Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone marrow infiltration and the presence of monoclonal proteins in the blood and urine. However, despite the advances that have been made in terms of its treatment, relapsed/refractory MM (RRMM) remains a significant challenge. Chimeric antigen receptor (CAR)-T cell therapy, which involves the engineering of T-cells to express CARs targeting specific antigens on tumor cells, has emerged as a promising therapeutic approach for RRMM. The present case report presents a patient with RRMM with liver extramedullary disease (EMD) who achieved stringent complete remission following CAR-T cell therapy. This case report highlights the efficacy of CAR-T cell therapy in treating RRMM, also discussing the patient's clinical course, treatment outcomes and side effects, and moreover, a review of the literature that focuses on the treatment of EMD using CAR-T cell therapy.

The deregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is a hallmark of aggressive tumors with metabolic plasticity, eliciting their adaptation to the microenvironment and resistance to chemotherapy. A significant gap lies between the biological features of PI3K-driven tumors and the specific targeting of their vulnerabilities. Here, we explore the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We report a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR reveals the singular plasticity of PI3K-altered cells toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, the combination of glutamine degradation and mTOR inhibition demonstrates robust cytotoxicity in PI3K-driven solid and hematological tumors in pre-clinical and clinical settings. We propose a novel therapeutic strategy to circumvent metabolic adaptation and efficiently target PI3K-driven cancer.

The role of first-line single-agent rituximab immunotherapy in follicular lymphoma (FL) remains debated, as most patients eventually undergo chemotherapy.

In this study, we retrospectively analyzed 81 FL patients treated with first-line single-agent rituximab monotherapy with (n = 53) or without (n = 28) consolidation. Fifty-one patients (63%) were high-tumor burden according to Group d'Etude des Lymphomes Folliculaires (GELF) criteria.

After a median follow-up of 11 years, overall survival (OS) and progression-free survival (PFS) rates were 85% and 32%, respectively. Targeted gene expression profiling (T-GEP) was performed in 40 patients, revealing a 26-gene expression signature distinguishing complete responders and non-responders. This signature included genes involved in T-regulatory (Treg) and natural-killer cell activity, and interleukin-17 signaling. A simplified 14-gene prognostic score (ImSig) enabled accurate outcome stratification in terms of PFS. These data were validated in silico using two independent publicly available cohorts of FL patients treated with chemoimmunotherapy. Deconvolution analyses demonstrated an enrichment in Treg cells in high-risk ImSig patients, which was validated by immunohistochemistry.

These findings demonstrate that the efficacy of front-line anti-CD20 immunotherapy may depend on microenvironment-related factors, and that specific immune signatures could identify patient subsets obtaining long-term benefit from a chemo-free immunotherapeutic approach.

The authors have confirmed clinical trial registration is not needed for this submission.

Obinutuzumab was approved in China in June 2021 used in combination with chemotherapy (followed by obinutuzumab maintenance) for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL). The clinical application of obinutuzumab has recently begun in China, but there is a lack of evidence to determine under which circumstances it should be considered the treatment of choice. A comprehensive assessment is necessary to evaluate the efficacy, safety, and cost-effectiveness of obinutuzumab in adult patients with FL.

To summarize the evidence on the efficacy, safety, and cost-effectiveness of obinutuzumab in adult patients with FL, aiming to provide medical professionals with evidence for informed choices in clinical practice.

The approach to this evidence synthesis was a rapid review of systematic reviews/meta-analyses (SR/meta-analyses), health technology assessment (HTA) reports, and pharmacoeconomic studies that brings together and summarizes the efficacy, safety, and cost-effectiveness of obinutuzumab in adult patients with FL. A literature search was conducted across multiple databases, including PubMed, Embase, Wanfang, CNKI, Weipu database, the Cochrane Library, the Centre for Reviews and Dissemination (CRD) database, International Network of Agencies for Health Technology Assessment (INAHTA) and Canada's Drug Agency (CDA-AMC), International Society for Pharmacoeconomics and Outcomes Research (ISPOR), National Institute For Health and Care Excellence (NICE), Institute For Clinical And Economic Review (ICER), Grey Literature Database and Grey Net International. The studies on obinutuzumab for FL were searched in full text with obinutuzumab, systematic review, meta-analysis, economics, cost, and health technology assessment as keywords, with a search time frame from the date of database creation to 29 November 2024. The literature was screened based on predefined inclusion and exclusion criteria, and data were meticulously extracted and synthesized by two authors. Simultaneously, the quality of the literature was thoroughly assessed.

