young Kim, Manish R. Patel. A Phase I study evaluating AC676, an innovative BTK chimeric degrader, in patients with relapsed and refractory B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT156.

Ibrutinib (Imbruvica)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses ibrutinib (Imbruvica), 140 mg capsule, oral.&#x0D; Indication: For the treatment of adult patients with:&#x0D; &#x0D; Waldenström macroglobulinemia (WM) as a monotherapy or in combination with rituximab&#x0D; Previously untreated active chronic lymphocytic leukemia (CLL), including patients with 17p deletion&#x0D; CLL who received at least one prior therapy, in combination with bendamustine and rituximab&#x0D; Relapsed or refractory mantle cell lymphoma (MCL)&#x0D; marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy&#x0D; Steroid-dependent or refractory chronic graft vs. host disease (cGVHD)&#x0D; &#x0D; &#x0D;

Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia.

The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM. Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.

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.

Abstract 6044: EPriL: A platform for the rapid identification of degraders of inhibitor-resistant kinases

Abstract Heterobifunctional kinase degraders (HKDs) are an important new class of therapeutic modalities, of which the first have recently entered clinical trials. HKDs are small molecules that comprise a kinase-of-interest binding moiety and an E3 ligase binding moiety connected via a spacer. HKDs are excellently suited to target kinases that have a scaffolding function, or that are resistant against conventional inhibitors. A HKD brings a kinase and an E3 ligase in proximity forming a ternary complex leading to ubiquitin-dependent catalytic degradation of the kinase of interest. This ternary complex formation is unique for each kinase which can make HKDs highly specific. To discover novel HKDs, we have developed a platform called Energetically Privileged Ligands (EPriLs), which is based on a macrocycle scaffold that binds non-covalently in the kinase ATP pocket with near-covalent affinity, and allows binding to kinases that have acquired known inhibitor resistance mutations. The macrocyclic structure allows attachment of E3 ligase ligands with multiple exit vectors. With the EPriL platform, we have developed novel HKDs for various clinically relevant kinase targets, including Bruton’s Tyrosine Kinase (BTK). BTK inhibitor drugs are used as first line treatment for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM) and as second line treatment for mantle cell lymphoma (MCL). Despite their great success in the clinic, many patients on BTK inhibitors relapse eventually, mostly because of the emergence of resistance mutations in the BTK protein. These include BTKC481S, which abrogates binding of covalent drugs, and BTKT474I, BTKL528W and BTKV416L which preclude binding of non-covalent inhibitors like pirtobrutinib. HKDs can combat resistance by degrading such BTK variants, and by removing the scaffold function of BTK. BTK degraders such as NX-5948 and NX-2127 are currently in clinical Phase 1. To show the applicability of the EPriL platform for the discovery of novel BTK degraders, we screened a library of more than 100 EPriL HKDs for biochemical binding to BTK, and tested their propensity to induce degradation of HiBiT-tagged BTKWT, BTKC481S and BTKT474I in HEK293 cell lines. The degrading activity of hits was verified through western blot on the BTK-dependent DLBCL cell line TMD8. The best degraders - based on potency and efficacy - were tested in cell proliferation assays on a panel of TMD8 BTK mutant cell lines. In these lines, endogenous BTK was mutated by CRISPR to BTKC481S, BTKT474I, BTKL528W or BTKV416L. Several BTK degraders had potent (&amp;lt; 20 nM IC50) antiproliferative activity on most TMD8 lines, including difficult-to-target variants such as BTKV416L and BTKL528W. The unique binding mode of the EPriL scaffold thus translates to broad activity on resistance variants, while its selectivity ensures minimal degradation of off-target tyrosine kinases as observed for other degraders. Citation Format: Michelle Muller, Jos de Man, Joost C. Uitdehaag, Freek van Cauter, Sander van Gemert, Milan Hoffmann, Yvonne G. van Mil, Winfried R. Mulder, Martine B. Prinsen, Jan Gerard Sterrenburg, Diep Vu, Joeri de Wit, Erik Ensing, Rogier C. Buijsman. EPriL: A platform for the rapid identification of degraders of inhibitor-resistant kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6044.

