Search Results (1,036)

Background: Second salvage autologous stem cell transplantation (SAT) is a therapeutic option for patients with multiple myeloma (MM) who relapse after a first autologous stem cell transplantation (ASCT) in the era of novel agents. However, the clinical context in which SAT provides benefit relative to contemporary salvage regimens remains unclear. Methods: We retrospectively analyzed 51 patients who underwent SAT after novel agent-based induction and first ASCT, and salvage re-induction, and compared outcomes with 113 patients treated with salvage carfilzomib–lenalidomide–dexamethasone (KRd) without SAT. Results: Median interval from first ASCT to relapse was 27 months. In the SAT cohort, median progression-free survival (PFS) and overall survival (OS) from initiation of salvage therapy were 30 and 99 months, respectively. A time to relapse ≥18 months after first ASCT and receipt of SAT as second-line of therapy were associated with significantly longer PFS and OS. In multivariate analysis, administration of SAT at later lines was independently associated with inferior outcomes, while a time to relapse ≥18 months after first ASCT was associated with significantly longer OS. Compared with the KRd-only cohort, SAT was associated with longer OS, whereas PFS was numerically longer without statistical significance. Among patients who had received both a proteasome inhibitor and an immunomodulatory drug as salvage induction, SAT was associated with longer PFS and OS. Conclusions: SAT may provide clinical benefit in selected patients with MM, particularly those with a durable response to first ASCT and those undergoing SAT at an earlier line of relapse in the novel agent era. Full article

Background/Objectives: Relapsed and refractory (rr) primary large B-cell lymphoma of the central nervous system (PCNSL) has a dismal prognosis, and the standard of care is not established. The most common genetic imbalance includes the B-cell lymphoma 2 (BCL-2) locus. Methods: We planned a bi-centric phase Ib dose-escalation study with the chemotherapy-free combination of the BCL-2 inhibitor venetoclax and CD20 antibody obinutuzumab for rrPCNSL patients in Germany. The intended treatment consisted of 6 cycles of fixed-dose obinutuzumab at 1000 mg intravenously every 3 weeks, and an oral daily dose of 600, 800, or 1000 mg venetoclax, depending on the planned dosing group, followed by a 12-month venetoclax maintenance period. The primary endpoint was the pharmacokinetics of venetoclax and obinutuzumab in cerebrospinal fluid (CSF). Results: This study was prematurely terminated after registration of 5/15 (33%) patients in dosing group 1 (600 mg oral daily dose of venetoclax) between May 2020 and November 2021. The mean ratio of the concentration of venetoclax in CSF over peripheral blood was 0.55% (±0.28 standard deviation (SD)) and 0.25% (±0.23 SD) for obinutuzumab. Two of five patients achieved complete remission, and each one patient achieved partial remission and stable disease as best response. The median duration of response was 6.5 months (range 0.7–47). Conclusions: Venetoclax and obinutuzumab can penetrate into the central nervous system, but the CSF concentration did not correlate with the outcome. The combination is feasible, tolerable, and may lead to durable responses in selected rrPCNSL patients. Full article

The pivotal clinical trials, CARTITUDE-1 and KarMMa-3, showed promising response rates in relapsed and refractory multiple myeloma (RRMM) with use of BCMA-directed CAR T-cell therapy; however, a major challenge is determining suitability in patients who do not meet trial inclusion criteria due to suboptimal organ function. In this multicenter retrospective study, we evaluated the safety and efficacy of BCMA CAR-T therapy in patients with RRMM and renal impairment (RI), defined as creatinine clearance (CrCL) of less than 45 mL/min. We evaluated 223 patients treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) between May 2021 and April 2024. Outcomes were compared between baseline RI (11.2%) and normal renal function (nRF) cohorts. Response rates were similar at 1 month (p = 0.09), 3 months (p > 0.9), and 6 months (p = 0.8). Progression-free survival (PFS) was 21.9 months in the RI group compared to 15 months in the nRF group (p = 0.32), while overall survival (OS) was 27.9 months for patients with RI versus not reached for patients with nRF (p = 0.87). Patients with RI had higher rates of immune effector cell-associated neurotoxicity syndrome (ICANS) (60% vs. 19%, p = 0.04) and infections (44% vs. 20%, p = 0.008). We found that BCMA CAR-T demonstrated comparable efficacy in RRMM patients with baseline RI, although these patients exhibited increased rates of neurotoxicity and infections. Full article

