Search Results (571)

Diffuse large B-cell lymphoma (DLBCL) is the most common and clinically aggressive subtype of non-Hodgkin lymphoma (NHL). While novel therapies such as rituximab and polatuzumab vedotin have led to improved outcomes, approximately 35% of patients eventually develop relapsed or refractory disease. MicroRNAs (miRNAs), a class of endogenous single-stranded RNAs approximately 22 nucleotides in length, play a pivotal role in the regulation of gene expression at the post-transcriptional level through interactions with complementary target RNAs and contribute significantly to the development, progression, and treatment response of DLBCL. Oncogenic miRNAs, such as miR-155, miR-21, and the miR-17–92 cluster, promote proliferation, survival, immune evasion, and therapy resistance by modulating pathways including PI3K/AKT, NF-κB, and MYC. Conversely, tumor-suppressive miRNAs such as miR-34a, miR-144, miR-181a, and miR-124-3p inhibit oncogene activity and enhance apoptosis, with their loss often associated with adverse outcomes. Among these, miR-155 and miR-21 are particularly well studied, playing central roles in both tumor progression and remodeling of the tumor microenvironment. This review summarizes current evidence on the biological and clinical relevance of miRNAs in DLBCL, emphasizing their diagnostic and prognostic potential. Full article

Background/Objectives: Multiple myeloma (MM) patients receiving immunomodulatory drugs (IMiDs) are at increased risk of venous thromboembolism (VTE). Standard prophylaxis typically involves aspirin or low-molecular-weight heparin (LMWH), guided by risk assessment tools such as SAVED and IMPEDE-VTE. However, these models have practical limitations, and real-world evidence supporting novel oral anticoagulants (NOACs) as primary prophylaxis remains limited. Methods: In this retrospective, single-center study, we analyzed 101 MM patients treated with IMiD-based therapy between January 2020 and December 2024. All patients received NOAC prophylaxis (apixaban 2.5 mg twice daily or rivaroxaban 10–20 mg once daily), irrespective of baseline thrombotic risk. Clinical characteristics, comorbidities, and treatment details were collected. The primary outcome was objectively confirmed VTE, while secondary outcomes included bleeding events and treatment feasibility, assessed by treatment continuation without clinically significant bleeding. Results: Median age was 63 years (range 35–89); 36.6% were female. Lenalidomide and pomalidomide were used in 86.1% and 13.9%, respectively. Twenty-eight patients (27.7%) had relapsed/refractory disease, while 72.3% were newly diagnosed. Over a median NOAC exposure of 6 months, two patients (2.0%) developed VTE (both deep vein thrombosis). One major bleeding event (1.0%) occurred. Conclusions: Universal NOAC prophylaxis in MM patients receiving IMiD-based therapy was associated with a low incidence of thromboembolic events and an acceptable safety profile. These real-world findings suggest that NOACs may represent a practical and effective alternative to aspirin or LMWH, potentially overcoming the limitations of score-based prophylaxis strategies. Full article

Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma characterized by overlapping clinicopathologic and molecular features of primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Under current WHO-HEMA5 and International Consensus Classification (ICC) frameworks, MGZL is restricted to EBV-negative lymphomas arising in the mediastinum. Methods: This review summarizes current evidence on epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic challenges, and therapeutic approaches to MGZL, with data derived from retrospective series, limited prospective cohorts, and recent molecular studies. Results: MGZL predominantly affects young adults and commonly presents with bulky mediastinal disease. Diagnosis is challenging due to transitional morphology, pleomorphic Reed–Sternberg-like cells, and variable expression of B-cell and activation markers. Molecular studies demonstrate shared alterations with PMBL and CHL, including 9p24.1 (JAK2/PD-L1/PD-L2) gains, while additional reported features such as HOXA5 hypomethylation and MYC copy number gains support its biological distinctiveness, although evidence remains limited. Frontline treatment commonly involves intensive chemoimmunotherapy regimens such as DA-EPOCH-R; however, outcomes remain inferior to PMBL and CHL, with 5-year overall survival rates of approximately 40–60%. Relapsed or refractory disease frequently requires salvage chemotherapy and autologous stem cell transplantation. Immune-based therapies, including brentuximab vedotin and PD-1 inhibitors, have shown promising activity, particularly in combination. Conclusions: MGZL remains a diagnostically challenging and therapeutically complex lymphoma with inferior outcomes compared with related mediastinal lymphomas. Advances in molecular profiling and immunotherapy offer promising avenues toward more personalized treatment; however, prospective clinical trials and international collaboration are urgently needed to establish evidence-based management strategies for this rare entity. Full article

Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease. Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence of TP53 mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure. Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p = 0.01), independently of TP53 mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p = 0.01). Pairwise log-rank tests confirmed TP53 mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clusters TP53-mut vs. TP53-WT, p = 0.001, HR = 3.92; and p = 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity of TP53 mutation. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) exhibits substantial clinical heterogeneity and poor prognosis in relapsed/refractory (R/R) settings. PRO-MIND is a prospective, multicenter real-world study evaluating tafasitamab–lenalidomide followed by tafasitamab monotherapy in patients with transplant-ineligible R/R DLBCL in Italy. This ad hoc, cross-sectional, baseline analysis aimed to characterize health-related quality of life (HRQoL) and symptom burden before tafasitamab–lenalidomide initiation in the PRO-MIND cohort. Methods: Thirty-eight patients across 30 centers completed the EORTC QLQ-C30 and QLQ-NHL-HG29 questionnaires at pretreatment baseline, prior to starting tafasitamab–lenalidomide. EORTC QLQ-C30 scores (0–100) were compared with age-specific normative values for the Italian general population using Welch’s t-test. Differences of ≥5 points were considered clinically meaningful and ≥10 points clearly clinically important. Effect sizes (Cohen’s d) were calculated to complement p-values for between-group comparisons. Results: Compared with normative data, the PRO-MIND cohort had significantly lower EORTC QLQ-C30 functioning scores for physical (Δ 12.7, p = 0.0135), role (Δ 16.1, p = 0.0168), social (Δ 15.2, p = 0.0019), and cognitive (Δ 8.5, p = 0.0460) functioning. Symptom scales revealed worse fatigue (Δ 14.8, p = 0.0097), insomnia (Δ 13.9, p = 0.0291), appetite loss (Δ 9.4, p = 0.0435), and pain (Δ 8.7, p = 0.0430) in the PRO-MIND cohort versus normative data, with effect sizes in the small-to-moderate range. EORTC QLQ-NHL-HG29 scores indicated a high prevalence of concerns about future health (84.2%), disease recurrence (81.6%), and dependency (78.9%), as well as physical symptoms, including lack of energy (71.1%), sleep difficulties (63.2%), and pain or discomfort (60.5%). Conclusions: This cross-sectional, baseline-only analysis of the PRO-MIND real-world cohort showed that patients with transplant-ineligible R/R DLBCL scheduled to receive tafasitamab–lenalidomide already had pronounced impairments in physical, role, social, and cognitive functioning, along with substantial fatigue, insomnia, pain, appetite loss, and psychological concerns. These baseline benchmarks underscore the importance of systematic HRQoL assessment and targeted supportive interventions focusing on these domains before and during treatment. Future longitudinal PRO-MIND analyses will complement these findings by describing how HRQoL evolves after tafasitamab–lenalidomide initiation. Full article

