Treatment of relapsed refractory follicular lymphoma (R/R FL) still remains challenging. Several strategies have been used against R/R FL. Recently, two chemotherapy-free regimens have gained space, epcoritamab-lenalidomide-rituximab (Epco-R2) and tafasitamab-lenalidomide-rituximab (Tafa-R2). Herein, we performed an indirect trial comparison (ITC) between the two regimens using the Bucher method as they both have the common comparator arm R2. The ITC between the two study arms showed an overall response rate (ORR; p = 0.020), and complete remission rates (CR; p < 0.0001), in favor of Epco-R2. Analysis regarding time to next treatment (TTNT) interval also favored Epco-R2 (p = 0.0011). The ITC in the progression free survival (PFS) context showed the anchored comparison favored Epco-R2 over Tafa-R2 [HR 0.51 (95% CI 0.31-0.86)], p = 0.011, a finding more pronounced in patients with progression of disease within 24 months (POD24) negativity. Regarding the safety profile, Epco-R2 was associated with more hematological toxicity and infections, whereas, Tafa-R2 was associated with more COVID-19 infections probably reflecting the pandemic era enrollment timing. In conclusion, Epco-R2 is more effective in terms of treatment outcomes, but comes with greater toxicity. Tafa-R2 seems more suitable for patients with limited bone marrow reserves, patients who wish to avoid hospitalization, patients at a higher risk for cytokine release syndrome, and patients with high-risk infection vulnerability. Finally, this is not a direct comparison of two therapeutic regimens and the results should be cautiously interpreted. Treatment choice should be decided on a case-by-case scenario based on several different variables.

We report the first case of using teclistamab, a BCMA × CD3 bispecific antibody, in a 63-year-old male with κ-light chain deposition disease (LCDD) involving the kidneys and probably the heart. The patient initially responded to daratumumab-pomalidomide-dexamethasone but experienced hematologic relapse. Salvage therapy with teclistamab induced a rapid and sustained hematologic complete response without cytokine release syndrome or neurotoxicity. Renal and cardiac functions remained stable. This case provides critical early evidence that BCMA-directed immunotherapy may serve as an effective salvage strategy for this rare plasma cell disorder, addressing a significant unmet therapeutic need.

Bispecific antibodies (BsAbs) redirect T-cells to tumor antigens in an MHC-independent manner. These universally available, off-the-shelf products have demonstrated unprecedented efficacy in heavily pretreated patients with relapsed/refractory (R/R) hematological malignancies (HMs). The indefinite treatment duration associated with most BsAb products, coupled with neutropenia, B-cell aplasia, and hypogammaglobulinemia result in significant immune-related toxicities and infections. Hence, non-relapse mortality (NRM) which represents the cumulative burden of treatment-related toxicities, defined as death from any cause other than disease relapse or progression, is a patient-centric endpoint across cellular therapy platforms. While recent NRM estimates with CAR T-cell therapy have identified infections as major drivers of NRM, real-world NRM estimates remain limited with BsAbs. To mitigate the limitations associated with each of the methods, we conducted a systematic review and meta-analysis of the existing literature, supplemented concurrently by a pharmacovigilance analysis using the FAERS database, to estimate NRM with BsAbs and compare real-world findings between commercially available BsAb products approved for relapsed/refractory multiple myeloma (RRMM) and NHL. The primary endpoint was NRM; secondary endpoints included CRS, ICANS, infections, and death. Teclistamab demonstrated a high toxicity burden across both analytic methods, with the highest ICANS incidences, significantly greater infection rates (particularly grade > 3), and a non-negligible NRM estimate in the SRMA as well in FAERS. Glofitamab was associated with severe toxicities, including increased reporting odds for NRM and overall mortality. Mosunetuzumab showed lower pooled estimates and lower reporting odds, as seen in both analytic approaches. Low pooled incidences of infections, and ICANS were calculated in the SRMA. FAERS analyses also suggested reduced reporting odds for NRM and neurotoxicity. While trial-level data and real-world reporting largely converged for severe toxicities, divergences in other agents underscore the importance of continuous post-marketing surveillance. Given the risks associated with prolonged treatment, future protocols must prioritize infection management and adopt NRM as a standardized endpoint to guide appropriate therapeutic selection and sequencing.