Obinutuzumab based chemotherapy (the chemotherapy regimen-cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine) significantly prolonged progression free survival (PFS) compared to other chemotherapy regimen at primary and updated analyses. The incidence of grade 3-5 AEs, infusion-related reactions (IRRs), and infection were higher in the obinutuzumab based chemotherapy group compared to other chemotherapies. The economic researches conducted in China, United States, Japan, Italy and Norway had demonstrated that obinutuzumab-based chemothrepy was cost-effective compared to other chemothrepies. Although obinutuzumab significantly prolonged PFS and was cost-effective, its safety profile was considered lower.

Compared with other chemothrapy regimen, obinutuzumab based chemotherapy significantly prolonged PFS and was cost-effective, while its safety profile was considered lower. Therefore, medical professionals should be caution when using or introducing obinutuzumab treatment for FL patients.

The treatment of CLL has evolved from traditional chemoimmunotherapy (CIT) to an increasing number of targeted and biologic approaches. Randomized trials have demonstrated superiority of covalent bruton tyrosine kinase inhibitors (cBTKis) over CIT, and second-generation compounds such as acalabrutinib and zanubrutinib appear to have a more favorable efficacy/safety profile than ibrutinib. The noncovalent BTKi, pirtobrutinib, has shown impressive activity after failure of the cBTKis and is quite tolerable. The Bcl-2 inhibitor venetoclax plus a CD20, generally obinutuzumab, provides a high level of efficacy as initial treatment or after failure on a cBTKi, with many patients achieving a state of undetectable minimal residual disease. Promising novel approaches include BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T)-cell therapy. What is clear is that CIT is archaic, and current and future targeted approaches will continue to improve the outcome for patients with chronic lymphocytic leukemia.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare entity classified under the umbrella of monoclonal gammopathy of renal significance. The clinical implications of circulating monoclonal immunoglobulin (MIg), light chain restriction on immunofluorescence (IF) microscopy, histopathological pattern, and type of therapy on renal outcomes are not clearly defined.

Sixteen patients of PGNMID diagnosed between 2013 and 2020 were included from a biopsy registry of 11,459 patients at a single center. Follow-up data was collected from electronic medical records until June 2021.

The mean age of the cohort was 41.7 ± 13.5 years. Forty-four (7/16) percent showed monoclonal protein on serum or urine electrophoresis, 25% (3/12) had IgG kappa by serum immunofixation electrophoresis (IFE) and 38% (5/13) had abnormal kappa: lambda free light chain (FLC) ratio. The predominant light microscopy pattern, membranoproliferative glomerulonephritis (MPGN) was seen in 7/16 (43.7%) patients. The predominant heavy chain detected by IF microscopy was IgG (13/16, 81.3%). Kappa and lambda light chain restriction were seen in 56.3 (9/16) and 43.8 (7/16) percent of patients respectively. Circulating monoclonal kappa light chains were detected in 50 and 29% of kappa-PGNMID patients by IFE and FLC assay respectively. None of the lambda-PGNMID patients had detectable circulating monoclonal lambda light chains. Patients with circulating MIg had more proteinuria, lower estimated glomerular filtration rate, and a higher percentage of plasma cells on bone marrow biopsy. Thirty-eight percent of our cohort (5/13) progressed to kidney failure over a median (range) period of 3 (IQR, 1-7) months. Of these, 4/5 received immunosuppression, and 1/5 were treated with plasma cell-targeted chemotherapy.

PGNMID is a rare disease with a biopsy incidence of 0.1%. Only a quarter of patients with PGNMID have circulating MIg. Presence of circulating MIg, type of monoclonal light chain restriction in kidney biopsy, and type of therapy did not predict renal outcomes. Patients with MPGN pattern had favorable renal outcomes despite a higher degree of proteinuria at presentation.

Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77-86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72-86) for R-bendamustine vs. 67% (95% CI: 61-73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86-96) for R-B vs. 91% (95% CI: 87-94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality.

Patients with asymptomatic follicular lymphoma (AFL) are candidates for observation or immunotherapy. Given the effectiveness of radiation therapy in FL, another option is 90Yttrium-ibritumomab tiuxetan radioimmunotherapy (RIT). We conducted a trial where untreated AFL patients were randomized to rituximab 375 mg/m2 weekly × 4 or rituximab 250 mg/m2 days 1, 8, and 0.4 mCi/kg (maximum 32 mCi) of RIT day 8. Twenty patients were enrolled before the study was halted due to unavailability of RIT. The ORR for rituximab and RIT were 90% and 80%, respectively; the CR rate at 6 months was 30% and 60%, respectively. After a median follow-up of 67 months, eight patients have progressed-three in the rituximab arm and five in the RIT arm and five have required systemic therapy. All patients remain alive. Both agents are highly active for AFL. The 1-week treatment with RIT and sparing of T-cells make combination therapy with newer agents attractive.

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

There is no standard first-line immunochemotherapy regimen for transplant-ineligible patients with mantle cell lymphoma (MCL) currently, and the efficacy of various treatment remains unclear.

