Lymphoplasmacytic lymphoma and multiple myeloma coexisting in the same patient: a case series and literature review.

The simultaneous occurrence of Waldenström macroglobulinemia and multiple myeloma in the same patient has been published as case reports. Patients with Waldenström macroglobulinemia often have a small clone of plasma cells. However, the concurrent occurrence of symptomatic myeloma with lytic bone lesions is rare. The diagnosis of this 'hybrid' entity is challenging, and there are no standard therapies. We present six patients from five centers (three in Israel and two in the United States). We describe these patients' unique clinical course and treatment approaches.

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

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.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia.

ABSTRACT: Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.

Optimization of Advanced Molecular Genetic Testing Utilization in Hematopathology: A Goldilocks Approach to Bone Marrow Testing.

PURPOSE: This study investigated the effectiveness of algorithmic testing in hematopathology at the Brigham and Women's Hospital and Dana-Farber Cancer Institute (DFCI). The algorithm was predicated on test selection after an initial pathologic evaluation to maximize cost-effective testing, especially for expensive molecular and cytogenetic assays. MATERIALS AND METHODS: Standard ordering protocols (SOPs) for 17 disease categories were developed and encoded in a decision support application. Six months of retrospective data from application beta testing was obtained and compared with actual testing practices during that timeframe. In addition, 2 years of prospective data were also obtained from patients at one community satellite site. RESULTS: A total of 460 retrospective cases (before introduction of algorithmic testing) and 109 prospective cases (following introduction) were analyzed. In the retrospective data, 61.7% of tests (509 of 825) were concordant with the SOPs while 38.3% (316 of 825) were overordered and 30.8% (227 of 736) of SOP-recommended tests were omitted. In the prospective data, 98.8% of testing was concordant (244 of 247 total tests) with only 1.2% overordered tests (3 of 247) and 7.6% omitted tests (20 of 264 SOP-recommended tests; overall P < .001). The cost of overordered tests before implementing SOP indicates a potential annualized saving of $1,347,520 in US dollars (USD) in overordered testing at Brigham and Women's Hospital/DFCI. Only two of 316 overordered tests (0.6%) returned any additional information, both for extremely rare clinical circumstances. CONCLUSION: Implementation of SOPs dramatically improved test ordering practices, with a just right number of ancillary tests that minimizes cost and has no significant impact on acquiring key informative test results.

Waldenström Macroglobulinemia: Targeted Agents Taking Center Stage.

With the worldwide approval of the oral covalent Bruton tyrosine kinase (BTK) inhibitors ibrutinib and zanubrutinib for treating patients with Waldenström macroglobulinemia (WM), targeted agents have certainly taken center stage in the therapeutic landscape of WM. This review discusses the biological and clinical data supporting current and up-and-coming targeted agents in WM. Bruton tyrosine kinase inhibitors induce fast, deep, and durable responses in patients with WM, comparable to chemoimmunotherapy; however, there is a glaring absence of comparative studies between these regimens. The high response and progression-free survival rate and the ease of administration of BTK inhibitors must be balanced against their specific adverse-event profile with unique toxicity (e.g., bleeding and cardiac arrhythmia) and the indefinite duration of the therapy. Novel targeted agents of interest include BCL2 antagonists (e.g., venetoclax and sonrotoclax) and non-covalent BTK inhibitors (e.g., pirtobrutinib and nemtabrutinib), among others. The therapeutic landscape of patients with WM will benefit from the robust participation of patients in clinical trials.

Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia.

ABSTRACT: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

Situational diagnosis of policies in Latin American and Caribbean countries for the use of fluoride and reduction of sugar consumption.

Policy evaluation and guidance on fluoride use and sugar consumption in Latin American and Caribbean countries (LACC) may provide a scientific evidence basis for policymakers, dental professionals, civil society organizations and individuals committed to improving public oral health. A cross-sectional study was conducted to evaluate the extent of implementation of policies/guidelines on fluoride use, and sugar consumption in LACC. The study had two stages. First a questionnaire covering four major areas was developed: fluoridation of public water supplies; salt fluoridation; fluoride dentifrices, and sugar consumption. Then, the questionnaire was applied to collect data among representative participants in public oral health from LACC. Ninety-six participants from 18 LACC answered the questionnaire. One-hundred seventy documents were attached, and 285 links of websites were provided by the respondents. Implementation of policies and guidelines on water and table salt fluoridation and processed and ultra-processed food consumption were found in most countries, with some issues in the consensus and coverage. Thus, differences were identified in the extent of implementation of public oral health strategies on sugar consumption and fluoridation among the countries. There is no consensus on the policies in LACC to reduce sugar consumption and for the use of fluoride. A few policies and guidelines were applied in isolated countries, with a variety of strategies and standards. For future actions, it will be important to encourage the development of strategies and public policies within countries, and to evaluate the effectiveness of existing policies in reducing dental caries and in improving oral health in LACC.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Small Cell Neuroendocrine Carcinoma of the Lung Discovered by Acute Appendicitis Metastasis: An Experience at Our Hospital.