Background: The FLT3-ITD mutation is associated with a poor prognosis in acute myeloid leukemia (AML), particularly in relapsed or refractory (R/R) cases. Although Gilteritinib has been approved for the treatment of R/R AML with FLT3-ITD mutation, the emergence of resistance in clinical settings remains a major challenge. Homoharringtonine (HHT), a plant-derived alkaloid with antitumor properties, has also been used in AML treatment. However, the combination effects of HHT and gilteritinib have not been investigated. Methods: The cell viability and apoptosis of MV4-11 and MOLM-13 cells in the treatment of HHT, gilteritinib and the combination were assessed by CCK-8 assay and flow cytometry, respectively. Combination index (CI) values were calculated using CompuSyn 1.0. Western blotting was used to investigate the molecule mechanisms of HHT and gilteritinib mediated anti-leukemia effects in time- and dose-dependent experiments. To investigate the role of p53 status in drug responses, MV4-11-p53R248W and MV4-11-p53WT subclones were isolated and MV4-11-p53knockout cells was established through CRISPR/Cas9 system. The cell viability and apoptosis of MV4-11 cells with various p53 status were compared. Moreover, RNA-seq analysis was performed in MV4-11 cells treated with or without HHT. RT-qPCR and Western blotting were conducted to verify the mechanism underlying HHT-induced p53 upregulation. Results: HHT and gilteritinib exerted a significant synergistic effect on cell viability and apoptosis in MV4-11 and MOLM-13 cells, which was markedly diminished in the cells with the p53-R248W muta-tion or without p53. Mechanistically, HHT and gilteritinib both suppressed FLT3 signaling. Interestingly, HHT mediated the upregulation of p53 through HSPA8 downregulation, while gilteritinib downregulated the p53 level. The combination enhanced the p53 expression. Conclusions: Our findings elucidate the mechanism underlying this synergistic interaction and underscore the potential of p53 status as a predictive biomarker for identifying patients most likely to benefit from HHT and gilteritinib combination therapy. Full article

Background/Objectives: CAR-T-cell therapy has become a key treatment for relapsed or refractory hematologic malignancies such as diffuse large B-cell lymphoma (r/r DLBCL), although patient outcomes differ considerably. The intestinal microbiome has been proposed as an important factor influencing CAR-T-cell therapy efficacy; accordingly, antibiotic exposure, which may induce dysbiosis, has been associated with inferior outcomes after CAR-T-cell therapy. Methods: We retrospectively analyzed clinical data from 140 patients to assess the impact of infection-related antibiotic therapy prior to CAR-T-cell therapy, stratifying them into two cohorts: 67 patients with previous antibiotic exposure and 73 without exposure. Results: Patients exposed to antibiotics prior to CAR-T therapy had significantly reduced progression-free survival (p = 0.016) and overall survival (p = 0.002) compared to those without exposure. Multiple antibiotic courses and shorter intervals between the last antibiotic treatment and CAR-T-cell therapy were linked to poorer outcomes. Conclusions: Our data suggest that pre-CAR-T-cell-therapy antibiotic exposure is associated with inferior outcomes, although it remains unclear whether this effect is causal or reflects underlying patient comorbidities. These findings highlight the need for further studies investigating the role of antibiotic-induced dysbiosis on CAR-T-cell therapy efficacy. Full article