From Biological Activity to Stereoselectivity: A Portrait of Molecular and Mechanistic Profiles of the Therapeutic Potential of G-1 and LNS8801 as GPER-1 Activator in the Treatment of Waldenström’s Macroglobulinemia

Therapeutic activation of G protein-coupled estrogen receptor 1 (GPER-1) shows promise for treating Waldenström's Macroglobulinemia (WM). Recently, the selective small-molecule agonist G-1 or its enantiomer LNS8801 were reported as potent GPER-1 pharmacological activators, however, the molecular events surrounding their chirality towards GPER-1 is still unexplored. This study aimed to explore the molecular events surrounding the chirality of the selective small-molecule agonists G-1 and LNS8801 towards GPER-1. Molecular docking and dynamics simulations revealed strong binding affinities and key amino acid residues involved in the activation process. The results revealed favourable binding affinities of -29.87kcal/mol, and -28.09kcal/mol for G-1 and LNS8801 towards GPER-1, respectively. Per-residue energy decomposition and time-dependent analysis proved that Arg253 and Arg254 are key amino acid residues in binding these activators towards GPER-1. The activators affected stability, flexibility, and structure of GPER-1. G-1 exhibited greater rigidity when bound to GPER-1 compared to LNS880. This study's findings illuminate chirality and the potential for optimizing the enantiomer ratio to enhance inhibitory effects. These results could also reveal the molecular specifics and binding mechanism of the G-1 and its enantiomer LNS8801 with GPER-1, laying the basis for the rational design of enhanced chiral molecules against WM.

Abstract 4813: Demographic, treatment, and survival patterns in Hispanic vs. non-Hispanic patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: A national retrospective analysis from the National Cancer Database

Abstract Background: Lymphoplasmacytic lymphoma (LPL) is a rare type of non-Hodgkin B cell lymphoma. Waldenstrom macroglobulinemia (WM) is a form of LPL that presents with overproduction of IgM monoclonal protein. The understanding and treatment of LPL/WM has improved. However, few studies analyze LPL/WM in Hispanic (HI) patients specifically. This study aims to evaluate demographics, treatment, and survival patterns in HI vs. Non-Hispanic (NH) patients with LPL/WM. Methods: Data were analyzed on LPL/WM patients in the US reported to the NCDB from 2004-2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH. Multivariate analysis and propensity score matching were performed with adjustment for age, stage, co-morbidity score, insurance status, type of facility and great circle distance (GCD). Results: 17,915 patients were identified. 92% were NH, 3% were HI. Most patients were male in both NH and HI (p = 0.120). The median age at diagnosis for HI was 68 vs. 71 for NH (p &amp;lt; 0.001). Most HI and NH were white (87% HI, 91% NH p &amp;lt; 0.001). More HI were uninsured (8% HI, 1% NH p &amp;lt; 0.001) and were less likely to have government sponsored insurance (60% HI, 66% NH p &amp;lt; 0.001). Regarding income, most NH (42%) were in the $63,000+ bracket while most HI were in the $48,000-$62,999 bracket. Regarding education, reported in percent quartiles with no high school degree, most HI (41%) were in the &amp;gt; 21% bracket while most NH (35%) were in the 7-12.9% bracket (p &amp;lt; 0.001). Most HI (43%) were treated at academic/research programs; most NH were treated at comprehensive community cancer programs (38.4%, p &amp;lt; 0.001). Regarding comorbidities score, 9% of HI scored ≥ 2 vs 8% of NH (p 0.029). Regarding GCD, the median distance in miles between the patient’s residence and the hospital that reported the case, HI lived at a median of 6.7 miles vs 9 miles for NH (p &amp;lt; 0.001). Regarding treatment, 68% of HI were given treatment vs. 62% of NH (p &amp;lt; 0.001). There was no difference in mortality between HI vs. NH (30 day mortality p = 0.322; 90 day mortality p = 0.217). On survival analysis, the survival probability at 2, 5 and 10 years of HI vs NH were 81% vs 83%, 69% vs 68%, and 52% vs 46%, respectively. The median survival time (MS) was 10.6 years for HI vs 9 years for NH. There was no OS difference between HI vs. NH (p = 0.47). On multivariate analysis, there were no independent variables associated with better or worse OS. The propensity matched analysis showed no MS difference between HI vs NH (8.96 y vs. 8.74 y). Conclusion: We identified ethnic differences in age, race, insurance, education, income, location of treatment, GCD, staging, and treatment patterns. However, there was no statistically significant ethnic difference in MS or OS. Citation Format: Maria Elena Fierro, Heidi Latiolais, Qianquian Liu, Joel Michalek, Adolfo Enrique Diaz Duque. Demographic, treatment, and survival patterns in Hispanic vs. non-Hispanic patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: A national retrospective analysis from the National Cancer Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4813.

