Tamer Othman, Ibrahim AldossDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USACorrespondence: Ibrahim Aldoss, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA, Tel +1 626 218-2405, Fax +1 626 389-3058, Email ialdoss@coh.orgAbstract: Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) has historically been associated with poor outcomes in adults treated with conventional chemotherapy. Allogeneic hematopoietic cell transplantation (HCT) in second remission has been the only strategy associated with durable remissions and potential cure. However, achieving remission after first relapse was challenging in the era predating immunotherapy, and remissions were often brief, frequently limiting the ability to proceed to HCT. Consequently, for decades there has been a critical need for more effective therapeutic approaches in R/R B-ALL. Fortunately, in the last decade, B-ALL has undergone a remarkable therapeutic transformation with the introduction of novel targeted immunotherapies. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy have substantially improved patient outcomes in the R/R disease settings while reducing reliance on intensive cytotoxic chemotherapy, and their use has increasingly expanded into the frontline setting as well. This literature review summarizes the pivotal clinical trials supporting the use of blinatumomab, inotuzumab ozogamicin, and CAR T-cell therapies in B-ALL, with a particular focus on their efficacy and toxicity profiles. We also provide our perspective on how these agents can be incorporated into clinical practice and highlight emerging therapeutic agents and strategies. In conclusion, continued advancement and earlier integration of immunotherapeutic approaches could improve long-term outcomes in patients with B-ALL.Keywords: B-cell acute lymphoblastic leukemia, B-ALL, blinatumomab, chimeric antigen receptor T-cells, CAR T, inotuzumab
Purpose:Neurolymphomatosis (NL) is a rare infiltration of cranial nerves, nerve roots, plexuses, or peripheral nerves by malignant lymphoid cells. We aimed to describe the clinical spectrum, diagnostic work-up, treatment, and outcomes of NL in a Middle Eastern tertiary cancer center. Patients and methods:We conducted a retrospective single-center case series of patients with clinically and/or radiologically confirmed NL managed at the National Center for Cancer Care and Research, Qatar, from January 2020 to April 2026. Clinical, imaging, cerebrospinal fluid, treatment, response, and survival data were summarized descriptively. Results:Ten patients were identified; median age was 44.5 years, eight were male, eight had B-cell malignancies, and two had T-lymphoblastic leukemia/lymphoma. Three had synchronous NL at initial diagnosis, whereas seven developed NL with relapsed, refractory, or recurrent disease. MRI supported NL in 7/10 patients, cerebrospinal fluid in 4/10, and PET/CT in 3/10; none underwent direct nerve biopsy. Best neurologic response was complete in three patients, partial in four, and absent in three. Four patients were alive at censoring, and six had died of progressive disease. Conclusion:In this regional cohort, NL usually occurred with aggressive active disease and showed heterogeneous neurologic presentations. Diagnosis depended on integrating clinical findings with MRI, PET/CT, and cerebrospinal fluid studies. Although overall outcomes were poor, durable disease control was achieved in selected patients. Multicenter studies are needed to refine diagnostic pathways and treatment strategies.
Safaa Alazzawi,1 Mohammed Abdulgayoom,1 Ruba Y Taha,1 Mohamed Abdelrazek,2 Wafa M Mohammed,1 Yahya Mulikandathil,1 Afaf H Al Battah,1 Sarah A Elkourashy,1,3 Yeslem Ekeibed,1 Honar Cherif1,41Department of Hematology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar; 2Department of Radiology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar; 3Weill Cornell Medicine – Qatar (WCM-Q), Doha, Qatar; 4College of Medicine, Qatar University, Doha, QatarCorrespondence: Mohammed Abdulgayoom, Department of Hematology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Al-Rayyan Road, PO Box 3050, Doha, Qatar, Tel +0097450691083, Fax +0097444397857, Email mmohammed35@hamad.qaPurpose: Neurolymphomatosis (NL) is a rare infiltration of cranial nerves, nerve roots, plexuses, or peripheral nerves by malignant lymphoid cells. We aimed to describe the clinical spectrum, diagnostic work-up, treatment, and outcomes of NL in a Middle Eastern tertiary cancer center.Patients and methods: We conducted a retrospective single-center case series of patients with clinically and/or radiologically confirmed NL managed at the National Center for Cancer Care and Research, Qatar, from January 2020 to April 2026. Clinical, imaging, cerebrospinal fluid, treatment, response, and survival data were summarized descriptively.Results: Ten patients were identified; median age was 44.5 years, eight were male, eight had B-cell malignancies, and two had T-lymphoblastic leukemia/lymphoma. Three had synchronous NL at initial diagnosis, whereas seven developed NL with relapsed, refractory, or recurrent disease. MRI supported NL in 7/10 patients, cerebrospinal fluid in 4/10, and PET/CT in 3/10; none underwent direct nerve biopsy. Best neurologic response was complete in three patients, partial in four, and absent in three. Four patients were alive at censoring, and six had died of progressive disease.Conclusion: In this regional cohort, NL usually occurred with aggressive active disease and showed heterogeneous neurologic presentations. Diagnosis depended on integrating clinical findings with MRI, PET/CT, and cerebrospinal fluid studies. Although overall outcomes were poor, durable disease control was achieved in selected patients. Multicenter studies are needed to refine diagnostic pathways and treatment strategies.Keywords: neurolymphomatosis, lymphoma, acute lymphoblastic leukemia, MRI, PET/CT, cerebrospinal fluid