Background/Objectives: Relapsed or refractory follicular lymphoma (rrFL) remains difficult to treat in elderly or frail patients who cannot tolerate standard-dose immuno-chemotherapy as well as novel therapies. Metronomic chemotherapy (mCHEMO) may offer sustained antitumor activity with reduced toxicity. This study assessed the clinical activity and safety of R-DEVEC or R-DEVEC-light in rrFL patients following lenalidomide discontinuation or ineligibility. Methods: Data from the ReLLi Lymphoma Registry (2013–2025) were retrospectively analyzed. Eligible patients had rrFL after ≥1 prior therapy and initiated mCHEMO at least six months before data cutoff. Thirteen patients received DEVEC or the etoposide-free DEVEC-light regimen; all but one also received rituximab. Responders received maintenance vinorelbine, low-dose prednisone, and rituximab, followed by vinorelbine-only maintenance until progression or intolerance. Responses were assessed by CT after cycle two and PET/CT at completion of six induction cycles. Results: median age was 77 years (range 58–92); most patients were frail and had advanced disease. At the end of induction, 84% achieved remission (46% CR, 38% PR), with three PR converting to CR during maintenance. After a median follow-up of 27 months, the PFS was 42% (95CI 15–69%) and the OS 73% (95CI 47–100%). A transformation occurred in one patient; the main toxicity was grade 3 neutropenia (31%). DEVEC-light showed improved tolerability versus full DEVEC, with manageable infections and rare discontinuations. Conclusions: Metronomic R-DEVEC-light is a feasible and effective disease-controlling strategy for frail, heavily pretreated rrFL patients who do not tolerate lenalidomide and are excluded from modern therapies. This schedule warrants further prospective evaluation and exploration in combination with targeted agents. Full article

The search for new therapeutic principles is essential for treating relapsed/refractory (r/r) acute myeloid leukemia (AML). Novel principles include genome-agnostic differentiation induction, controlling AML-triggering inflammation, potentiating the immune response and ‘normalizing’ AML metabolism. This review summarizes data from a phase I study (10 patients, pts) and three case reports reporting 7 pts on the treatment of r/r AML by reprogramming AML hallmarks using APA, low-dose azacitidine, pioglitazone (PPARα/γ agonist) and all-trans retinoic acid. APA reprograms the r/r AML phenotype in patients with clinically and molecularly/genetically unfavorable risk profiles (17 pts, 16 refractory, one relapsed) in a genome-agnostic manner, restoring the plasticity of AML hallmarks, thereby improving immune surveillance, attenuating inflammation-triggered promotion of AML and distant microbial inflammation (healing of fungal pneumonia during induction of complete remission (CR) with APA), while normalizing leukemia metabolism (restoring phagocytosis and ROS production in leukemic neutrophils). APA induces CR in 10 pts (59%), with only modest hematotoxicity following CR induction. This allows treatment to be carried out in an outpatient setting, including for elderly and comorbid patients. Triple transcriptional modulation, facilitated by epigenetic modelling with azacitidine, targets reprogramming of non-oncogene addiction networks in AML, re-establishing functionally active, closely interrelated myeloid hallmarks and AML cell death genome-agnostically. Full article

Background/Objectives: Real-world data on the therapeutic use of FLT3 inhibitors in Turkey remain limited. Therefore, we retrospectively evaluated outcomes from 13 academic centers nationwide, focusing on the multikinase inhibitor midostaurin in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML). Methods: We collected comprehensive information regarding treatment efficacy, safety, and tolerability. Results: The overall response rate to intensive chemotherapy (3 + 7) plus midostaurin was 87.7%, with a complete remission rate of 84.2%, consistent with previously reported clinical trial results. Treatment discontinuation due to intolerance or toxicity was low (3.5%). One patient discontinued therapy because of septic shock during induction, and another due to a drug–drug interaction during consolidation. Median overall survival was 21.4 months. Allogeneic stem cell transplantation was performed in first remission in 52.6% of patients. Five patients (8.8%) were refractory to induction therapy, and relapse occurred in 21.1% (12 patients). Conclusions: These findings support the effectiveness and acceptable tolerability of midostaurin in routine clinical practice for FLT3-mutated AML. Full article

Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL) harbor a poor prognosis. Novel therapies, such as bispecific antibodies (BsAbs), provide an effective therapeutic option for such patients. BsAbs are studied both as monotherapy and combination therapy for patients with R/R DLBCL with promising results. Unlike cellular therapies, such as autologous stem cell transplant (ASCT) or chimeric antigen receptor therapy (CAR-T), BsAbs are more amenable to administration in a community setting, given the lower incidence and severity of key toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS). Deployment of BsAbs in the community setting requires operational considerations and a multidisciplinary team approach. This review will discuss the currently approved BsAb treatment regimens and our community institution’s experience in implementing BsAbs. Full article