Long-term results of Waldenström macroglobulinaemia treatment by bendamustine and rituximab: A study on behalf of the French Innovative Leukemia Organization (FILO).

The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval [CI] 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.

Clinical Characteristics and Treatment Outcome of Waldenstrom Macroglobulinemia: Experience from a Tertiary Cancer Centre

Background: Waldenstroms macroglobulinemia (WM) or Lymphoplasmacytic lymphoma is a rare B cell lymphoproliferative malignancy characterized by serum monoclonal immunoglobulin M (IgM) protein and lymphoplasmacytic infiltration in the bone marrow. Patients usually present in their seventh decade with symptoms related to the infiltration of the marrow or the effects of monoclonal IgM in the blood. Objective: Was to study the clinical characteristics and treatment outcome of patients diagnosed with WM. Materials and Methods: This is a retrospective analysis of 26 cases of WM treated at a tertiary cancer centre. Results: WM constituted 0.68% of our nonHodgkin’s lymphoma. The median age at presentation was 67 years with a male to female ratio of 2:1. Four patients had lymphadenopathy, six had splenomegaly and four patients had evidence of hyper viscosity. All patients had IgM paraproteinemia, the M band was IgM-kappa in 19 patients and IgM-lambda in seven patients. All patients had a histopathological confirmation. According to IPSS-WM, 12 patients each were in the intermediate and high risk group and 2 in the low risk group. Among the 26 patients, 20 patients received upfront treatment and four patients were kept under observation. The indications for treatment were cytopenia in ten patients, constitutional symptoms in five, hyper viscosity in four and symptomatic lymphadenopathy in one patient. Sixteen patients received rituximab-based chemotherapy. Four patients with features with hyper viscosity underwent plasmapheresis. The three year progression free survival and overall survival were 69.4% and 78 % respectivel. Conclusions: WM is a low grade B cell lymphoproliferative disorder having an indolent course and do not require treatment for prolonged period. Diagnosis is challenging due to lack of distinct diagnostic features. Rituximab containing regimens are the standard of care. Newer targeted treatment options may improve the outcome of this incurable disease.

Serum CXCL13 level is related to treatment response and predicts disease prognosis in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1pg/ml (range 0.0-6741.5) after 6months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher β2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2pg/ml vs 798.6pg/ml, p = 0.002). The median follow-up period was 40months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0months in patients with serum CXCL13 > 2 000pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0months in patients with serum CXCL13 > 200pg/ml, while it was not reached in patients with CXCL13 ≤ 200pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis.

ST2825, independent of MyD88, induces reactive oxygen species-dependent apoptosis in multiple myeloma cells

Myeloid differentiation factor 88 (MyD88), which is a key regulator of nuclear factor kappa B (NF-κB), plays an important role in tumorigenesis in lymphoid malignancies such as Waldenstrom's macroglobulinemia (WM). However, its biological function in multiple myeloma (MM), which is a malignant plasma cell disorder like WM, remains unexplored. In this article, we first demonstrated that higher expression MyD88 was significantly correlated with poor survival in patients with MM using multiple publicly available datasets. Interestingly, bioinformatic analysis also revealed that MyD88 gene alteration, which is recognized in nearly 80% of patients with WM, was extremely rare in MM. In addition, ST2825 (a specific inhibitor of MyD88) suppressed cell growth followed by apoptosis. Furthermore, ST2825 induced intracellular reactive oxygen species (ROS) in MM cells, and N-acetyl-l-cysteine, which is known as a ROS scavenger, significantly decreased the number of apoptotic MM cells evoked by ST2825 treatment. Taken together, our results indicated that ST2825 leads to ROS-dependent apoptosis in MM cells and could be an attractive therapeutic candidate for patients with MM. By highlighting the pathological mechanism of MyD88 in MM, this study also provides novel treatment strategies to conquer MM.

