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The Waste Management Hierarchy is used as a guiding principle for waste management of industrial solid waste. Further, it is extended for the management of industrial liquid effluents as well. The Waste Management Hierarchy consists of the five levels namely; waste prevention, reuse, recycling, recovery, and disposal. This five-tiered Waste Management Hierarchy has been adopted by the European Union under the Waste Framework Directive as a decision-making tool. This paper explores some of the technology options known and available and categorizes them according to the five levels of the Waste Management Hierarchy. This paper presents brief case studies that highlight some benefits to those who embrace this decision-making tool. [ABSTRACT FROM AUTHOR]

B Introduction: b The prognosis of histological transformation (HT) in Waldenström macroglobulinemia (WM) is unfavourable despite the use of diffuse large B-cell lymphoma-directed chemo-immunotherapy. B Methods: b Patients who received autoSCT or alloSCT between January 1996 and December 2021 were identified in an international multicenter database of 285 patients with transformed WM. The aim of this study was to evaluate the outcomes after autologous stem-cell transplantation (autoSCT) or allogeneic stem-cell transplantation (alloSCT) in patients with transformed WM. [Extracted from the article]

Background. Toxin-induced methemoglobinemia is seen in poisoning with oxidizing agents. We report the clinical features and outcome of patients admitted with severe methemoglobinemia due to intentional ingestion of toxicants. Methods. In this observational case series, patients admitted with toxin-induced methemoglobinemia between September 2011 and January 2014 were identified from the institutional poisoning database. Clinical profile and outcome of patients with methemoglobin concentration greater than or equal to 49% is reported. Results. Of the 824 patients admitted with poisoning, 5 patients with methemoglobin concentration greater than or equal to 49% were included. The implicated compounds were nitrobenzene, benzoylphenylurea, flubendamide and RishabTM. One patient refused to name the compound. All patients were managed in the intensive care unit. Altered sensorium [Glasgow coma scale (GCS) < 10] was common (80%); 2 patients presented with a GCS greater than 4. All patients manifested cyanosis, low oxygen saturation and chocolate-brown-colored blood despite supplemental oxygen therapy. The median methemoglobin concentration was 64.7% (range 49.8-91.6%); 2 patients had methemoglobin concentration greater than 70%. One patient needed inotropes. Four patients required mechanical ventilation for 4-14 days. All patients were treated with methylene blue; 4 received more than one dose. Three patients also received intravenous ascorbic acid 500 mg, once daily, for 3 days. Following treatment, there was evidence of haemolysis in all patients; 2 required blood transfusion. All patients survived. Conclusion. Patients with severe toxin-induced methemoglobinemia present with altered sensorium and cyanosis and may require ventilatory support and inotropes. Though methemoglobin concentrations greater than 70% are considered fatal, aggressive management with methylene blue and supportive therapy can lead to survival. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Therapeutic role of alemtuzumab in patients who have failed fludarabine: results of a large international study" by M. J. Keating, I. Flinn and V. Jain in the 2002 is presented.

A letter to the editor is presented in response to the article "Who and what is a veterinary specialist?," by Gardiner, Lowe, and Armstrong in the October 1, 2011 issue.

Local anaesthetic drugs are commonly used in dental practice, with few complications. We describe an unusual complication of an inferior dental nerve block where, as the needle was advanced through the mucosa, the patient experienced profound numbness and skin pallor in the distribution of the infra-orbital nerve. We discuss the possible mechanism for this complication. [ABSTRACT FROM AUTHOR]

Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton's tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). In-vivo inhibition of BCL2 has been shown to lead to apoptosis of LPL/WM cells. Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax. Fixed-duration venetoclax resulted in high response rates, but many patients relapsed following the completion of therapy. The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will be key, although an additional treatment modality for quadruple-refractory patients with limited treatment options is urgently required., Competing Interests: SD’S has received research support from Janssen and BeiGene, and advisory board honoraria from Janssen, BeiGene, HillStarBio, Kite and Sanofi. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tomkins and D’Sa.)