Acute appendicitis is the most common cause of abdominal pain that requires surgery. Appendiceal cancer is rare, comprising nearly 4% of all gastrointestinal diagnoses. It is common to find neuroendocrine neoplasms due to metastasis in this site. Appendix tumors are usually asymptomatic; however, if they are advanced or have metastases, they can cause abdominal symptoms. Computed tomography (CT) is commonly used to diagnose acute appendicitis in these cases. CT usually shows an increased appendiceal diameter with thickening (>3 mm) of the appendiceal wall, an intraluminal fluid depth >2.6 mm, and periappendiceal inflammation. Histopathological findings confirm the diagnosis. Medical and surgical management depends on physical characteristics such as size, location, and degree of evolution. We present the case of a 77-year-old woman with a family history of well-controlled type 2 diabetes mellitus and hypertension. She was referred to our institution after four days of abdominal pain in the epigastrium and both flanks accompanied by fever. An abdominal CT showed left pleural effusion and appendicular thickening. Laboratory tests showed high blood glucose levels, leukocytosis at the expense of neutrophils, an increased platelet count, and decreased albumin and total proteins. The CT scan also showed a calcified granuloma in the anterior segment of the right upper lobe and an irregular image with partially defined hypodense borders in the liver in segment IVb. We report our experience with the diagnosis, management, and treatment decisions of this case. It is important to mention that the first diagnosis was acute appendicitis. This diagnosis motivated us to seek other symptoms and signs by direct questioning and imaging studies leading us to diagnose metastatic lung cancer.

Eficacia y seguridad de la administración de plasma de convaleciente en pacientes con COVID-19 / Efficacy and safety of convalescent plasma administration in patients with COVID-19 infection

Introducción Durante la pandemia de COVID-19 surgieron diversas estrategias para el manejo de la enfermedad, incluidos los tratamientos farmacológicos y no farmacológicos como el plasma convaleciente (PC). El uso de PC se sugirió debido a los resultados benéficos mostrados al tratar otras enfermedades virales. Objetivo Determinar la eficacia y la seguridad de la administración de PC obtenido de sangre total en pacientes con COVID-19. Métodos Ensayo clínico piloto en pacientes con COVID-19 de un hospital general. Los sujetos se separaron en 3 grupos que recibieron la transfusión de 400ml de PC (n=23) o 400ml de plasma estándar (PE) (n=19) y un grupo no transfundido (NT) (n=37). Los pacientes recibieron además, el tratamiento médico estándar disponible para COVID-19. El seguimiento de los sujetos se llevó a cabo diariamente desde el ingreso hasta el día 21. Resultados El PC no mejoró la curva de supervivencia en las variantes moderadas y graves de COVID-19, ni disminuyó el grado de severidad de la enfermedad evaluado con la escala de progresión clínica COVID-19, OMS y SOFA. Ningún paciente presentó una reacción postransfusional severa al PC. Conclusiones El tratamiento con PC no disminuye la mortalidad de los pacientes, aun cuando su administración tiene un alto grado de seguridad (AU)

Introduction During the COVID-19 pandemic, several strategies were suggested for the management of the disease, including pharmacological and non-pharmacological treatments such as convalescent plasma (CP). The use of CP was suggested due to the beneficial results shown in treating other viral diseases. Objective To determine the efficacy and safety of CP obtained from whole blood in patients with COVID-19. Methods Pilot clinical trial in patients with COVID-19 from a general hospital. The subjects were separated into three groups that received the transfusion of 400ml of CP (n=23) or 400ml of standard plasma (SP) (n=19) and a non-transfused group (NT) (n=37). Patients also received the standard available medical treatment for COVID-19. Subjects were followed up daily from admission to day 21. Results The CP did not improve the survival curve in moderate and severe variants of COVID-19, nor did it reduce the degree of severity of the disease evaluated with the COVID-19 WHO and SOFA clinical progression scale. No patient had a severe post-transfusion reaction to CP. Conclusions Treatment with CP does not reduce the mortality of patients even when its administration has a high degree of safety (AU)

Biomarkers of Progression and Risk Stratification in Asymptomatic Waldenström Macroglobulinemia.