Acute myeloid leukemia (AML) is a highly aggressive malignancy defined by significant biological diversity and variable patient outcomes. A key subset of AML is driven by abnormalities that lead to the overexpression of the oncogenic transcription factors HOXA9 and MEIS1. These abnormalities include KMT2A (formerly MLL) rearrangements and NPM1 mutations, as well as other rare lesions such as NUP98 rearrangements. This review focuses on the biology of the KMT2A, NPM1, and HOX/MEIS1 pathways, dissecting their molecular mechanisms of leukemogenesis. A central theme is the role of the scaffolding protein menin in the epigenetic regulation of this pathway, which ultimately drives malignant transformation. Currently, the clinical landscape is being transformed by the emergence of menin inhibitors as promising therapeutic agents for AML harboring these specific genetic anomalies. We evaluate the latest data on various menin inhibitors—both as monotherapy and in combinations—emphasizing their efficacy and safety profiles. As new evidence continues to accumulate with recent drug approvals and ongoing randomized, phase 3 studies, menin inhibitors are rapidly becoming a component of the AML treatment paradigm for relapsed/refractory and likely newly diagnosed disease. Full article

Background and Objectives: Oral Janus kinase (JAK) inhibitors have become an important therapeutic class in dermatology, with approved indications including atopic dermatitis and alopecia areata. Owing to their broad immunomodulatory effects and rapid onset of action, these agents are increasingly used off label for a variety of inflammatory skin disorders that are often refractory to standard therapies. The objective of this review was to provide a comprehensive overview of the published literature on the off-label dermatologic use of oral JAK inhibitors, summarizing clinical outcomes, safety profiles and treatment durations reported in real-world settings. Materials and Methods: A literature search was conducted in PubMed to identify case reports and case series describing off-label dermatologic use of baricitinib, abrocitinib, upadacitinib, and ritlecitinib. Extracted data included authorship and year, article type, treatment regimen, treatment duration and follow-up, prior systemic therapies, clinical outcomes, and reported adverse events. Results: A total of 136 articles were included, comprising 45 articles on abrocitinib (63 patients), 55 on upadacitinib (94 patients), 35 on baricitinib (45 patients), and 2 on ritlecitinib (2 patients). Across a wide spectrum of dermatological conditions, oral JAK inhibitors showed consistent clinical efficacy. Responses were frequently rapid and disease control was often maintained over several months of treatment. In many cases, dose reduction or treatment discontinuation did not lead to immediate relapse. Overall tolerability was favorable, with adverse events reported in a minority of patients and predominantly described as mild and transient. Conclusions: Although our data is limited to case-based literature, this review highlights the broad off-label therapeutic potential of oral JAK inhibitors in dermatology. Their rapid onset of action, sustained clinical responses, frequent maintenance of remission after dose tapering or discontinuation and generally acceptable safety profile support their consideration as treatment options in selected patients. Full article

Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma. Full article

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL); however, a significant proportion of patients fail to achieve a durable response, underscoring the need for reliable predictive biomarkers. We characterize T-lymphocyte subpopulations in apheresis samples from 23 r/r large B-cell lymphoma (LBCL) patients who received axicabtagene ciloleucel (axi-cel) to identify pre-treatment cell biomarkers associated with CAR T-cell kinetics and clinical outcomes. Immunophenotyping of T-cells within fresh apheresis samples and monitoring of circulating CAR T-cells were performed by multiparametric flow cytometry. The median peak CAR T-cell count was 45.2 CAR T-cells/mL. Strong CAR-T expanders (≥45.2 CAR T-cells/mL) exhibited higher values of both CD4⁺ (p = 0.011) and CD8⁺ (p = 0.023) central memory T-cells (T_CM; CCR7⁺CD45RA⁻), as well as lower proportions of CD8⁺CD38⁺ T-cells in apheresis samples. In apheresis, a cut-off value of >4.3% of CD8⁺ T_CM predicted strong CAR-T expansion (AUC: 0.80; p = 0.023) and superior progression-free survival (p = 0.04) compared with patients who had CD8⁺ T_CM below the cut-off. Our data suggest that high frequencies of CD8⁺ T_CM cells in apheresis samples may represent a promising pre-treatment biomarker associated with strong CAR-T expansion and superior clinical outcome in r/r LBCL patients following axi-cel. Full article

