ABSTRACT 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‐R 2 ) and tafasitamab‐lenalidomide‐rituximab (Tafa‐R 2 ). Herein, we performed an indirect trial comparison (ITC) between the two regimens using the Bucher method as they both have the common comparator arm R 2 . 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‐R 2 . Analysis regarding time to next treatment (TTNT) interval also favored Epco‐R 2 ( p = 0.0011). The ITC in the progression free survival (PFS) context showed the anchored comparison favored Epco‐R 2 over Tafa‐R 2 [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‐R 2 was associated with more hematological toxicity and infections, whereas, Tafa‐R 2 was associated with more COVID‐19 infections probably reflecting the pandemic era enrollment timing. In conclusion, Epco‐R 2 is more effective in terms of treatment outcomes, but comes with greater toxicity. Tafa‐R 2 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.
ABSTRACT 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.
ABSTRACT 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.
ABSTRACT 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.
ABSTRACT 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.
