Search Results (162)

Phosphatidylinositol-3-kinase (PI3K) inhibition has emerged as a therapeutic option against indolent lymphoma, including relapsed follicular lymphoma (FL). While inhibition of active signaling in the lymphoma cell represents the primary mode of action, PI3K inhibition also exerts immunomodulatory effects. Here we have analyzed 17 consecutive advanced treatment line FL patients treated with the delta-selective PI3K inhibitor idelalisib in a retrospective single-center observational study, with a specific focus on response and immune effects. Eleven patients achieved complete remission (CR) or partial remission (PR) with median response duration of 22 (11–88) months following a median idelalisib exposure of 15 (4–88) months. Disease response persisted in three patients for a median of 37 (21–63) months following cessation of idelalisib without another therapy being initiated. Autoimmune side effects occurred in eight of the eleven patients who responded, compared to none in six patients whose disease did not respond. In conclusion, a time-limited exposure to idelalisib may induce sustained remissions in a portion of patients with recurrent and/or refractory (r/r) FL, suggesting immunomodulatory effects of PI3K inhibition to be involved in the control of the disease. Full article

Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements (KMT2Ar) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with NPM1m—which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with KMT2Ar—and is present in 5–10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the MEIS1–HOXA axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For KMT2Ar AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In NPM1m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed NPM1m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by HOX and MEIS1, disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options. Full article

Background/Objectives: Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) mutations carries a poor prognosis. While FLT3 inhibitors like midostaurin show benefits in combination with chemotherapy, the role of allelic ratio (AR), NPM1 mutation status, and hematopoietic stem cell transplantation (HSCT) remains uncertain. Real-world data can help refine prognostic classification and treatment strategies. Methods: We retrospectively analyzed 37 fit patients with FLT3-ITD AML treated with standard “7+3” chemotherapy, with and without midostaurin, between 2013 and 2022. Patients were stratified by FLT3-ITD AR, NPM1 status, and treatment approach. Outcomes assessed included complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: Overall, 67.6% achieved CR/CRi. Response rates did not differ significantly by AR (low vs. high: 66.7% vs. 69.2%) or midostaurin use (72.6% vs. 60%; p = 0.49). NPM1 mutations were associated with improved DFS (10.3 vs. 3 months, p = 0.036) but not OS. HSCT, performed in 54.1% of patients, mainly in first remission (CR1), significantly prolonged DFS (not reached vs. 5.3 months, p = 0.005) and remained an independent predictor in multivariate analysis (HR: 0.160, p = 0.039). OS (median 15.1 months) did not vary significantly across subgroups. Among patients achieving CR1, OS was significantly longer in those who underwent HSCT after midostaurin-based induction compared to those not transplanted (median OS not reached vs. 12.8 months; 95% CI, 6.9–18.7; p = 0.045), whereas no significant benefit was observed after standard induction. In a landmark analysis restricted to patients transplanted in CR1, those who had received midostaurin-based induction showed a trend toward improved OS compared to those treated with standard induction (median OS not reached vs. 11.5 months; 95% CI, 0.5–25.0; p = 0.086). Conclusions: This real-life study supports the importance of NPM1 mutations and HSCT in CR1, especially in the midostaurin era, for improving DFS in FLT3-ITD AML. These findings support updated guidelines for reducing the prognostic weight of AR and highlight the need for improved post-remission strategies in this setting. Full article

Background/Objectives: The combination of venetoclax (VEN) and hypomethylating agents (HMA), such as azacitidine (AZA) or decitabine (DEC), has transformed the treatment landscape for acute myeloid leukemia (AML) in patients unfit for intensive chemotherapy. However, optimal management of neutropenia and the impact of post-remission treatment interruptions (washouts) remain unclear. This study aimed to evaluate the safety and efficacy of post-remission washouts and their effect on clinical outcomes. Methods: We conducted a retrospective single-center study of 44 AML patients treated with HMA/VEN between 2020 and 2021. Clinical, molecular, and treatment-related data were collected, including treatment duration, post-remission washout duration, response rates, disease-free survival (DFS), and overall survival (OS). Statistical analyses included Fisher’s exact test and univariate and multivariate Cox models. Results: Overall, 61% of patients responded to therapy, with significantly higher response rates among those potentially eligible for the VIALE-A trial (86% vs. 39%, p = 0.002). Neither treatment duration nor post-remission washout length was associated with DFS or OS. DFS was significantly longer in patients treated with AZA compared to DEC (p = 0.006). Median OS was 7.7 months, with longer OS observed in patients who did not meet VIALE-A trial eligibility criteria (p = 0.021). Achieving complete remission (CR) was associated with improved OS (14.5 months). Conclusions: Post-remission treatment interruptions (washouts) did not negatively impact DFS or OS, suggesting they may be a safe strategy to support hematologic recovery. However, the choice of HMA appears to influence response duration, with AZA outperforming DEC in maintaining disease control. Full article