Background:The optimal bridge-to-transplant strategy for patients with relapsed or refractory (R/R) acute leukemia who remain in non-remission (NR) is undefined. We evaluated the strategy-level use of CLAG (cladribine, cytarabine, and granulocyte colony-stimulating factor) as part of sequential conditioning, rather than as stand-alone salvage therapy, before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods:This single-center retrospective case series included nine consecutive patients with R/R acute leukemia and bone marrow blasts ≥10% who underwent CLAG-based sequential conditioning followed by allo-HSCT between January 2021 and July 2023. Engraftment, transplant-related complications, non-relapse mortality, relapse, disease-free survival (DFS), and overall survival (OS) were evaluated descriptively; no control group was available. Results:All nine patients achieved neutrophil and platelet engraftment and complete donor chimerism at approximately day +30. At a routine MFC/NGF analytical sensitivity of 10-4, all patients had negative bone marrow assessments at day +30 and month +3; abnormal/leukemic cells subsequently re-emerged in all five patients who relapsed, at months 4.1-9.8. Seven of nine patients (77.8%) developed infections during neutropenia, including one severe pulmonary infection with probable Aspergillus that improved with antifungal therapy. GVHD occurred in 3/9 patients (33.3%), and hemorrhagic cystitis occurred in 2/9 (22.2%). No non-relapse mortality occurred. Five patients (55.6%) relapsed, and all five deaths were relapse-related. Estimated 2-year DFS and OS were both 44.4% (95% confidence interval, 13.6-71.9%). Conclusion:In this highly selected cohort of nine NR patients, CLAG-based sequential conditioning permitted engraftment without non-relapse mortality, but infection and relapse remained frequent. These findings support technical feasibility only and should be regarded as exploratory and hypothesis-generating; efficacy or superiority cannot be established without larger prospective, multicenter, controlled studies.
Introduction:With the advent of modern therapies, including rituximab and novel oral targeted agents such as BTK inhibitors, the survival of lymphoma patients has significantly improved. However, the risk of secondary primary malignancies (SPMs) remains a critical concern. This study aims to evaluate the incidence, risk factors, latency, and survival outcomes of SPMs in lymphoma patients treated in the era of targeted therapies. Methods:A retrospective cohort study was conducted on 1,715 lymphoma patients diagnosed between October 2011 and October 2024 at Shanxi Bethune Hospital, China. Patients with incomplete records, pediatric cases, or immunodeficiency were excluded. Data on demographics, lymphoma characteristics, treatment modalities, and SPMs were collected. SPMs were classified as synchronous (diagnosed within 6 months of lymphoma) or metachronous (diagnosed after 6 months). Statistical analyses included Cox regression for risk factors and Kaplan-Meier for survival analysis. Results:Among 1,715 lymphoma patients, 65 (3.8%) developed SPMs, including 10 synchronous (0.6%, descriptive enumeration only), while 55 (3.2%) developed metachronous SPMs that constituted the primary analytic cohort. Aggressive B-cell non-Hodgkin lymphoma (43.6%) was the most common lymphoma subtype among patients who developed SPMs, followed by indolent B-cell non-Hodgkin lymphoma (38.2%). Digestive and respiratory system tumors were the predominant SPMs (34.5% and 23.6%, respectively). Multivariate analysis identified male sex, ECOG performance status ≥2, extranodal involvement, bone marrow infiltration, BTK inhibitor use, and radiotherapy as independent risk factors for SPMs. Competing-risk analysis showed a higher cumulative incidence of SPMs in patients exposed to BTK inhibitors than in those not exposed to BTK inhibitors (5-year CIF, 7.92% vs 2.57%; Gray's test [Formula: see text] =0.007). Kaplan-Meier analysis showed that patients with SPMs had significantly worse OS than those without SPMs (median OS, 10.3 years; 5-year OS, 69.6% vs 89.6%; log-rank [Formula: see text]<0.0001). No significant difference in OS was observed between patients with solid and hematologic SPMs (median OS, 12.8 vs 6.0 years; [Formula: see text]=0.76). Discussion:In the transitional era of conventional and targeted therapies, although data are limited.This exploratory analysis confirmed that gastrointestinal and respiratory SPMs predominated in this Asian cohort, and identified male sex, ECOG ≥2, extranodal involvement, bone marrow infiltration, radiotherapy, and BTK inhibitor use as independent risk factors. The association with BTK inhibitors (HR=2.56) warrants cautious interpretation and prospective validation. Early detection and tailored surveillance (prioritizing gastrointestinal screening) are essential for improving long-term outcomes.