Background/Objectives: Eltrombopag, a thrombopoietin receptor agonist, is widely used in the treatment of relapsed or refractory (R/R) immune thrombocytopenia (ITP). This study aimed to compare the efficacy, safety, and tolerability of generic eltrombopag (Rompag^®) with original eltrombopag (Revolade^®) in adult patients with R/R ITP. Methods: In this prospective, multicenter study conducted at 10 centers, 104 adult ITP patients were followed for at least 3 months. A total of 35 (33.7%) patients received Rompag^® and 69 (66.3%) received Revolade^®. The primary endpoint was platelet (PLT) response, defined as achieving a PLT count ≥50 × 10⁹/L and at least a twofold increase from baseline, without the need for rescue therapy or transfusion. Secondary endpoints included bleeding rates, fatigue-related quality of life, adverse events (AEs), and rescue therapy requirements. Results: PLT response was achieved in 94.2% of patients in the Revolade^® group and 85.7% in the Rompag^® group (p = 0.16). Bleeding rates decreased significantly in both groups (Revolade^®: 56.5% to 2.9%, p < 0.001; Rompag^®: 62.9% to 2.9%, p < 0.001). Although overall AE rates were similar (30.4% in the Revolade^® group and 42.9% in the Rompag^® group; p = 0.22), arthralgia (28.6% vs. 7.2%, p = 0.01) and vomiting (11.4% vs. 0%, p = 0.008) were more frequent with Rompag^®. Conclusions: Both generic and original eltrombopag demonstrated no statistically significant difference in efficacy in achieving PLT response, reducing bleeding, and improving fatigue-related quality of life in adult patients with R/R ITP. Although minor differences in AE profiles were observed, particularly arthralgia and vomiting, both formulations showed acceptable safety and tolerability. Full article

Background/Objectives: Some patients initially diagnosed with non-high-risk neuroblastoma follow a high-risk clinical course and have poor survival compared to those initially diagnosed with high-risk neuroblastoma. We aimed to identify molecular aberrations present at diagnosis that may explain the high-risk clinical course in this patient group. Methods: Data were collected from non-high-risk neuroblastoma patients diagnosed at our center between 2014 and 2021. Segmental chromosomal aberrations (SCAs), gene amplifications and mutations at diagnosis were detected by a single-nucleotide polymorphism array and next-generation sequencing. Telomere maintenance mechanisms (TMMs) were investigated using fluorescent in situ hybridization, whole genome sequencing (WGS) and RNA sequencing. SCA counts were imputed by using multiple imputation. Results: The total cohort included 89 patients. Thirteen patients developed a high-risk clinical course (group A) due to progression (n = 4), local relapse (n = 4), refractory disease (n = 3) or metastases (n = 2). Seventy-six patients followed a non-high-risk clinical course (group B). An SCA profile (≥1 SCA) was present in 76% of patients in group A and only 15% in group B (p = 0.004). 1p deletion was associated with a high-risk clinical course (p = 0.034). Gains of 1q, 2p and 17q, and deletions of 4p and 11q were more common in group A. After imputation, SCA count was associated with a high-risk clinical course (pooled OR 1.256 with 95% CI 1.006–1.568, p = 0.044). Two patients, both group A, exhibited MDM2/CDK4 amplification. Alternative lengthening of telomeres (ALT) was activated in 57% of group A. Conclusions: SCA profile and 1p deletion are associated with a high-risk clinical course. ALT activation, MDM2/CDK4 co-amplification, SCA count, gains of 1q, 2p, and 17q, and deletions of 4p and 11q may also be relevant molecular markers. Larger studies are needed for confirmation of these findings. Full article