Background/Objectives: The role of KDM6A gene mutations in acute myeloid leukemia (AML) remains poorly understood. This study aimed to evaluate the impact of KDM6A mutations on relapse risk, cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) in adult AML patients, with a particular focus on those with RUNX1::RUNX1T1 fusion. Methods: the retrospective analysis was conducted on 1970 adult AML patients treated at Peking University People’s Hospital. Of these, 1676 patients who achieved complete remission (CR) were included. Among them, 27 harbored KDM6A mutations. Propensity score matching (PSM) was used (1:10 ratio) to compare outcomes between patients with and without KDM6A mutations. Further analysis focused on 207 patients with RUNX1::RUNX1T1 fusion, among whom 13 had KDM6A mutations (PSM 1:5). Results: In the overall cohort, KDM6A variants (n = 27) had a higher 2-year CIR (45.7% vs. 28.6%, p = 0.04). Fine–Gray analysis showed KDM6A variants independently increased relapse risk (HR = 1.98 [1.08–3.63], p = 0.03). KDM6A mutations were associated with inferior 2-year RFS (36.3% vs. 60.9%, p = 0.044). Multivariable analysis confirmed KDM6A mutations as independent predictors of poor RFS (HR = 3.08 [1.56–6.08], p = 0.001). Among RUNX1::RUNX1T1 patients, KDM6A mutations significantly increased relapse risk (75.0% vs. 21.7%, p < 0.001), raised 2-year CIR (46.9% vs. 24.0%, p = 0.05), worsened 2-year RFS (31.3% vs. 71.9%, p < 0.001), and lowered 2-year OS (63.3% vs. 86.4%, p = 0.002). They were also independent predictors of CIR (HR = 2.46 [1.11–5.47], p = 0.03), RFS (HR = 5.1, [2.5–10.5], p < 0.001) and OS (HR = 12.9, [4.3–38.7], p < 0.001). Conclusions: KDM6A mutations are significantly associated with increased relapse risk and poor prognosis in AML, especially in patients with RUNX1::RUNX1T1 fusion, and may serve as a valuable prognostic biomarker. Full article

Background/Objectives: Ibrutinib is a selective Bruton’s tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL). This drug exhibits significant variability in response and toxicity profile, possibly due to genetic polymorphisms in drug-metabolizing enzymes and transporters. The aim of this observational study is to address interindividual variability in the efficacy and safety of ibrutinib treatment in 49 CLL patients. Methods: Genotyping of nine polymorphisms was performed by quantitative polymerase chain reaction (qPCR) using a ViiA7^® PCR Instrument and TaqMan assays, and ibrutinib plasma concentrations were determined using high-performance liquid chromatography coupled to a tandem mass spectrometry detector (HPLC-MS/MS). Results: Our study confirmed a high response rate, with 62% of patients achieving complete remission (CR), 9% CR with incomplete hematologic recovery (CRi), and 24% partial remission (PR). The impact of genetic polymorphisms on the CR rate was evaluated, revealing no statistically significant associations for CYP3A4, CYP3A5, ABCB1, ABCG2, and SLCO1B1 variants. However, a tendency was observed for patients carrying ABCB1 rs1128503, rs1045642 T/T, or rs2032582 A/A genotypes to achieve a higher CR rate. Adverse drug reactions (ADRs) were frequent, with vascular disorders (39%) and infections (27%) being the most common. Genetic polymorphisms influenced ibrutinib toxicity, with CYP3A4 *1/*22 appearing to be protective against overall ADRs. Conclusions: The unexpected association between CYP3A4 *1/*22 genotype and lower ADR incidence, as well as the trend toward improved treatment response in patients carrying ABCB1 genotypes, suggests compensatory metabolic mechanisms. However, given the small sample size, larger studies are needed to confirm these findings and their clinical implications, while also aiming to uncover other non-genetic factors that may contribute to a better understanding of the variability in treatment response and toxicity. Full article