Acute myeloid leukemia (AML) is a metabolically heterogeneous malignancy with poor outcomes and limited durable therapeutic options. We investigated NFS1, a key enzyme involved in iron-sulfur cluster biogenesis, as a potential metabolic vulnerability in AML. NFS1 was overexpressed in AML samples, and higher expression was associated with inferior overall survival in the TCGA-LAML cohort. Genetic knockdown of NFS1 markedly suppressed AML cell proliferation in vitro and reduced tumor growth in subcutaneous xenograft models. NFS1 knockdown induced disturbances in iron homeostasis accompanied by increased reactive oxygen species production and lipid peroxidation, together with reduced GPX4 expression. Together with the partial restoration of cell viability by ferrostatin-1, deferoxamine, and Z-VAD-FMK, these changes were consistent with concurrent apoptotic and ferroptosis-like cell death. Transcriptomic analysis revealed enrichment of type I interferon-related signaling pathways, while experimental validation demonstrated increased STAT1 phosphorylation at Tyr701 and increased expression of the downstream effector IFIT2. IFIT2 knockdown partially reversed the anti-proliferative effects of NFS1 knockdown, supporting an association between the growth-suppressive phenotype induced by NFS1 knockdown and STAT1/IFIT2-associated signaling. NFS1 knockdown was also accompanied by increased expression of PD-L1 and elevated concentrations of inflammatory cytokines such as IL-6 and IL-8, and reduced CD80 expression in THP-1-derived macrophage-like cells in an in vitro co-culture system. These findings indicate that NFS1 depletion is associated with immune-related transcriptional and phenotypic changes in vitro. Furthermore, NFS1 knockdown enhanced the in vitro sensitivity of AML cells to azacitidine, venetoclax, and bortezomib. Collectively, this study suggests that NFS1 may represent a metabolic vulnerability in AML that links its depletion to iron dysregulation, apoptotic and ferroptosis-like cell death, and STAT1/IFIT2-associated signaling, providing a rationale for further investigation of NFS1 as a potential therapeutic target in AML.

Coexistent chronic myeloid leukemia (CML) and BCR::ABL1-negative myeloproliferative neoplasms (MPN) are rare. We aimed to evaluate their clinical and therapeutic profiles. We retrospectively evaluated 36 institutional patients with coexistent CML and BCR::ABL1-negative MPN (Cohort A) and systematically reviewed 244 published cases (Cohort B). Patients were categorized by diagnostic sequence: prior CML, prior BCR::ABL1-negative MPN, or concurrent presentation. BCR::ABL1 p210 and JAK2V617 F aberrations predominantly co-occurred. Diagnoses in Cohort A were mostly concurrent (77.8%), whereas Cohort B predominantly featured prior BCR::ABL1-negative MPN (43.0%), followed by concurrent diagnoses (35.7%) and prior CML (21.3%). In Cohort B, myelofibrosis was significantly more prevalent in prior BCR::ABL1-negative MPN compared to those with prior CML or concurrent diagnoses (56.2% vs. 26.9% vs. 35.6%, respectively; p = 0.007). Persistent, unexplained cytosis despite active therapy triggered secondary mutation cross-screening in both cohorts. In Cohort A, exploratory survival analysis suggested a potential trend toward shorter overall survival in prior BCR::ABL1-negative MPN compared to concurrent diagnoses (90.5 months vs. not reached, p = 0.032). Multivariable analysis of Cohort B identified prior BCR::ABL1-negative MPN as an independent adverse predictor for major or deeper molecular responses (OR = 0.412, 95% CI: 0.197-0.861, p = 0.018), while tyrosine kinase inhibitor (TKI)-based therapy was favorable (OR = 9.74, 95% CI: 1.108-85.636, p = 0.040). Addition of JAK2 inhibitors to TKI therapy did not significantly improve molecular responses over TKI monotherapy (67.1% vs. 54.8%, p = 0.193). To summarize, prior BCR::ABL1-negative MPN, the most frequent presentation, predicted inferior molecular responses. Clinicians should screen for coexistent mutations if cytosis persisted despite treatment. TKI remained the therapeutic cornerstone, as combined JAK2 inhibition demonstrated limited additional benefit.