Objective:To evaluate the long-term efficacy and safety of high-dose idarubicin plus busulfan (I-Bu) conditioning followed by autologous stem cell transplantation (ASCT) compared to intermediate- to high-dose cytarabine (Ara-C) consolidation in young acute myeloid leukemia (AML) patients with favorable- or intermediate-risk in first complete remission (CR1). Methods:We retrospectively analyzed clinical data from 59 young AML patients (aged ≤ 65 years) with favorable- or intermediate-risk disease who received the I-Bu conditioning regimen followed by ASCT between December 2004 and December 2021 (ASCT group). Clinical outcomes were compared with 57 favorable- and intermediate-risk AML patients treated with intermediate- to high-dose Ara-C consolidation chemotherapy alone (chemotherapy group). Overall survival (OS) and disease-free survival (DFS) were evaluated, and univariate and multivariate analyses were performed to identify prognostic factors associated with OS. Results:A total of 116 patients were included with a median follow-up of 79.5 months. Median OS was not reached in either group. The ASCT group achieved a significantly higher 2-year OS rate (84.5% vs 59.7%, P=0.0018) and sustained a significant OS benefit in the 10-year OS rate (P=0.0017). DFS rate also showed superiority in the ASCT group at 2-year (77.7% vs 53.5%, P=0.0037) and maintained this benefit in the 10-year DFS rate (P=0.0038). Multivariate Cox regression identified treatment modality as an independent prognostic factor for OS (HR = 3.12, 95% CI: 1.48-6.59, P=0.0028). In subgroup analysis, ASCT significantly improved OS (P<0.001) and DFS (P=0.0014) in favorable-risk patients, whereas no differences were observed in intermediate-risk patients (OS, P=0.13; DFS, P=0.21). Conclusion:The I-Bu conditioning regimen followed by ASCT provides durable survival benefits and a favorable safety profile for young, favorable-risk AML patients in CR1, representing a potential post-remission therapeutic option. Its role in intermediate-risk AML requires further validation.
Chen Qiu,1,2,* Tingting Zhang,1,2,* Xuejing Yang,3,* Yafang Guo,4 Zihui Gong,5 Dong Song1,21Department of Lymphoma, Shanxi Bethune Hospital (Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University), Taiyuan, Shanxi, People’s Republic of China; 2Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital (Shanxi Academy of Medical Sciences), Taiyuan, Shanxi, People’s Republic of China; 3Department of Thoracic Oncology, Shanxi Bethune Hospital (Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University), Taiyuan, Shanxi, People’s Republic of China; 4Department of Hematology, Shanxi Bethune Hospital (Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University), Taiyuan, Shanxi, People’s Republic of China; 5Pre-Medical Program, School of Arts and Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts, USA*These authors contributed equally to this workCorrespondence: Dong Song, Email songdong@sxbqeh.com.cnIntroduction: With the advent of modern therapies, including rituximab and novel oral targeted agents such as BTK inhibitors, the survival of lymphoma patients has significantly improved. However, the risk of secondary primary malignancies (SPMs) remains a critical concern. This study aims to evaluate the incidence, risk factors, latency, and survival outcomes of SPMs in lymphoma patients treated in the era of targeted therapies.Methods: A retrospective cohort study was conducted on 1,715 lymphoma patients diagnosed between October 2011 and October 2024 at Shanxi Bethune Hospital, China. Patients with incomplete records, pediatric cases, or immunodeficiency were excluded. Data on demographics, lymphoma characteristics, treatment modalities, and SPMs were collected. SPMs were classified as synchronous (diagnosed within 6 months of lymphoma) or metachronous (diagnosed after 6 months). Statistical analyses included Cox regression for risk factors and Kaplan-Meier for survival analysis.Results: Among 1,715 lymphoma patients, 65 (3.8%) developed SPMs, including 10 synchronous (0.6%, descriptive enumeration only), while 55 (3.2%) developed metachronous SPMs that constituted the primary analytic cohort. Aggressive B-cell non-Hodgkin lymphoma (43.6%) was the most common lymphoma subtype among patients who developed SPMs, followed by indolent B-cell non-Hodgkin lymphoma (38.2%). Digestive and respiratory system tumors were the predominant SPMs (34.5% and 23.6%, respectively). Multivariate analysis identified male sex, ECOG performance status ≥ 2, extranodal involvement, bone marrow infiltration, BTK inhibitor use, and radiotherapy as independent risk factors for SPMs. Competing-risk analysis showed a higher cumulative incidence of SPMs in patients exposed to BTK inhibitors than in those not exposed to BTK inhibitors (5-year CIF, 7.92% vs 2.57%; Gray’s test =0.007). Kaplan-Meier analysis showed that patients with SPMs had significantly worse OS than those without SPMs (median OS, 10.3 years; 5-year OS, 69.6% vs 89.6%; log-rank < 0.0001). No significant difference in OS was observed between patients with solid and hematologic SPMs (median OS, 12.8 vs 6.0 years; =0.76).Discussion: In the transitional era of conventional and targeted therapies, although data are limited.This exploratory analysis confirmed that gastrointestinal and respiratory SPMs predominated in this Asian cohort, and identified male sex, ECOG ≥ 2, extranodal involvement, bone marrow infiltration, radiotherapy, and BTK inhibitor use as independent risk factors. The association with BTK inhibitors (HR=2.56) warrants cautious interpretation and prospective validation. Early detection and tailored surveillance (prioritizing gastrointestinal screening) are essential for improving long-term outcomes.Keywords: lymphoma, secondary primary malignancies, targeted therapy, risk factors