The optimal therapeutic approach for relapsed/refractory (R/R) Waldenström's Macroglobulinaemia (WM) has not been clearly defined, especially after treatment with chemoimmunotherapy (CIT) and covalent Bruton's tyrosine kinase inhibitors (cBTKi). The PembroWM trial is a multi-centre, phase II, single-arm study assessing the safety, tolerability and efficacy of rituximab with pembrolizumab in R/R WM patients who had received at least one prior line of treatment, with all having relapsed post-CIT and most also exposed to cBTKi. A total of 17 patients were enrolled, with a median age of 70, and median of three prior lines of therapy with 15 either refractory or intolerant of a cBTKi. A significant proportion was identified as genomically high risk with BTKC481, CXCR4 and MYD88 L265P wild-type aberrations. Twenty-four-week overall response rate was 50% (60% CI 39.3%-60.7%), and median duration of response was 11.6 months (IQR: 6.3-17). The median progression-free survival was 13.6 months (95% CI 3-19.8), and the median overall survival (OS) was not reached. Treatment was well tolerated, with minimal numbers of immune-mediated AEs typically seen with checkpoint inhibitors. PembroWM is the first study to evaluate the feasibility of PD-1 axis modulation in WM and has shown that in combination with Rituximab the combination is safe and deliverable., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: During the last decades, the pathogenesis of cold agglutinin disease (CAD) has been well elucidated and shown to be complex. Several documented or investigational therapies have been made available. This development has resulted in major therapeutic advances, but also in challenges in choice of therapy., Areas Covered: In this review, we address each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation. We also discuss the heterogeneous clinical features and their relation to specific steps in pathogenesis, in particular with respect to the impact of complement involvement. CAD can be classified into three clinical phenotypes with consequences for established treatments as well as development of new therapies. Some promising future treatment approaches - beyond chemoimmunotherapy and complement inhibition - are reviewed., Expert Opinion: The patient's individual clinical profile regarding complement involvement and hemolytic versus non-hemolytic features is important for the choice of treatment. Further development of treatment approaches is encouraged, and some candidate drugs are promising irrespective of clinical phenotype. Patients with CAD requiring therapy should be considered for inclusion in clinical trials.

Purpose: Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters., Patients and Methods: We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort., Results: In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001)., Conclusion: Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

Background: Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated., Methods: The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout., Findings: In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 μmol/L on-treatment vs 35.0 μmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD., Interpretation: The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs., Funding: Sanofi., Competing Interests: AR has received consultancy fees from Alexion Pharmaceuticals, Inc, Apellis Pharmaceuticals, Bioverativ, a Sanofi company, Novartis, Roche, and Sanofi; honoraria from Alexion, Amgen, Apellis, Novartis, Roche, Sanofi and Sobi, and advisory board fees from Alexion, Amgen, Apellis, Bioverativ, Novartis, Roche, Sanofi, and Sobi. SB has received research support from Mundipharma; lecture honoraria from Apellis, Bioverativ (a Sanofi company), Janssen-Cilag, Momenta Pharmaceuticals and True North Therapeutics; and consultancy and advisory board honoraria from Apellis, Bioverativ, and Momenta Pharmaceuticals. WB has received research support from Alexion; honoraria from Agios, Alexion, Apellis, Biocryst, Incyte, Janssen, Momenta, Novartis, Sanofi, and Sobi; and advisory board fees from Alexion, Novartis, Roche, Sanofi, and Sobi. SD reports speaker fees and research funding from Janssen, BeiGene and Sanofi. BJ has received reimbursement for travel costs related to scientific advice and scientific presentations from Sanofi. MM has received research support for clinical studies from Roche; received fees from Amgen and GlaxoSmithKline for their participation in scientific advisory boards. ICW has received consultancy fees from Alexion, Apellis, Novartis, and Biocryst; and honoraria from Alexion. MY has no disclosures. JN is a member of the advisory board for Chugai Pharmaceuticals and Alexion Pharmaceuticals and has received research funding and honorarium from Alexion Pharmaceuticals. JMIV has received honoraria from Sanofi, Amgen, and BMS; research support from Beigene and AbbVie/Genmab, and advisory board fees from Sanofi and Janssen; all of these are institutional. JC received research funding from Cerus, Kawasumi Laboratories and Sanofi; he also received speaker or advisory fees from Cerus, Fresenius Kabi, Grifols, MacoPharma, Pharm-Olam, Sanofi and Terumo Blood and Cell Technologies. CMB has received research support from Alexion, Argenx, Electra, Novartis, and Sanofi; honoraria from Alexion, Argenx, and Sanofi; and advisory board fees from Argenx, Novartis, and Sanofi. DJ, FS, ML, MS, MW, NW, RY, SS are Sanofi employees and may hold stock and/or stock options in the company., (© 2024 The Author(s).)