In recent years the addition of the oral BCL2 inhibitor venetoclax to hypomethylating agents (HMAs) has emerged as the standard-of-care for patients with acute myeloid leukemia (AML) who are not fit for intensive chemotherapy, significantly improving survival and quality-of-life. Venetoclax is metabolized mainly by cytochrome P450 3A4 enzymes and serves as a P-glycoprotein substrate, which make it largely affected by interactions with drugs. Dose reductions are needed to allow mold active antifungal prophylaxis, but there is no consensus on the exact venetoclax target dose concomitantly with posaconazole. We report on efficacy and safety of venetoclax combinations in 38 first-line (FL) and 51 relapsed-refractory (R/R) AML patients. Although complete remission (CR) rate was lower in R/R than in FL (49% vs. 68%; p = 0.08), achievement of this status was associated with comparable median overall survival (OS) in R/R and FL (13.67 vs. 13.72 months). Eighteen (20%) patients underwent allogenic hematopoietic stem cell transplantation (HSCT) with a 2-year OS probability of 66.7%. Although antifungal prophylaxis was associated with a lower rate of grade 3-4 fungal infections (6% vs. 24%, p 0.044), patients treated with venetoclax daily dose of 50 mg with posaconazole had significantly shorter mOS in multivariate analysis (16.5 vs. 4.5 months; p 0.011). We conclude that AML patients in remission with venetoclax combinations may still be consolidated, and potentially cured, by HSCT, even after failure of intensive chemotherapy. Posaconazole prophylaxis effectively reduces risk of severe fungal infections, but a concomitant venetoclax dose of 50 mg may be sub-optimal.

Conventional glofitamab step-up dosing reaches the 30-mg target dose approximately 3 weeks after obinutuzumab. This interval may be difficult to accommodate in patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) who require disease control within days before cellular therapy. We retrospectively evaluated an accelerated bridging schedule of obinutuzumab 1000 mg on day 1 followed by glofitamab 2.5 mg on day 4, 10 mg on day 8, and 30 mg on day 11. Forty-one consecutive adults with R/R LBCL were included. All patients had a documented plan to proceed to chimeric antigen receptor (CAR) T-cell therapy after glofitamab initiation. The cohort was high risk: 90.2% had stage III-IV disease, 70.7% had an International Prognostic Index score of 3%-5%, and 46.3% had central nervous system (CNS) involvement. Cytokine release syndrome (CRS) occurred in 8 patients (19.5%), including 1 grade 3 event; immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients (4.9%), both grade 1-2. At the prespecified day-12 assessment, the overall response rate was 80.5% (33/41). Among 19 patients with CNS involvement, 18 (94.7%) responded, and cerebrospinal fluid cytology cleared in all evaluable patients with baseline positivity. After one cycle, 38 of 41 patients (92.7%) proceeded to planned CAR T-cell therapy. In this relatively small retrospective cohort, accelerated glofitamab bridging therapy showed rapid early antitumor activity and manageable toxicity, and a high response rate after subsequent CAR T-cell therapy. Longer-term outcomes could not be attributed to glofitamab alone. These findings are descriptive and require prospective validation.