Introduction:To establish a dynamic metabolic subtyping system for acute myeloid leukemia (AML) based on longitudinal metabolomics and multi-omics integration, and to evaluate its ability to predict treatment response. Methods:We enrolled 29 AML patients and performed untargeted metabolomics on pre‑ and post-treatment serum samples. Based on finite cyclic combinations of metabolic pathways, pre-treatment patients were classified into G1 (glycolysis/gluconeogenesis/TCA cycle) and G2 (fatty acid/folate biosynthesis). Post‑treatment patients were categorized into TG1 (α-linolenic acid metabolism, pantothenate/CoA biosynthesis) and TG2 (purine metabolism, cysteine/methionine metabolism). Baseline transcriptome data were integrated and validated in three external cohorts (Beat2, GSE6891, GSE37642; total n=994). Single cell and spatial transcriptomics were used to investigate cellular heterogeneity and resistance mechanisms. Results:The complete remission (CR) rate was significantly higher in G2 (71%) than in G1 (29%). After treatment, TG2 showed an 83% CR rate versus 17% in TG1. All patients transitioning from G2 to TG2 achieved CR (100%), whereas those from G1 to TG2 maintained poor response. Baseline metabolic subtype was an independent predictor of treatment response (p<0.05). To explore candidate cellular niches linking G1 metabolic features to chemotherapy resistance, we further integrated single-cell and spatial transcriptomic analyses. The results revealed co-localization of CA2-high immature erythrocytes and neutrophils in non-CR patients. Discussion:Dynamic metabolic subtyping (G1/G2, TG1/TG2) strongly correlates with AML treatment response. The co-localization of CA2-high immature erythrocytes and neutrophils in the bone marrow microenvironment of non-CR patients provides a candidate cellular and microenvironmental correlate of the G1 metabolic phenotype, suggesting a mechanistic link between systemic metabolic reprogramming and chemotherapy resistance. Collectively, these findings highlight the potential of combining dynamic metabolic subtyping with identified microenvironmental features to guide precision therapy.
Purpose:To assess transplant outcomes after umbilical cord blood transplantation (UCBT) in patients with T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) and identify factors associated with relapse. Patients and Methods:We retrospectively analyzed 105 patients with T-ALL/LBL (age, 2-53 years), who underwent single-unit UCBT as their first transplant at our center between January 2014 and June 2024. Transplant outcomes were assessed in the overall cohort. Relapse-associated factors were identified using Fine-Gray competing-risk regression in the subgroup with available 1-month peripheral blood natural killer (NK) cell measurements (58/105, 55.2%). The 1-month NK-cell count was dichotomized based on the median number in the analyzed cohort. A simplified risk score was derived from the final multivariable model. Model performance was assessed using time-dependent area under the curve (AUC) and calibration analysis. Results:In the overall cohort, the 3-year overall survival, progression-free survival, and GVHD-free relapse-free survival were 57.3% (95% CI, 46.9-66.4%), 54.9% (95% CI, 44.9-63.9%), and 49.3% (95% CI, 39.5-58.5%), respectively, and the 3-year cumulative incidence of relapse was 34.5% (95% CI, 25.5-43.6%). In the NK-measured subgroup, multivariable Fine-Gray analysis identified high refined Disease Risk Index (R-DRI) (sHR, 4.561; 95% CI, 1.662-12.51; P = 0.003) and low 1-month NK-cell count (< 0.165 × 109/L) (sHR, 6.175; 95% CI, 1.711-22.280; P = 0.005) as independent factors associated with relapse. A 2-point score stratified patients into low-, intermediate-, and high-risk groups with 3-year relapse incidences of 0, 43.5% (95% CI, 23.3-62.1%), and 89.7% (95% CI, 48.6-98.4%), respectively (P < 0.001). The apparent 3-year AUC was 0.539 (95% CI, 0.255-0.823), and the optimism-corrected AUC was 0.523. Conclusion:Relapse remains a major cause of treatment failure after UCBT in T-ALL/LBL. High R-DRI and low 1-month NK-cell count were independently associated with relapse and allowed apparent risk stratification in the development cohort. This exploratory 2-factor model may provide a basis for future studies of relapse assessment incorporating early immune recovery.