We conducted a Bayesian network meta-analysis (NMA) of all eligible randomized controlled trials. Pairwise comparisons and ranking of different first-line treatment options were performed.

Nine studies were included in the NMA, involving a total of 2897 MCL patients. The BR-Ibrutinib+R regimen showed the best progression-free survival (PFS), with a surface under the cumulative ranking curve (SUCRA) of 0.89 and probability of being the best treatment (PbBT) of 69%. The VR-CAP regimen was the most potential intervention to improve overall survival (OS), with a SUCRA of 0.89 and PbBT of 63%. Compared with the R-CHOP regimen, the BR regimen achieved a better PFS (hazard ratio [HR] 0.45 [95% credible interval 0.2-0.96]). The BR-Ibrutinib+R regimen (HR 0.14 [0.02-0.99]), BR+R regimen (HR 0.19 [0.034-0.99]), and BR regimen (HR 0.3 [0.08-1.03]) were superior to CHOP regimen with better PFS. The R-FC regimen (HR 2.27 [1.01-5.21]) or FC regimen (HR 3.17 [1.15-8.71]) was inferior to the VR-CAP regimen with a worse OS.

Our study presents the most promising first-line treatment strategy for transplant-ineligible MCL patients in terms of PFS and OS, which provides innovative treatment strategy for MCL treatment.

Arsenic trioxide is an activist agent in the treatment of acute promyelocytic leukemia (APL), which acts alone, but has an adverse effect on patients. Moreover, deferoxamine has antiproliferative activity and induces leukopenia. In order to enhance antileukemic effectiveness and to reduce the dosage of arsenic trioxide, the combination effect of it with deferoxamine (DFO) was evaluated on the APL cell line (NB4).

In this experimental study, to investigate the cytotoxic effects of ATO/DFO in acute promyelocytic leukemia, the NB4 cell line (provided by Pasteur Institute of Iran) was treated with different doses and then at 24, 48, and 72 hrs intervals, the percentage of survival, cell count, metabolic activity and apoptosis induction were investigated respectively. Also, hTERT gene expression was analyzed by the RT-PCR method.

We found that DFO alone and in combination with ATO has cytotoxic and antiproliferative effects, and reduces viability and cell metabolic activity in the NB4 cell line in a dose and time-dependent manner. In addition, this combination causes an increase in apoptosis, up-regulation of Caspase-3, and down-regulation of hTERT genes in cells.

Combined ATO/ DFO treatment cooperatively decreased the mRNA levels of the hTERT and increased the mRNA levels of Caspase-3 in a time-dependent manner compared to DFO alone.

Follicular lymphoma (FL) is the most common low-grade lymphoma, and although nodal FL is highly responsive to treatment, the majority of patients relapse repeatedly, and the disease has been incurable with a poor prognosis. However, primary FL of the gastrointestinal tract has been increasingly detected in Japan, especially due to recent advances in small bowel endoscopy and increased opportunities for endoscopic examinations and endoscopic diagnosis. However, many cases are detected at an early stage, and the prognosis is good in many cases. In contrast, in Europe and the United States, gastrointestinal FL has long been considered to be present in 12%-24% of Stage-IV patients, and the number of advanced gastrointestinal cases is expected to increase. This editorial provides an overview of the recent therapeutic advances in nodal FL, including antibody-targeted therapy, bispecific antibody therapy, epigenetic modulation, and chimeric antigen receptor T-cell therapy, and reviews the latest therapeutic manuscripts published in the past year. Based on an understanding of the therapeutic advances in nodal FL, we also discuss future possibilities for gastroenterologists to treat gastrointestinal FL, especially in advanced cases.

Treatment of multiple myeloma (MM) is complex; however, with equal access to care, clinical outcomes for Black patients match those in other patient groups. To reveal and begin to address clinical practice barriers to equitable, patient-centered MM care, this quality improvement (QI) initiative assessed patient electronic medical records (EMRs) and surveyed patients and providers at two large hospital systems and four community-based practices. For the educational intervention, providers participated in feedback-focused grand rounds sessions to reflect on system barriers and develop action plans to improve MM care. EMR reviews revealed infrequent documentation of cytogenetics and disease staging at community-based practices compared to large hospital systems. In surveys, providers from each care setting reported different challenges in MM care. Notably, the goals of treatment for patients and providers aligned at community clinics while providers and patients from large hospital systems had discordant perspectives. However, providers in community settings underreported race-associated barriers to care and identified different factors impacting treatment decision-making than Black patients. Relative to pre-session responses, providers were more likely to report high confidence after the educational sessions in aligning treatment decisions with guidelines and clinical evidence and shared decision-making (SDM). This QI study identified discordant perceptions among providers at large hospital systems and community-based practices in providing quality MM care. Provider education yielded increased confidence in and commitment to patient-centered care.