Despite the groundbreaking impact of currently approved CAR T-cell therapies, substantial unmet clinical needs remain. This highlights the need for CAR T treatments that are easier to tune, combine, and program with logic rules, in oncology and autoimmunity. Modular CAR T cells use a two-part system: the CAR on the T cell binds an adaptor molecule (AM), and that adaptor binds the tumour-associated antigen (TAA). This design separates recognition of the target antigen and activation of the T cells, resulting in a cellular therapy concept with better control, flexibility, and safety compared to established direct-targeting CAR T-cell systems. The key advantage of the system is the adaptor molecule, often an antibody-based reagent, that targets the TAA. Adaptors can be swapped or combined without re-engineering the T cells, enabling straightforward multiplexing and logic-gated control. The CAR itself is designed to recognise the AM via a unique tag on the adaptor. Only when the CAR, AM, and antigen-positive target cell assemble correctly is T-cell effector function activated, leading to cancer cell lysis. This two-component system has several features that need to be considered when designing a modular CAR: First, the architecture of the CAR, i.e., how the binding domain and the backbone are designed, can influence tonic signalling and activation/exhaustion parameters. Second, the affinity of CAR–AM and AM–TAA will mostly define the engagement kinetics of the system. Third, the valency of the AM has an impact on exhaustion and non-specific activation of CAR T cells. And lastly, the architecture of the AM, especially the size, defines the pharmacokinetics and, consequently, the dosing scheme of the AM. The research conducted on direct-targeting CAR T cells have generated in-depth knowledge of the advantages and disadvantages of the technology in its current form, with remarkable clinical success in relapsed/refractory disease and long-term survival in otherwise difficult-to-treat patient populations. On the other hand, CAR T-cell therapy poses the risk of severe adverse events and antigen loss coupled with antigen-negative relapse which remains the main reason for failed therapies. Addressing these issues in the traditional setting of one CAR targeting one antigen will always be difficult due to the heterogeneous nature of most oncologic diseases, but the flexibility to change target antigens and the modulation of CAR T response by dosing the AM in a modular CAR system might be pivotal to mitigate these hurdles of direct CAR T cells. Since the first conception of modular CARs in 2012, there have been more than 30 constructs published, and some of those have been translated into phase I/II clinical trials with early signs of success, but whether these will progress into a late-stage clinical trial and gain regulatory approval remains to be seen. Full article

For patients with relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy, T-cell-redirecting therapies—including the bispecific CD3xCD20 antibody (BsAbs) mosunetuzumab (mosu) and chimeric antigen receptor T-cell (CAR-T) therapies such as axicabtagene ciloleucel (axi-cel), lisocabtagen maraleucel (liso-cel), and tisagenlecleucel (tisa-cel)—are approved by the FDA and EMA. Treatment selection should consider patient-related factors, prior therapeutic exposure, and toxicity profiles. We describe the 20-year history of a patient with R/R FL. At the fourth relapse, both BsAbs and CAR-T cells were available; however, due to the cumulative toxic burden and the high risk of cytopenias, mosu was selected as the preferred option. During mosu, the patient developed pure red cell aplasia unrelated to infections. Despite achieving a partial response after eight cycles of mosu, this complication led to the decision to proceed with allogeneic stem cell transplantation (allo-HSCT). The course was ultimately complicated by severe early toxicity with massive hemoptysis, acute respiratory failure, and hemorrhagic alveolitis, resulting in a fatal outcome. This case illustrates the delicate balance required in selecting between BsAbs and CAR-T therapy in R/R FL. Contributing factors to the patient’s fragility included profound immune status, transfusion-dependent red cell aplasia, prior cumulative chemotherapy, and pulmonary toxicity associated with conditioning regimens. The case underscores the importance of individualized treatment strategies and suggests that earlier integration of novel T-cell-redirecting therapies may mitigate cumulative toxicity and infection risk. Individualized therapeutic planning is critical in heavily pretreated R/R FL. In select cases, bridging strategies using BsAbs can provide disease control and facilitate transplantation. Still, careful assessment of patient fitness, marrow reserve, and cumulative toxicity is essential to minimize the risk of fatal complications. Full article