Acute myeloid leukemia (AML) is an aggressive and genetically heterogeneous hematological malignancy characterized by the accumulation of immature myeloid blasts that disrupt healthy hematopoiesis. Despite advances in molecular profiling and targeted therapies, overcoming drug resistance and relapse remains a significant clinical challenge, resulting in poor long-term outcomes. Crucially, disease persistence is sustained not merely by intrinsic genetic lesions but by a highly adaptive bone marrow microenvironment (BMME) that functions as a therapeutic barrier. While the healthy niche tightly regulates hematopoietic stem cell maintenance, leukemic blasts co-opt stromal, vascular, and immune components to establish a sanctuary that fuels proliferation and shields the disease from cytotoxic stress. However, dissecting these reciprocal dependency mechanisms uncovers critical vulnerabilities, presenting a vital opportunity to develop novel targeted therapies. In this review, we discuss the architecture of the healthy BMME and its pathological AML-driven remodeling. We describe the role of specific signaling axes that govern AML-BMME crosstalk and evaluate targeted therapeutic strategies designed to uncouple these protective interactions. Finally, we highlight that current preclinical models lack the complexity of the BMME stromal components and its spatial organization, a limitation that continues to hinder clinical translation and delay the development of effective combination therapies.
Purpose:Alterations in gut microbiota may influence immune response and treatment outcomes in patients with diffuse large B-cell lymphoma (DLBCL). However, the dynamics during anti-CD19 CAR-T cell therapy remain unclear. Methods:We conducted a short-term longitudinal microbiome analysis in DLBCL patients (n=12) undergoing CAR-T cell therapy targeting CD19. Stool samples were collected at baseline, 1 week, and 2 weeks post-infusion. 16S rRNA gene sequencing was used to assess microbial diversity, taxonomic composition, and functional pathways. Correlation analyses were then conducted between microbial taxa and inflammatory biomarkers. Results:Alpha diversity indices showed no statistically significant differences across time points. Beta diversity analysis revealed distinct clustering between baseline and week 1 samples in sPLS-DA, although PERMANOVA did not reach statistical significance. At the phylum level, Bacteroidota abundance significantly increased at week 2 compared with baseline (P = 0.008), accompanied by a marked reduction in the Firmicutes/Bacteroidota ratio. Genus-level heatmap and LEfSe analysis identified enrichment of Parabacteroides, and Prevotella at week 2, whereas baseline samples were enriched in Clostridium sensu stricto 13 and Fusobacterium. Functional prediction indicated that lipoic acid metabolism pathways were significantly upregulated at weeks 1 and 2 compared with baseline (both P < 0.05). Correlation analysis demonstrated that specific bacterial taxa, including Parabacteroides and Prevotella, were positively associated with lymphocyte counts and inversely correlated with C-reactive protein levels. Conclusion:Gut microbiota alterations following CAR-T infusion, characterized by increased Bacteroidota abundance, specific taxonomic shifts, and enhanced lipoic acid metabolism, may provide early microbial signatures for monitoring immune modulation in DLBCL patients.