Bispecific antibodies (BsAbs) targeting CD20 × CD3 have achieved remarkable efficacy in relapsed or refractory (R/R) B-cell lymphoma, yet clinical responses remain heterogeneous and predictive biomarkers are lacking. We retrospectively evaluated associations between peripheral immune profiles and outcomes in 40 patients treated with CD20 × CD3 BsAbs and explored BTK inhibitor-associated immune changes using a paired BTK inhibitor cohort, functional assays, mouse models, and single-cell RNA sequencing. Higher baseline CD4[+] T-cell counts correlated with superior response rates and prolonged progression-free survival, whereas CD8[+] counts showed no association. Elevated CD4[+] T-cell levels were linked to increased activation of effector CD8[+]CD28[+] T cells and greater induction of IL-2 and IFN-γ following treatment. Across paired clinical samples and experimental models, BTK inhibition was associated with CD4[+] T-cell expansion and enhanced T/NK-cell proliferative and cytotoxic signatures. In an exploratory real-world observation, three patients received BTK inhibition before glofitamab; all achieved complete responses, with two remaining in remission at data cutoff and one relapsing after 8.4 months. These findings identify peripheral CD4[+] T-cell reserve as a potential biomarker associated with BsAb outcomes and provide a rationale for further investigation of BTK inhibitor-mediated immune modulation in BsAb treatment strategies.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm with a high risk of leukemic transformation. Alternative polyadenylation (APA) is an important post-transcriptional mechanism, and its dysregulation is closely linked to the pathogenesis of hematological malignancies. This study aimed to clarify the regulatory role of the NUDT21-APA-SRSF2 axis in the progression of myelodysplastic syndrome (MDS). To this end, we established MDS cell models overexpressing or knocking down NUDT21 and SRSF2. The regulatory mechanism and functional impacts of this axis were systematically evaluated using RT-qPCR, Western blot, CCK-8 assay and flow cytometry; APA site analysis mediated by specific primers and transcriptome sequencing. The results showed that the expression of NUDT21 was negatively correlated with that of SRSF2 (p < 0.05). Overexpression of NUDT21 promoted the utilisation of distal polyadenylation sites on SRSF2, increasing the expression of its long 3'UTR variants; conversely, NUDT21 knockdown produced the opposite effect (p < 0.05). Functionally, NUDT21 enhanced MDS cell proliferation and inhibited apoptosis, though this effect was reversed by co-overexpression of SRSF2. Furthermore, SRSF2 could antagonize the regulatory effect of NUDT21 on the cell cycle. In summary, our in vitro data demonstrate that NUDT21 remodels SRSF2 isoform balance via alternative polyadenylation (APA) and regulates biological functions of MDS-derived cells. The NUDT21-APA-SRSF2 axis represents a key regulatory cascade with potential therapeutic implications.

Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) is a highly effective treatment option for patients with relapsed refractory multiple myeloma (RRMM). However, reliable biomarkers predicting long-term treatment response remain elusive. Germline single-nucleotide polymorphisms (SNPs) in immune checkpoint regulators, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activation gene 3 (LAG3) may affect CAR T-cell functionality and clinical efficacy. We conducted a retrospective analysis of 87 patients with RRMM treated with BCMA-directed CAR T-cells at a single academic center between May 2021 and September 2025, evaluating the impact of CTLA4 rs231775 and LAG3 rs870849 on relapse, progression-free survival (PFS), and overall survival (OS). The minor allele rs231775 of CTLA4 was present in 48%, while the minor allele of LAG3 rs870849 was observed in 87% of patients. Carriers of the CTLA4 rs231775 minor allele demonstrated lower relapse (40 vs. 53%) and mortality rates (31 vs. 44%) compared with major allele homozygotes, accompanied by significantly prolonged PFS and OS. Likewise, patients homozygous for the LAG3 rs870849 minor allele experienced reduced relapse (36 vs. 52%) and mortality rates (28 vs. 42%), significantly longer PFS, and a trend toward improved OS relative to carriers of the major allele. In conclusion, in our study, the minor alleles of CTLA4 rs231775 and LAG3 rs870849 were associated with superior clinical outcomes following BCMA-directed CAR T-cell therapy in RRMM patients. These findings suggest to further evaluate whether immune checkpoint SNPs could be biomarkers predicting response to BCMA-directed CAR T-cell therapy in MM which needs prospective studies and validation.