Listeria monocytogenes is a relatively uncommon cause of foodborne infection in the general population. Most cases of Listeriosis occur among newborns, pregnant women, the elderly and those with impairment of cellular immunity. Neonatal Listeria meningitis is rare. We present a case of Listeria meningitis at the age of 15 days in a previously healthy neonate who presented with acute onset of fever, poor feeding and lethargy. Sepsis workup revealed L. monocytogenes identified in cerebrospinal fluid PCR and culture. The infant's course was complicated by transient syndrome of inappropriate antidiuretic hormone and subsequent hydrocephalus that required a ventriculoperitoneal shunt placement. Though rare, neonatal infections due to Listeria can present with meningitis leading to serious and devastating complications. Our case emphasises the importance of considering Listeria in cases of neonatal meningitis and the value of close follow-up of such cases through early detection and management of acute and long-term complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Peripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: The 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., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrőm macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by complement pathway-mediated hemolysis. Riliprubart (SAR445088, BIVV020), a second-generation classical complement inhibitor, is a humanized monoclonal antibody that selectively inhibits only the activated form of C1s. This Phase 1b study evaluated the safety, tolerability, and effect on hemolysis of riliprubart in adult patients with cold agglutinin disease. On day 1, 12 patients received a single IV dose of either 30 mg/kg (n = 6) or 15 mg/kg (n = 6) of riliprubart and were subsequently followed for 15 weeks. Riliprubart was generally well tolerated; there were no treatment-emergent serious adverse events, or treatment-emergent adverse events leading to death or permanent study discontinuation. There were no reports of serious infections, encapsulated bacterial infections including meningococcal infections, hypersensitivity, or thromboembolic events. Rapid improvements in hemoglobin (day 5) and bilirubin (day 1) were observed in both treatment cohorts. Mean hemoglobin levels were maintained at >11.0 g/dL from day 29 and mean levels of bilirubin were normalized by day 29; both responses were maintained throughout the study. Improvements in clinical markers closely correlated with a sustained reduction in the 50% hemolytic complement (CH50) throughout the study. Mean C4 levels, an in vivo marker of treatment activity, increased 1 week after treatment with either dose of riliprubart and were sustained throughout the study. In conclusion, a single IV dose of riliprubart was well tolerated, and led to rapid classical complement inhibition, control of hemolysis, and improvement in anemia, all of which were sustained over 15 weeks. This trial was registered at www.ClinicalTrials.gov as #NCT04269551., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient's quality of life. CARDINAL was a 2-part, open-label, single-arm, multicenter phase 3 study evaluating the C1s inhibitor, sutimlimab, for treatment of CAD. Part A consisted of the pivotal study phase, with the part B extension phase assessing long-term safety and durability of response including patient-reported outcomes, which is the focus of this report. Altogether, 22 patients continued from part A to part B, majority female (68.2%) with a median age of 71.5 years (range, 55-85). Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale exceeded a predefined, group-level clinically important change of ≥5 points vs baseline, with a mean (standard error [SE]) change of 11.7 (3.7) points at week 135. The 12-Item Short Form Health Survey physical and mental component scores remained above baseline, with week 123 mean change (SE) exceeding clinically important changes of 3.9 for physical and 2.8 for mental component scores at 4.7 (2.8) and 3.8 (5.7) points, respectively. EuroQol Visual Analogue Scale, scoring patients' self-rated health, also remained above baseline with a change of 17.1 (5.6) points at week 135. Patient Global Impression of (fatigue) Severity improved vs baseline, corroborating FACIT-Fatigue scores. Patient Global Impression of Change indicated a reduction in perceived disease burden. Data from CARDINAL part B support sustained alleviation of CAD disease burden after long-term treatment with sutimlimab over 2 years, returning toward baseline upon treatment cessation. This trial was registered at www.clinicaltrials.gov as #NCT03347396., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The immunoglobulin M (IgM)-associated peripheral neuropathies (PN) are a heterogeneous group of disorders representing most paraproteinemic neuropathy cases. They are associated with IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia. Establishing a causal link between a paraprotein and neuropathy can be challenging but is necessary to adopt an appropriate therapeutic approach. The most common type of IgM-PN is Antimyelin-Associated-Glycoprotein neuropathy, but half of the cases are of other causes. Progressive functional impairment is an indication for treatment, even when the underlying disorder is IgM MGUS, involving either rituximab monotherapy or combination chemotherapy to achieve clinical stabilization., (Copyright © 2023 Elsevier Inc. All rights reserved.)