Object:The prognostic significance of P16 (CDKN2A) deletion (P16del ) in pediatric acute lymphoblastic leukemia (ALL) remains controversial, potentially due to the historical reliance on binary classification. Methods:In this prospective cohort study (SCCLG-ALL-2016 protocol), we analyzed 413 pediatric ALL patients. P16del status and ratio were quantified using standardized FISH. Statistical models adjusting for key prognostic factors were performed. Piecewise linear regression identified prognostic thresholds for P16del ratio. Survival outcomes (relapse-free survival, RFS; overall survival, OS) and interactions with minimal residual disease (MRD) were assessed. Results:P16del prevalence was 18.2% (75/413). Multivariable analysis confirmed P16del as an independent adverse prognostic factor (RFS: HR=2.2, p=0.020; OS: HR=2.7, p=0.024). Crucially, a nonlinear dose-response relationship identified 0.8 as the critical P16del ratio threshold: Below 0.8, each unit ratio increase conferred a 93% higher relapse/death risk (adjusted LogHR=1.93, p=0.031); above 0.8, higher ratios reduced risk by 33% (adjusted LogHR=0.67, p=0.048). Patients with low ratios (<0.8, n=37) had significantly inferior 5-year outcomes (RFS: 57.7%, OS: 72.2%) compared to high ratios (≥0.8, n=38; RFS: 88.5%, OS: 94.7%) (p<0.001). The prognostic impact of MRD was critically dependent on P16del ratio: Low ratio with D33 MRD+ predicted catastrophic outcomes (5-year RFS=27.8%), while high ratio patients maintained excellent survival regardless of MRD status (D33 MRD+ RFS=100%). High-ratio patients exhibited enrichment for RAS mutations (p=0.046). Conclusion:The identified P16 deletion ratio threshold of 0.8 may guide precision risk-adapted therapy in pediatric ALL, but its clinical utility must be validated in larger, diverse cohorts before implementation.
Purpose:Evidence supporting venetoclax combined with hypomethylating agents (HMAs) in treatment-naïve myelodysplastic syndromes with increased blasts (MDS-IB), a biologically aggressive subset with high risk of leukemic transformation, remains lacking. We conducted a prospective, multicenter cohort study to evaluate the efficacy and safety of venetoclax plus HMAs in newly diagnosed MDS-IB. Patients and Methods:In this prospective, multicenter, single-arm trial conducted at six hospitals in China (August 2022-September 2024), 43 newly diagnosed adults with MDS-IB received venetoclax (ramp-up to 400 mg on days 1-14) plus azacitidine or decitabine in 28-day cycles. Dose adjustments were made for cytopenias, infections, or drug interactions. Primary endpoints were overall response rate (ORR), duration of response (DoR), and safety. Secondary endpoints included overall survival (OS) and transformation to acute myeloid leukemia. The study was registered in the Chinese Clinical Trial Registry (registration number: [ChiCTR2200055204]). Results:The ORR was 74.4% (95% CI, 58.8-86.5%), comprising 34.4% complete remission (CR), 59.4% marrow CR (mCR), and 6.3% partial response (PR). Among the thirty-two patients who got ORR, the median DoR was 8.1 months (range, 0.9-29.0). The 6-, 12-, and 24-month DoR rates were 68.8% (95% CI, 49.7-81.8%), 53.2% (95% CI, 33.7-69.4%), and 47.7% (95% CI, 27.8-65.1%), respectively. Median OS was 12.8 months, with 12- and 24-month OS rates of 62.4% (95% CI, 46.1-75.1%) and 49.3% (95% CI, 32.2-64.3%), respectively. Grade 3/4 neutropenia/febrile neutropenia occurred in 60% (26/43), and pneumonia in 16% (7/43). The median interval between cycles was 59 days (range 33-113), mainly due to hematologic toxicity. Conclusion:Venetoclax plus HMAs demonstrated promising clinical activity with manageable toxicity in newly diagnosed MDS-IB, supporting further prospective evaluation of this combination in treatment-naïve patients with increased-blast MDS. Trial Registration:Chinese Clinical Trial Registry, ChiCTR2200055204, https://www.chictr.org.cn/index.html.
Although modern therapies have significantly improved survival, multiple myeloma (MM) remains incurable and biologically heterogeneous, resulting in substantial variability in treatment response and outcomes. Effective risk stratification is therefore critical to guide therapy intensity, predict relapses, and inform prognosis. This review critically examines the current biological determinants of high-risk MM and their implications for treatment intensification, selection of novel therapeutic agents, and stratified clinical trial enrollment. High-risk MM is driven by three major biological determinants: (1) molecular and genomic abnormalities, including high-risk IgH translocations, del(17p), TP53 mutation, gain(1q), and high-risk gene expression signatures; (2) increased proliferative capacity, with an elevated plasma-cell S-phase fraction identifying a subgroup with markedly inferior survival independent of conventional staging; and (3) extramedullary dissemination biology, reflected by circulating tumor cells and soft-tissue extramedullary disease, both associated with marrow independence, clonal evolution, and poor outcomes. The 2024 IMS/IMWG framework integrates the genomic aspects of these biological markers and certain clinical factors into a more precisely defined disease. Complementing baseline classification, dynamic risk stratification using measurable residual disease (MRD) provides real-time prognostic refinement across the treatment course. Future advances will rely on comprehensive molecular profiling and AI-driven data integration to enable precision-guided treatment based on individualized disease biology.