Current Approaches in the Management of Monoclonal Gammopathies: an approach to Waldenström Macroglobulinemia

Monoclonal gammopathies encompass a spectrum of disorders characterized by the abnormal proliferation of plasma cells, leading to the production of monoclonal immunoglobulins. Waldenström macroglobulinemia (WM) is a rare, indolent lymphoproliferative disorder characterized by the presence of an IgM monoclonal gammopathy, bone marrow infiltration by lymphoplasmacytic cells, and clinical features such as hyperviscosity, lymphadenopathy, and hepatosplenomegaly. Recent advances in understanding the pathogenesis of WM have led to the development of novel therapeutic strategies, including targeted therapies and immunomodulatory agents, which have significantly improved outcomes for patients. This article provides an overview of the current understanding of WM pathophysiology, clinical presentation, diagnostic approach, and recent advancements in its management.

[Diagnosis and treatment understanding of Waldenström macroglobulinemia in China: a cross-sectional study].

Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces. As for diagnosis, the laboratory tests prescribed by physicians for suspected WM patients were relatively consistent (92% -99% recommendation for laboratory, 79% -95% recommendation for pathology, 96% recommendation for gene testing, and 63% -83% recommendation for imaging examination). However, from a physician's perspective, there was 22% misdiagnosis occurred in clinical practice. The rate of misdiagnosis was higher in lower-level hospitals than in tertiary grade A hospitals (29% vs 21%, P<0.001). The main reasons for misdiagnosis were that WM was easily confused with other diseases, and physicians lacked the necessary knowledge to make an accurate diagnosis. In terms of gene testing in clinical practice, 96% of participating physicians believed that WM patients would require gene testing for MYD88 and CXCR4 mutations because the results of gene testing would aid in confirming diagnosis and treatment options. In terms of treatment, 55% of physicians thought that the most important goal was to achieve remission, while 54% and 51% of physicians wanted to improve laboratory and/or examination results and extend overall survival time, respectively. Among patients with treatment indications, physicians estimated that approximately 21% of them refused to receive treatment, mainly owing to a lack of affordable care and disease awareness. When selecting the most appropriate treatment regimens, physicians would consider patient affordability (63% ), comorbidity (61% ), and risk level (54% ). Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% ). For those patients who received treatment, physicians reported that approximately 23% of patients did not comply with the treatment regimen due to a lack of affordability and disease awareness. Furthermore, 66% of physicians believe that in the future, increasing disease awareness and improving diagnosis rates is critical. Conclusions: This study is the first national physician survey of WM conducted in China. It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia

AbstractThe phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Single-cell analysis of MYD88L265P and MYD88WT Waldenström macroglobulinemia patients.

Waldenström macroglobulinemia (WM) is characterized by the expansion of clonal lymphoplasmacytic cells; the MYD88L265P somatic mutation is found in >90% of patients, but malignant B cells may still display intra-clonal heterogeneity. To assess clonal heterogeneity in WM, we generated and performed single-cell RNA sequencing of CD19+ sorted cells from five patients with MYD88 L265P and two patients with MYD88 WT genotype as well as two healthy donors. We identified distinct transcriptional patterns in the clonal subpopulations not only between the two genetically distinct WM subgroups but also among MYD88 L265P patients, which affected the B cell composition in the different subgroups. Comparison of clonal and normal/polyclonal B cells within each patient sample enabled the identification of patient-specific transcriptional changes. We identified gene signatures active in a subset of MYD88L265P patients, while other signatureswere active in MYD88 WT patients. Finally, gene expression analysis showed common transcriptional features between patients compared to the healthy control but also differentially expressed genes between MYD88 L265P and MYD88 WT patients involved in distinct pathways, including NFκΒ, BCL2, and BTK. Overall, our data highlight the intra-tumor clonal heterogeneity in WM with potential prognostic and therapeutic implications.