Waldenström macroglobulinemia is an indolent IgM-secreting B-cell lymphoplasmacytic lymphoma that is preceded by an asymptomatic stage. Clinical and molecular features have been used in risk models to predict progression rates in different asymptomatic subgroups. Risk models used both disease-specific and nonspecific biomarkers for asymptomatic patients. Recently, models that incorporate continuous variables rather than distinct cutoffs have emerged to more accurately predict the risk of progression. Integrating genetic alterations to the clinical models is a promising approach that could improve risk stratification and management of asymptomatic patients.

HIV-1 Low-Frequency Variants Identified in Antiretroviral-Naïve Subjects with Virologic Failure after 12 Months of Follow-Up in Panama.

Low-frequency mutations associated with drug resistance have been related to virologic failure in subjects with no history of pre-treatment and recent HIV diagnosis. In total, 78 antiretroviral treatment (ART)-naïve subjects with a recent HIV diagnosis were selected and followed by CD4+ T lymphocytes and viral load tests to detect virologic failure. We sequenced the basal samples retrospectively using next-generation sequencing (NGS), looking for low-frequency mutations that had not been detected before using the Sanger sequencing method (SSM) and describing the response to ART. Twenty-two subjects developed virologic failure (VF), and thirteen of them had at least one drug-resistance mutation associated with Reverse Transcriptase Inhibitors (RTI) and Protease Inhibitors (PIs) at frequency levels ≤ 1%, not detected previously in their basal genotyping test. No resistance mutations were observed to Integrase Strand Transfer Inhibitors (INSTIs). We identified a possible cause of VF in ART-naïve subjects with low-frequency mutations detected. To our knowledge, this is the first evaluation of pre-existing drug resistance for HIV-1 minority variants carried out on ART-naïve people living with HIV/AIDS (PLWHA) by analyzing the HIV-1 pol gene using NGS in the country.

[Efficacy and safety of convalescent plasma administration in patients with COVID-19 infection]. / Eficacia y seguridad de la administración de plasma de convaleciente en pacientes con COVID-19.

INTRODUCTION: During the COVID-19 pandemic, several strategies were suggested for the management of the disease, including pharmacological and non-pharmacological treatments such as convalescent plasma (CP). The use of CP was suggested due to the beneficial results shown in treating other viral diseases. OBJECTIVE: To determine the efficacy and safety of CP obtained from whole blood in patients with COVID-19. METHODS: Pilot clinical trial in patients with COVID-19 from a general hospital. The subjects were separated into three groups that received the transfusion of 400ml of CP (n=23) or 400ml of standard plasma (SP) (n=19) and a non-transfused group (NT) (n=37). Patients also received the standard available medical treatment for COVID-19. Subjects were followed up daily from admission to day 21. RESULTS: The CP did not improve the survival curve in moderate and severe variants of COVID-19, nor did it reduce the degree of severity of the disease evaluated with the COVID-19 WHO and SOFA clinical progression scale. No patient had a severe post-transfusion reaction to CP. CONCLUSIONS: Treatment with CP does not reduce the mortality of patients even when its administration has a high degree of safety.

Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study.

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.

The prognostic role of red cell distribution width on all-cause and cause-specific outcomes in peripheral T-cell lymphoma: a retrospective cohort study.

Readily accessible biomarkers for risk stratification in settings with limited resources are lacking. We evaluated the effect of high red distribution width-coefficient of variation (RDW-CV) values (>14%) on all-cause and lymphoma-specific mortality outcomes among 118 patients with peripheral T-cell lymphoma (PTCL) who received systemic treatment at two tertiary centers between 2010 and 2019. With a median follow-up of 45 months, patients with a high RDW-CV had a lower 4-year overall survival rate (34% vs. 45%, p = 0.015) and higher cumulative incidence of lymphoma mortality (54% vs. 34%, p = 0.007). RDW-CV >14% was associated with all-cause (adjusted Hazard Ratio [aHR] 1.98, 95% confidence interval [CI] 1.10-3.56) and lymphoma-specific mortality (aHR 2.64, 95% CI 1.32-5.29). In our study, RDW-CV emerges as an easily accessible and complementary prognostic biomarker for risk stratification among treated patients with de novo PTCL. Further research should validate the predictive role of RDW-CV in prospective cohorts.