Background: Urticarial vasculitis (UV) is a rare form of small-vessel vasculitis characterized by persistent urticarial lesions and systemic manifestations. It differs from chronic spontaneous urticaria (CSU) both clinically and pathogenetically, often requiring systemic therapy. Despite its complexity, no standardized treatment algorithm exists. Methods: We conducted a retrospective, monocentric, observational study on 11 patients diagnosed with UV at the Dermatology Unit of Tor Vergata University Hospital (Rome) between 2014 and 2024. Demographic, clinical, serological, and therapeutic data were collected from medical records. The therapeutic response was assessed using the Urticaria Control Test (UCT) score. Results: The cohort comprised predominantly women (91%), with a mean age at diagnosis of 52.8 years. Autoimmune thyroiditis was the most frequent comorbidity (64%). Hypocomplementemia was detected in only one patient (9%), who also had systemic lupus erythematosus. Antihistamines, while usually prescribed, showed limited efficacy since none of the patients achieved complete remission with monotherapy. Systemic corticosteroids demonstrated rapid and effective control in acute phases. Omalizumab produced variable responses, with two patients achieving a high response (HR) and one reaching complete remission (CR). Methotrexate and cyclosporine yielded inconsistent outcomes. Due to the heterogeneity and limited sample size, statistical analyses were not performed. Conclusions: UV presents with diverse clinical profiles and therapeutic responses. No treatment proved universally efficacious, but corticosteroids and omalizumab were effective in an acute and maintenance phase, respectively. Our findings underscore the importance of individualized treatment plans and the need for further studies to define predictive biomarkers and therapeutic strategies in UV. Full article

Triple negative breast cancer (TNBC) is the most aggressive molecular subtype and it lacks targetable receptors. Patients have an increased risk of recurrence and poor prognosis. Little is known concerning the characteristics of disseminated tumor cells (DTCs) and their role in TNBC patients. We analyzed the bone marrow aspirates of 80 patients with primary (n = 67) or recurrent (n = 13) TNBC, using a multi-parameter immunofluorescence staining procedure, including Pan-CK as an epithelial marker, vimentin (vim) as a marker of epithelial–mesenchymal transition, Ki67 for cell proliferation, and HER2 as well as PD-L1 as therapy-related markers. The DTC positive rate was 56% (n= 45) among the cohort. We found 20 different DTC subpopulations. The most frequently detected profile was CK+Vim+Ki67+ (n = 75 cells). The occurrence of CK- DTCs (n = 69) was significantly correlated to PD-L1 (r = −0.305, p < 0.01) and HER2 positivity (r = −0.234, p < 0.001). DTC positive patients that received neoadjuvant chemotherapy (NACT) and did not reach pathologic complete response were more likely to have CK- DTCs. Our data indicate that the occurrence of DTC subpopulations positive for Vim, Ki67, and HER2 appear to be markers for bad prognosis and could be therapeutically relevant. Furthermore, our results raise the question of whether DTCs are dormant in TNBC patients and persistent towards chemotherapy. Full article

Background: Fibrillary glomerulonephritis (FGN) is a rare and poorly understood kidney disease characterized by the deposition of non-amyloid fibrils in the glomeruli. Its clinical heterogeneity and high rate of progression to end-stage renal disease (ESRD) pose significant diagnostic and therapeutic challenges. This case series aims to enhance awareness of FGN and emphasizes the need for further research to improve patient outcomes. Case Reports: We reviewed the clinical, histopathological, and therapeutic data of three patients with FGN diagnosed by kidney biopsy. The cases included variations in clinical presentation from nephrotic syndrome to rapidly progressive glomerulonephritis (RPGN). Diagnostic methods incorporated light microscopy, immunofluorescence, and electron microscopy, with the integration of DnaJ homolog subfamily B member 9 (DNAJB9) staining for confirmation. Patient 1 showed a more favorable response to rituximab, achieving complete remission (CR) at 6 months and maintaining CR after 3 years. Patient 2 showed only partial remission after 2 years following treatment with rituximab. Patient 3 presented with RPGN and rapidly progressed to ESRD despite aggressive immunosuppressive therapy. Discussion: DNAJB9 has emerged as both a specific and sensitive biomarker in patients with FGN and has facilitated accurate differentiation from other glomerulopathies. This series underscores the variability in clinical outcomes and responses to therapy as well as the importance of early and accurate diagnosis. Conclusions: FGN remains a diagnostic and therapeutic challenge due to its rarity and heterogeneity. Advances in biomarkers like DNAJB9 have improved diagnostic accuracy, distinguishing FGN from similar conditions such as immunotactoid glomerulopathy. Further research into pathophysiological mechanisms and targeted therapies is essential to optimize management and outcomes for affected patients. Full article