A phase II study of ibrutinib in combination with ixazomib in patients with Waldenström macroglobulinaemia.

This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

Monoclonal immunoglobulin as a prognostic factor for the severity of bone damage in paraproteinemic hemoblastoses and Waldenström’s macroglobulinemia

Aim. Identify risk factors for the development of osteodestructive syndrome. To determine the relationship between the types of secreted monoclonal immunoglobulin (paraprotein) and the severity of osteodestructive syndrome in patients with paraproteinemic hemoblastoses (PH) and Waldenström’s macroglobulinemia (WM).Materials and methods. A retrospective analysis of data from 116 patients with PH and WM was performed. 104 patients (89.6 %) were diagnosed with multiple myeloma. Less commonly observed were WM (in 8 patients – 6.9 %), plasma cell leukemia (in 2 patients – 1.8 %), solitary plasmacytoma and monoclonal gammopathy of unknown significance were diagnosed in one case (0.9 %) each. According to the severity of osteodestructive syndrome, all patients were divided into 4 groups. The first group (0) included patients who did not have osteodestructive changes in the bones. In patients of the second group, a mild degree (I) osteodestructive process was observed, and in patients from the third and fourth groups – moderate (II) and severe (III) degrees, respectively. All patients underwent protein electrophoresis followed by immunofixation to determine the type of paraprotein and its concentration in serum and urine.Results. In the majority of patients, paraproteins were detected in the blood – Gκ (35.1 %), Gλ (24.6 %), Bence Jones protein λ-type (BJλ) (14.9 %); in urine – BJλ protein (14.9 %) and Bence Jones protein κ-type (BJκ) (28.1 %). Secretion of other types of paraproteins in the blood was less frequently detected – Aκ (9.6 %), Aλ (7.0 %), Mκ (3.5 %), Mλ (3.5 %), Dλ (2.6 %), BJκ (4.4 %). Osteodestructive syndrome of I and II severity was diagnosed in 43 (37.1 %) and 40 (34.5 %) patients, respectively; lytic destruction of III degree was less frequently detected in 20 (17.2 %) patients, in 13 (11.2 %) patients osteodestruction was not detected (degree 0). It was noted that a higher degree of destruction (II, III) was observed in patients with multiple myeloma occurring with paraproteinemia Dλ and BJλ in the blood, as well as hypercalcemia. Osteodestructive syndrome of the lowest degree (0, I) was diagnosed in patients with the secretion of monoclonal proteins Ak and Mλ. There was no statistically significant relationship between the type of secretion of paraproteins Gκ, Gλ, Aλ, Mκ, BJκ in the blood, as well as proteins BJκ and BJλ in the urine and the severity of the osteodestructive process.Conclusion. The results obtained in the study make it possible to identify risk groups, and parameters such as the type of paraprotein, the concentration of calcium in the blood serum can be considered as prognostic factors when assessing the severity of osteodestructive syndrome in patients with PH and WM.

Ibrutinib (Imbruvica)

&#x0D; CADTH recommends that Imbruvica, with or without rituximab, should be reimbursed by public drug plans for the treatment of adult patients with previously treated relapsed or refractory Waldenström’s macroglobulinemia (WM) if certain conditions are met.&#x0D; Imbruvica should only be covered to treat adult patients who have WM and have received at least 1 prior line of therapy, have good performance status, and who meet at least 1 criterion for treating WM according to the latest International Workshop on WM criteria.&#x0D; Imbruvica should not be reimbursed for patients who have received prior treatment with a Bruton tyrosine kinase inhibitor and whose disease responded poorly or for patients with disease transformation. Imbruvica should only be prescribed by hematologists or oncologists with experience in treating patients with WM, and the cost of Imbruvica should be negotiated to provide cost savings for drug programs relative to zanubrutinib.&#x0D;