Background: Ewing sarcoma (ES) is a highly aggressive malignant tumor that predominantly affects children and young adults. Despite advances in multimodal therapy, relapse and refractory disease remain the leading causes of treatment failure. High-dose chemotherapy followed by autologous stem cell transplantation (HDCT-ASCT) has been proposed as a consolidation strategy for high-risk or relapsed ES; however, its clinical value remains controversial. Methods: We retrospectively analyzed 46 consecutive patients with locally advanced or metastatic ES who underwent HDCT-ASCT after at least one prior systemic therapy line. Clinical, pathological, and transplant-related variables were evaluated for associations with overall survival (OS), post-transplant OS (OS-2), and progression-free survival (PFS). Survival was estimated using the Kaplan–Meier method, and prognostic factors were assessed by Cox proportional hazards modeling. Results: The median age at diagnosis was 23 years (range: 14–55). Median OS from diagnosis was 42 months, while post-transplant OS-2 and PFS were 8 and 5 months, respectively. Younger patients (≤23 years) had significantly longer OS (50 vs. 34 months; p = 0.027). Liver metastasis predicted inferior OS (HR = 5.411; p = 0.006), whereas lung metastasis was associated with shorter OS-2 (HR = 2.672; p = 0.025) and PFS (HR = 6.037; p = 0.016). Treatment-related mortality was low (2.1%), though hematologic toxicity was universal. Overall, HDCT-ASCT provided transient disease control, with modest benefit confined to younger, chemosensitive, and medically fit patients. Conclusions: In this real-world cohort, HDCT-ASCT was feasible and safe but offered limited survival advantage in heavily pretreated Ewing sarcoma. Prognosis was primarily influenced by age and metastatic distribution, particularly hepatic and pulmonary involvement. These findings support a risk-adapted, biology-driven approach reserving HDCT-ASCT for selected patients and highlight the need for post-transplant maintenance strategies integrating targeted or immunotherapeutic modalities. Full article

Background/Objectives: Vogt–Koyanagi–Harada (VKH) disease is a bilateral granulomatous panuveitis that can progress to a chronic, relapsing phase. Patients refractory or intolerant to systemic corticosteroids and conventional immunomodulatory therapy pose a major therapeutic challenge, as persistent inflammation can lead to cumulative ocular damage and permanent vision loss. This study assessed the efficacy of tumor necrosis factor-α (TNF-α) inhibitor adalimumab in chronic recurrent VKH disease. Methods: We retrospectively reviewed 16 eyes from 8 patients with chronic recurrent VKH disease who had persistent inflammation despite treatment with corticosteroids and conventional immunomodulatory therapy, and subsequently received adalimumab. Primary outcomes were changes in subfoveal choroidal thickness (SFCT) and systemic corticosteroid dose reduction. Secondary outcomes included visual acuity, inflammatory parameters (anterior chamber cell, flare, and vitreous haze), and central macular thickness (CMT). All outcomes were compared between baseline and 6 months after adalimumab initiation using the Wilcoxon signed-rank test. Results: Mean patient age was 47.6 years and mean follow-up was 31.8 months. SFCT decreased from 326.7 ± 129.1 µm to 231.6 ± 72.9 µm at 6 months (p < 0.001). Systemic steroid dose decreased from 14.7 ± 14.0 mg to 4.1 ± 3.8 mg (p = 0.027). Mean annualized relapse rate decreased from 3.61 to 0.08 episodes/year (p = 0.012). Anterior chamber cell grade decreased from 0.81 ± 0.66 to 0.09 ± 0.20 (p < 0.001). Visual acuity, flare, vitreous haze, and CMT showed no significant change. No serious adverse events occurred. Conclusions: TNF-α inhibition with adalimumab appears effective as steroid-sparing therapy for controlling recurrent inflammation and reducing steroid dependence in patients with chronic recurrent VKH disease refractory to conventional treatment. Full article