It is reported that AML with RUNX1 mutations is associated with poorer response to conventional chemotherapy, lower rates of complete remission (CR), leukemia-free survival (LFS), and overall survival (OS). We aimed to evaluate the prognostic impact of RUNX1 mutations following allogeneic hematopoietic stem cell transplantation (allo-HSCT) by comparing clinical outcomes in AML patients with and without RUNX1 mutations. We retrospectively analyzed 91 AML patients (33 RUNX1+ and 58 RUNX1−) who received their first HSCT at Peking University People’s Hospital. The median age of the cohort was 38 years (range: 6–64), with 73 patients (80%) receiving Haploidentical HSCT and 18 patients (20%) receiving sibling-matched allo-HSCT. In univariate analyses, no significant differences in survival outcomes were observed. For the RUNX1-mutation group and RUNX1-wild-type group, the 2-year cumulative incidence of relapse (CIR) was (12.6% vs. 7.6%, p = 0.472), the 2-year non-relapse mortality (NRM) rate was (9.6% vs. 7.2%, p = 0.747), the 2-year LFS was (77.8% vs. 85.2%, p = 0.426), and the 2-year OS rate was (85.9% vs. 92.7%, p = 0.397). We did not observe any negative impact of RUNX1 mutations on clinical outcomes, suggesting that allo-HSCT (especially Haplo-HSCT) may mitigate the adverse prognostic influence of RUNX1 mutations in AML. Full article

Background/Objectives: Classic Hodgkin lymphoma (cHL) is a predominantly curable B-cell malignancy. However, primary refractory and relapsed (R/R) cHL remain therapeutic challenges, especially in regions with high tuberculosis (TB) prevalence, where clinical and radiologic features overlap and can obscure the correct diagnosis. This article, presenting a case of R/R cHL mimicking disseminated TB, reviews the evolving paradigm in R/R cHL management. Methods: A 30-year-old Middle Eastern male with advanced nodular sclerosis cHL initially achieved a complete remission (CR) with escalated BEACOPP chemotherapy. Shortly afterward, he developed respiratory symptoms and diffuse miliary pulmonary nodules, highly suggestive of disseminated TB. Despite extensive negative TB workup, including QuantiFERON-TB Gold testing, sputum acid-fast bacilli (AFB) staining, and PCR, his imaging raised concern for recurrent cHL. Due to the small size and diffuse distribution of nodules, biopsy was unfeasible, prompting empiric salvage therapy with DEHAP-Carbo, brentuximab vedotin (BV), and nivolumab. Results: The rapid and robust metabolic response on PET/CT supported lymphoma relapse rather than TB. Following four cycles of this combined regimen, he proceeded to autologous stem cell transplantation and achieved a second CR. Conclusions: This case highlights the diagnostic difficulties in differentiating cHL relapse from TB in endemic regions, emphasizes the critical role of PET/CT in guiding therapy when histopathological confirmation is impractical, and illustrates the impact of novel immunotherapies in improving outcomes. By underscoring the importance of early diagnostic suspicion and multimodal assessment, this article also reviews the evolving paradigm in R/R cHL management, where personalized approaches and targeted agents increasingly complement or replace traditional chemotherapy regimens. Full article

Background: Classical Hodgkin lymphoma (cHL) is a treatable malignancy; however, relapsed or refractory (R/R) cases pose significant challenges. PD-1 inhibitors have shown efficacy, but the role of hematopoietic stem cell transplantation (HSCT) following PD-1 blockade remains uncertain. This study aims to evaluate the impact of HSCT after PD-1 blockade on progression-free survival (PFS) and overall survival (OS) in patients with R/R cHL. Methods: We conducted a multicenter, retrospective study involving 42 patients with R/R cHL who received PD-1 inhibitors between 2016 and 2021. Patients were categorized into two groups: those who underwent HSCT after PD-1 therapy (n = 19) and those who continued PD-1 inhibitors without HSCT (n = 23). Results: Among the 42 patients, 27 achieved complete remission (CR) and 15 achieved partial remission (PR) following PD-1 blockade. In the HSCT group, 92% of patients remained progression-free at 3 years, compared to 65% in the non-HSCT group (p = 0.021). OS rates were similar between groups (100% vs. 96%, p = ns). Notably, 80% of PR patients in the HSCT group converted to CR. Relapse rates were significantly lower in the HSCT group (5%) compared to the non-HSCT group (43%, p = 0.005). Conclusions: HSCT following PD-1 blockade enhances PFS in patients with R/R cHL, particularly among those with PR, without offering a significant OS benefit. Further research is warranted to optimize treatment strategies for this patient population strategies. Full article