Introduction:The search for novel cancer treatment strategies is of great interest. Recently, it has been reported that laccases from various sources exhibit anti-tumor effects. In addition, the use of nanometric platforms for delivering therapeutic agents at the cellular level is a promising approach for efficient cancer treatment. In this work, the cytotoxicity of Coriolopsis gallica laccase on human leukemia MOLT-4 cells was evaluated. Methods:Laccase was nanoconfined in a virus-like nanoparticle (VLPs) of the brome mosaic virus (BMV), and both free and nanoconfined preparations were evaluated the activation of prodrugs. The cytotoxicity was evaluated by neutral red to obtain the dose-response curve. Afterward, the death cell and mechanisms were characterized using flow cytometry of combinations of laccase (free and VLPs) with prodrugs (Doxorubicin, Irinotecan, and Procarbazine). Results:Laccase alone showed an apoptotic effect at a concentration of 0.35 μM (IC20), with a 49% of apoptotic cells at 24 hours. This effect was enhanced by the presence of doxorubicin (63.79%), irinotecan (43.44%), and procarbazine (53.27%) in the presence of both the free version (Lac) and the nano-encapsidated version (VLP-saLac). A similar effect was observed for the necroptosis population. Finally, the CI (Combination Index) was estimated by two different models, and the synergistic effect on cell death was confirmed. Discussion:The laccase pro-apoptotic effect in MOLT-4 cells has been demonstrated, increasing cytotoxicity by activating prodrugs in both free and nanoconfined forms.
Background:The aggregate index of systemic inflammation (AISI, calculated as neutrophil count × monocyte count × platelet count/lymphocyte count) reflects systemic inflammatory status; however, its prognostic role in diffuse large B-cell lymphoma (DLBCL) remains underexplored. This study aimed to investigate the prognostic value of AISI in DLBCL. Methods:A total of 1332 DLBCL patients (median age 62 years; 52.3% male) were included in this study. Patients were stratified based on AISI quartiles, and a cut-off value was determined using restricted cubic splines (RCS) analysis. The associations between AISI and Overall survival (OS) were assessed using Kaplan-Meier analysis and Cox proportional hazards models. Results:Higher AISI levels were associated with adverse clinical features, including advanced Ann Arbor stage, poor performance status, and higher-risk categories of both the IPI and the NCCN-IPI. RCS analysis revealed a nonlinear relationship between AISI and OS, with an inflection point at 261.33. Kaplan-Meier analysis demonstrated that patients with AISI > 261.33 had significantly worse OS compared to those with AISI ≤ 261.33 (P = 0.003). Similarly, patients in the Q4 group had poorer OS than those in the lowest two quartiles (Q1-Q2) (P = 0.008). In fully adjusted Cox proportional hazards models (adjusted for age, sex, Ann Arbor stage, LDH, ECOG performance status, BMI, albumin, B symptoms, bone marrow involvement, central nervous system involvement, and liver/spleen involvement), high AISI level (> 261.33) were associated with increased mortality risk (HR = 1.28, 95% CI: 1.04-1.57, P = 0.018). Subgroup analyses indicated that the prognostic impact of AISI was particularly evident among patients classified as low risk by conventional prognostic systems. Conclusion:Elevated AISI was associated with inferior OS in DLBCL patients and may potentially serve as a prognostic biomarker.
Xicheng Chen,1,* Linyu Huang,2,* Qiming Zhang,1,* Xing Xing,3 Shuo Zhang,4 Chunling Wang,5 Ling Wang,6 Ziyuan Shen,7,* Wei Sang1,8,* On behalf of the Huaihai Lymphoma Working Group1Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Department of Quality Management, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 4Department of Hematology, Linyi People’s Hospital, Linyi, Shandong, People’s Republic of China; 5Department of Hematology, The First People’s Hospital of Huai’an, Huai’an, Jiangsu, People’s Republic of China; 6Department of Hematology, Tai’an Central Hospital, Tai’an, Shandong, 271000, People’s Republic of China; 7Clinical Research Institute, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 8Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyuan Shen, Email sshenzy@126.com Wei Sang, Email xyfylbl515@xzhmu.edu.cnBackground: The aggregate index of systemic inflammation (AISI, calculated as neutrophil count × monocyte count × platelet count/lymphocyte count) reflects systemic inflammatory status; however, its prognostic role in diffuse large B-cell lymphoma (DLBCL) remains underexplored. This study aimed to investigate the prognostic value of AISI in DLBCL.Methods: A total of 1332 DLBCL patients (median age 62 years; 52.3% male) were included in this study. Patients were stratified based on AISI quartiles, and a cut-off value was determined using restricted cubic splines (RCS) analysis. The associations between AISI and Overall survival (OS) were assessed using Kaplan-Meier analysis and Cox proportional hazards models.Results: Higher AISI levels were associated with adverse clinical features, including