Gene fusions involving NUTM1 have been increasingly recognized in hematologic malignancies, though their role in acute myeloid leukemia (AML) remains poorly understood. We retrospectively analyzed 565 unique AML patients with reported fusion results who underwent comprehensive next-generation sequencing (NGS) between March 2022 and December 2023. Among them, three novel in-frame NUTM1 fusion transcripts, LARP1::NUTM1, ARHGAP15::NUTM1, and GABPB1::NUTM1, were identified in three relapsed or refractory AML cases, all with monocytic differentiation. Ancillary studies included flow cytometry, cytogenetics, FISH, and comprehensive mutational profiling. All three patients eventually relapsed and succumbed to their disease, despite initial responses in one case. Each case also harbored co-occurring mutations associated with adverse prognosis, such as BCOR, ASXL1, and RUNX1. These findings suggest NUTM1 fusions in AML could represent a distinct molecular subset with potentially poor prognosis, warranting further functional and clinical investigation to clarify their biological and therapeutic significance. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease. Full article

Multiple myeloma (MM) is a clonal malignancy of plasma cells that remains largely incurable despite major advances in proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Chimeric antigen receptor (CAR)-engineered immune cells have transformed the therapeutic landscape, but CAR-T cell therapy faces challenges such as severe cytokine release syndrome (CRS), neurotoxicity, limited persistence, and logistical complexity. In recent years, natural killer (NK) cells have emerged as a promising platform for next-generation cellular immunotherapy, offering innate antitumor activity, a reduced risk of graft-versus-host disease (GvHD), and the feasibility of “off-the-shelf” allogeneic production. This review summarizes current advances in CAR-NK cell therapy for MM, focusing on two major aspects: the diversity of cell sources—including NK-92, peripheral (PB) and cord blood (CB), and induced pluripotent stem cell (iPSC)-derived NK cells—and the expanding repertoire of target antigens such as BCMA (B-cell maturation antigen), NKG2D, CD38, CD70, SLAMF7, CD138, and GPRC5D. We highlight preclinical and early clinical studies demonstrating potent cytotoxicity, favorable safety profiles, and innovative multi-targeting strategies designed to overcome antigen escape and enhance persistence. Emerging clinical data suggest that CAR-NK cell therapy may combine the specificity of CAR recognition with the inherent safety and versatility of NK biology, offering a potential paradigm shift in the treatment of relapsed or refractory MM. Further clinical validation will determine whether CAR-NK cell therapy can achieve durable remission and complement or surpass current CAR-T modalities. Full article