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established curative treatment option for acute myeloid leukemia (AML) in second complete remission (CR2). However, whether the addition of consolidation chemotherapy after achieving CR2 can improve transplant outcomes remains controversial. Methods: In this single-center retrospective study, we analyzed consecutive AML patients who underwent their first HSCT in CR2 at our institution between January 2015 and December 2019. Results: For the consolidation (n = 72) and no consolidation groups (n = 63), the 5-year cumulative incidence of relapse (CIR) was (17.6% vs. 19.9%; p = 0.54), the 5-year non-relapse mortality rate (NRM) was (9.7% vs. 17.5%; p = 0.20), the 5-year leukemia-free survival (LFS) was (72.7% vs. 62.7%; p = 0.15), and the 5-year overall survival (OS) was (81.9% vs. 68.3%; p = 0.08). Additional consolidation therapy to achieve negative measurable residual disease (MRD) did not result in significantly improved outcomes compared to immediate HSCT in MRD positive status, with similar LFS (76.9% vs. 67.0%, p = 0.2) and OS (88.3% vs. 75.0%, p = 0.14). Multivariable analysis indicated that consolidation chemotherapy did not significantly affect CIR, NRM, LFS, or OS. Conclusions: Our findings suggest no significant differences in clinical outcomes between the groups, indicating that AML patients in CR2 might proceed to HSCT without delay. Full article

Background: Acute myeloid leukemia (AML) primarily affects older adults and is associated with poor prognosis, particularly in patients aged ≥ 60 years with comorbidities and adverse disease characteristics. Standard intensive chemotherapy, such as the “7 + 3” regimen, has shown limited efficacy and substantial toxicity in this population, underscoring the need for alternative treatment strategies. In recent years, venetoclax-based regimens have emerged as an important option, demonstrating promising outcomes in elderly patients traditionally considered unfit for intensive therapy and, more recently, even in selected fit patients. Methods: This narrative review provides a comprehensive comparative analysis of intensive chemotherapy and venetoclax-based regimens in elderly AML patients. This review synthesizes evidence from prospective and retrospective clinical trials, with focuses on treatment efficacy, safety, and the ability to bridge patients to curative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: Intensive chemotherapy has achieved complete remission (CR) rates of 40–60% in elderly AML patients, though the median overall survival (OS) rarely exceeds 12 months. Conversely, venetoclax combined with hypomethylating agents has recently demonstrated CR rates of up to 74%, with 83% of responders proceeding to allo-HSCT in selected studies. Venetoclax-based regimens have also been associated with improved tolerability and reduced treatment-related mortality. Discussion: This review highlights a paradigm shift in the management of AML in the elderly. While intensive chemotherapy remains a standard option for selected patients, the increasing use of venetoclax-based regimens represents a novel and effective strategy with the potential to overcome traditional limitations, especially in patients previously deemed ineligible for curative approaches. The high remission and transplantation rates observed with non-intensive therapies support their role not only as a palliative alternative but as a bridge to cure. Conclusions: Venetoclax-based regimens are reshaping the treatment landscape of AML in the elderly, offering high response rates and facilitating access to allo-HSCT. Further research is needed to optimize treatment sequencing, explore novel combinations, and reduce relapse rates after transplants, ultimately improving the long-term outcomes in this high-risk population. Full article

Background/Objectives: Down syndrome (DS), affecting 1 in 1000 births, has been linked to an increased risk of acute leukemia (AL). Patients with DS–acute lymphoblastic leukemia (DS-ALL) have historically had inferior outcomes when they have received risk-adapted therapy. Transient abnormal myelopoiesis (TAM) constitutes a transient leukemia with spontaneous remission in the neonatal period or represents a preleukemic state, preceding DS–acute myeloid leukemia (DS-AML). DS-AML has a better prognosis than that of AML without DS (NDS-AML) due to genetic and biological underlying features, a better response to chemotherapeutic agents, and a lower frequency of relapses. Methods: This retrospective cohort study presents the DS-AL outcomes from a nationwide survey in pediatric oncology centers. A total of 20 patients were studied, 10 with DS-ALL, 4 with DS-AML, 5 with TAM, and 1 with DS-AML after TAM, at median follow-ups of 9.25 (0.6–17.42) years and 7.25 (0.25–18.25) years for DS-ALL and DS-AML, respectively. Results: The median age at diagnosis was 4.7 (1.16–13.83) and 1.92 (1.25–3) years for ALL and AML, respectively. All DS-ALL patients had B-cell precursor ALL and achieved complete remission (CR). One patient relapsed and succumbed due to a severe infection. Three DS-AML patients had AMKL. All DS-AML patients achieved CR. One patient with TAM demanded treatment, all achieved CR, and one progressed to DS-AML. The overall survival (OS) was 70% and 80% for DS-ALL and DS-AML. Conclusions: The improved survival rates of our patients have been due to new protocols with less toxic therapies and better supportive care. Full article