advanced Ann Arbor stage, poor performance status, and higher-risk categories of both the IPI and the NCCN-IPI. RCS analysis revealed a nonlinear relationship between AISI and OS, with an inflection point at 261.33. Kaplan-Meier analysis demonstrated that patients with AISI > 261.33 had significantly worse OS compared to those with AISI ≤ 261.33 (P = 0.003). Similarly, patients in the Q4 group had poorer OS than those in the lowest two quartiles (Q1-Q2) (P = 0.008). In fully adjusted Cox proportional hazards models (adjusted for age, sex, Ann Arbor stage, LDH, ECOG performance status, BMI, albumin, B symptoms, bone marrow involvement, central nervous system involvement, and liver/spleen involvement), high AISI level (> 261.33) were associated with increased mortality risk (HR = 1.28, 95% CI: 1.04– 1.57, P = 0.018). Subgroup analyses indicated that the prognostic impact of AISI was particularly evident among patients classified as low risk by conventional prognostic systems.Conclusion: Elevated AISI was associated with inferior OS in DLBCL patients and may potentially serve as a prognostic biomarker.Keywords: aggregate index of systemic inflammation, diffuse large B-cell lymphoma, prognosis, risk stratification
Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome characterised by the reactive activation of cytotoxic T-lymphocytes and macrophages along with a substantial amount of cytokine secretion caused by various inductions. Natural killer/T-cell lymphoma (NKTL)-associated HLH (NK/T-LAHLH) is rare in clinical practice with an incidence rate of 7.1-11.9% in NKTL patients. Currently, there is no standard first-line treatment with good efficacy for NK/T-LAHLH. The treatment of NK/T-LAHLH is still mainly based on chemotherapy regimens containing etoposide and dexamethasone. Recently, many new therapeutic drugs and schemes have been trialled for the treatment of NK/T-LAHLH, such as ruxolitinib, immune checkpoint inhibitors, pegaspargase, and the DEP regimen. However, NK/T-LAHLH is associated with overall poor prognosis. Improving overall understanding of NK/T-LAHLH is of great significance to ameliorating patient prognosis. This review systematically discussed the epidemiology, pathogenesis, clinical features, current treatment regimens, and prognosis of NK/T-LAHLH to comprehensively elucidate this disease.
Objective: To investigate the mechanism of FOXN3 in acute leukemia. Methods: ChIP-seq experiments were performed using FOXN3-specific antibodies to identify FOXN3 target genes in acute myeloid leukemia (AML). Bioinformatics analyses were conducted to determine the enrichment of biological processes and pathways related to cell cycle regulation and apoptosis among the target genes. The transcriptional regulation of the gene of interest was confirmed through RTqPCR, Western blotting, and luciferase reporter assays. Additionally, we examined the significance of FOXN3 on the prognosis of AML patients. Functional studies were performed following the knockdown and overexpression of the target gene in AML cells. Furthermore, we investigated the interaction between FOXN3 and the target gene by co-transfecting AML cells with lentiviruses overexpressing the target gene, followed by examinations of downstream signaling pathways through RNA-seq and pathway enrichment analyses. Results: FOXN3 regulates E2F5 expression, leading to decreased mRNA and protein levels of E2F5 upon FOXN3 overexpression, though additional factors may contribute to this repression. Notably, E2F5 expression was elevated in AML patients and cell lines, correlating with unfavorable clinical outcomes. Functional investigations revealed that E2F5 functions as an oncogene in AML, promoting cell proliferation, inhibiting apoptosis, and influencing cell cycle progression. Co-transfection experiments demonstrated that E2F5 could counteract the proliferation-inhibitory effect of FOXN3. Additionally, FOXN3 was found to modulate the MAPK signaling pathway and its downstream target, EZH2. Conclusion: This study reveals a novel regulatory axis involving FOXN3 and E2F5 in AML. FOXN3 acts as a tumor suppressor by regulating E2F5 and modulating downstream MAPK signaling pathways.
Acute Myeloid Leukemia (AML) is a common hematologic neoplasm in adults and usually carries a grim prognosis. Therapy has traditionally consisted of intensive chemotherapy; however, recent advances have led to the development of Tyrosine Kinase Inhibitors (TKI) as Targeted Therapies for subtypes carrying certain mutations. While the clinical impact of these therapies has been well described, there have been no studies looking at clinical disparities among different racial/ethnic groups receiving these therapies. We leveraged an EHR-derived database to evaluate real-world outcomes in patients receiving TKIs for AML. Our study found no significant differences between real-world Event Free Survival (rwEFS) and real world Overall Survival (rwOS) across patients of different racial/ethnic groups, this suggests that when patients have access to targeted therapy outcomes across different racial/ethnic groups become more equitable.