Background and Objective: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), has demonstrated promising efficacy in chronic lymphocytic leukemia (CLL), including treatment-naïve (TN) and relapsed/refractory (R/R) patients. However, evidence synthesis across clinical trials remains limited. We conducted a systematic review and single-arm meta-analysis to evaluate the efficacy of zanubrutinib in CLL. Methods: This study was performed in accordance with PRISMA guidelines and Cochrane recommendations. PubMed, Medline, Scopus, and Web of Science were searched up to August 2025 using terms related to zanubrutinib and CLL/SLL. Eligible studies included clinical trials of zanubrutinib in TN or R/R CLL/SLL patients. Risk of bias was assessed using the JBI tool for non-randomized studies and for RCTs. Pooled estimates of efficacy outcomes were calculated using a random-effects model. Pooled estimates were calculated using the DerSimonian–Laird random-effects model, which accounts for both within- and between-study variability. Results: Seven studies (n > 1000) were included, enrolling both TN and R/R patients across diverse global populations. The pooled overall response rate (ORR) was 93.3% (95% CI, 86.7–99.8%) in mixed TN and R/R populations, 94.4% (95% CI, 91.6–97.3%) in TN patients, and 83.9% (95% CI, 75.0–92.8%) in R/R patients. Complete response (CR) rates were 12.2% (95% CI, 0.3–24.2%) overall, 13.8% (95% CI, 1.5–26.2%) in TN patients, and 5.0% (95% CI, 0.3–9.8%) in R/R patients. Partial response (PR) rates reached 86.0% (95% CI, 82.6–89.5%) in TN and 63.2% (95% CI, 53.5–73.0%) in R/R patients. Progressive disease was rare (≤1% in R/R cohorts). Heterogeneity was moderate to high across several outcomes. Conclusions: Zanubrutinib demonstrates favorable efficacy in CLL, achieving high ORR in both TN and R/R patients, with particularly durable responses in TN populations. Although complete response rates remain modest, especially among R/R patients, overall disease control appears consistent. These findings support zanubrutinib as an effective treatment option across CLL settings; however, variability among studies and the modest CR rates highlight the need for longer follow-up and direct comparative trials to further define its clinical role. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is a molecularly and pathogenically heterogenous disease with varying clinical outcomes, as reflected by the significant number of patients who develop relapse/refractory disease (rrDLBCL) following standard treatment with the combined R-CHOP regimen. The molecular background of rrDLBCL is not yet fully understood, and prognostic and/or companion diagnostic biomarkers for identification and treatment stratification of these patients are in high demand. Methods: This exploratory study used comprehensive proteomic data to identify proteins associated with treatment response. Proteome profiles of DLBCL cells were analyzed through groupwise comparison between cell lines with a resistant or sensitive response to rituximab, cyclophosphamide, doxorubicin, and vincristine. Their responses were determined using subsequent drug response screens, mimicking the conditions of diagnostic samples prior to treatment. Results: A total of 98 differentially abundant proteins, including NSFL1C, GET4, PCNA, and SMC5, were found between resistant and sensitive cells. These same 98 proteins were examined in two cohorts of DLBCL patients, leading to the identification of 16 proteins whose expression was consistently associated with treatment response both in vitro and in patient tissue samples. Among these, GET4 and NSFL1C showed the highest enrichment in R-CHOP resistant patients compared to sensitive responders. In the cell line study, GET4 was enriched in cyclophosphamide-resistant cell lines and NSFL1C enriched in vincristine-resistant cell lines, associating GET4 and NSFL1C enrichment in patient samples to responsiveness to cyclophosphamide and vincristine, respectively. Enrichment of DNA damage repair proteins was observed within the differential proteins, highlighting the need to investigate DNA damage repair involvement in treatment responses. Conclusions: This study identifies 16 proteins with concordant treatment response specificity in DLBCL cell lines and lymphoma tissue patient samples, suggesting their potential as prognostic markers for DLBCL. Full article

Background: Pediatric non-Down Syndrome Acute Megakaryoblastic Leukemia (non-DS-AMKL) is a rare subtype of Acute Myeloid Leukemia (AML) arising from primitive megakaryocytes and is associated with poor outcomes. Given its high incidence of relapse, this subpopulation of children is frequently referred for allogeneic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Objectives: The objective of this study was to describe the clinical outcomes of non-DS-AMKL pediatric patients in a large, single-institution cohort. Methods: A retrospective review of the medical records of thirty-six patients diagnosed with non-DS-AMKL treated at Texas Children’s Hospital from 2000 to 2022 was conducted. Results: Twenty-nine patients were included in the analysis, with cohorts defined by intention to treat. Twelve patients received chemotherapy only during upfront therapy, and seventeen received upfront HSCT. The 5-year overall survival (OS) and disease-free survival (DFS) for the entire cohort were 19.1% and 24.1%, respectively, with a median survival of 17.4 months. A higher percentage of patients in the chemotherapy-only group had relapsed/refractory disease at death (chemotherapy only, n = 9; HSCT, n = 8). However, 5-year OS and DFS were similar for both groups (OS = 18.8% vs. 31.3%, p = 0.58; DFS = 37.6% vs. 22.2%, p = 0.51). Relapse was the leading cause of death (5-year cumulative incidence of relapse (CIR) 0.78). Treatment with allo-HSCT did not improve outcomes due to the high CIR, even after HSCT in CR1. Conclusions: These dismal outcomes highlight the need for development and incorporation of novel targeted agents into upfront therapy or in the post-HSCT setting for patients with this challenging disease. Full article