Search Results (593)

Acute myeloid leukemia (AML) harboring KMT2A rearrangements (KMT2A-r) accounts for approximately 5–10% of newly diagnosed cases and represents a high-risk AML subtype associated with poor clinical outcomes despite intensive treatment strategies, including allogeneic hematopoietic stem cell transplantation (HSCT). KMT2A-r AML is also characterized by a higher incidence of extramedullary disease compared with other AML subtypes. Therapeutic options for patients with relapsed/refractory (R/R) disease, particularly after post-HSCT relapse, remain extremely limited. In recent years, menin inhibitors have emerged as a promising targeted therapeutic class for KMT2A-r and NPM1-mutated AML by disrupting the aberrant HOX/MEIS1 transcriptional program. Revumenib, a first-in-class menin inhibitor, has shown encouraging efficacy in early-phase clinical trials. Other menin inhibitors, including ziftomenib, bleximenib, and enzomenib, have also demonstrated clinical activity, with distinct pharmacokinetic, pharmacodynamic, and safety profiles. We report the case of a 36-year-old patient with KMT2A-r AML who relapsed after HSCT with both bone marrow and hepatic involvement. Compassionate-use treatment with revumenib (160 mg twice daily on days 1–28 of each 28-day cycle) induced, after two treatment cycles, complete hematologic remission with no detectable abnormal myeloid blast population by multiparameter flow cytometry (MFC) and complete radiological resolution of hepatic lesions. However, despite prior intrathecal CNS-directed therapy and sustained systemic disease control, the patient subsequently developed an isolated central nervous system (CNS) relapse. This case highlights a potential discordance between systemic and CNS disease control during menin inhibitor therapy and emphasizes the need for further investigation into CNS surveillance and disease management in patients achieving deep systemic responses. Full article

Background: Cytomegalovirus (CMV) reactivation and graft-versus-host disease (GVHD) are major causes of morbidity and non-relapse mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although their association has been extensively investigated, the temporal relationship between these complications and their impact on survival remain incompletely understood, particularly in centers where routine letermovir prophylaxis is unavailable and CMV is managed using a pre-emptive treatment strategy. This study evaluated the bidirectional temporal association between CMV reactivation and GVHD using time-dependent analyses and assessed their impact on survival in a real-world allo-HSCT cohort. Methods: We retrospectively analyzed 100 consecutive adult patients who underwent allo-HSCT for hematologic malignancies between January 2016 and February 2025. CMV surveillance was performed by weekly quantitative CMV-DNA PCR, and reactivation was managed using a standardized pre-emptive treatment strategy. Patients who relapsed or died within the first 100 days after transplantation were excluded. The incidence, temporal sequence, risk factors, and prognostic impact of CMV reactivation and GVHD were evaluated. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan–Meier method, while temporal associations were assessed using time-dependent Cox regression analyses. Results: CMV reactivation occurred in 72 patients (72%), whereas GVHD developed in 51 patients (51%). Among patients who experienced both complications, CMV reactivation preceded GVHD in 32 patients, while GVHD preceded CMV reactivation in 14 patients. Older recipient age (42.3 ± 13.5 vs. 35.4 ± 11.2 years, p = 0.018) and older donor age (37.2 ± 10.9 vs. 32.5 ± 9.7 years, p = 0.048) were associated with CMV reactivation. Older donor age was also associated with GVHD development (38.1 ± 10.7 vs. 33.6 ± 10.5 years, p = 0.037). The median time to CMV reactivation was 37 days, and CMV end-organ disease occurred in 13.9% of affected patients. No significant differences in OS or RFS were observed according to CMV reactivation or GVHD status in the day-100 landmark cohort. In the AML subgroup, both CMV reactivation and GVHD showed a trend toward inferior OS and RFS without reaching statistical significance. Time-dependent Cox regression demonstrated that CMV reactivation independently increased the subsequent risk of GVHD (HR 2.93, 95% CI 1.51–5.69; p = 0.001), whereas GVHD also independently increased the subsequent risk of CMV reactivation (HR 1.98, 95% CI 1.06–3.71; p = 0.032). Conclusions: CMV reactivation was highly prevalent after allo-HSCT and frequently preceded GVHD, supporting a bidirectional temporal relationship between these complications. Older donor age was associated with both CMV reactivation and GVHD. Although survival did not significantly differ according to CMV or GVHD status in this day-100 landmark cohort, clinically important CMV-related complications, including end-organ disease and platelet engraftment failure requiring eltrombopag, remained common. These findings indicate that a standardized pre-emptive strategy did not completely prevent CMV-associated morbidity. Because letermovir was not evaluated in this cohort, any potential benefit of prophylaxis should be interpreted as an inference from external evidence rather than as a direct finding of this study. Prospective multicenter studies incorporating immune reconstitution analyses are warranted. Full article

Background: Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1), also known as 8p11 myeloproliferative syndrome, are rare and aggressive hematologic malignancies arising from pluripotent stem cells. The FGFR1::ZMYM2 fusion resulting from t(8;13)(p11.2;q12) characteristically co presents as T-lymphoblastic lymphoma in lymph nodes alongside a myeloproliferative neoplasm in the bone marrow. The disease is resistant to tyrosine kinase inhibitors and conventional chemotherapy, and carries a median survival of less than 12 months without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Case Presentation: We report a 23-year-old female who presented with progressive cervical lymphadenopathy and hyperleukocytosis (WBC 186.6 K/μL). Excisional lymph node biopsy demonstrated T-cell acute lymphoblastic lymphoma (T-ALL) with eosinophilic infiltration; immunohistochemistry confirmed lymphoblasts positive for CD1a, CD2, CD3, CD4, CD5, CD7, CD8, and TdT. Concurrent bone marrow biopsy showed a myeloproliferative neoplasm without excess blasts. Chromosomal analysis confirmed t(8;13)(p11.2;q12) with FGFR1::ZMYM2 rearrangement, and NGS identified a concurrent CSF3R variant (Q741*). She received induction chemotherapy per the PEDS AALL1231 protocol (Arm A) followed by consolidation, with a course complicated by hyperleukocytosis, venous thromboembolism, E. coli bacteremia, and severe mucositis requiring PICU admission. Despite initial response, the disease progressed to acute myeloid leukemia (AML) with acquisition of a PTEN variant; the patient was offered but did not complete allo-HSCT and died of refractory AML approximately 10 months after diagnosis. Conclusions: This case highlights the aggressive clinical course and diagnostic challenges of MLN-FGFR1, a rare stem cell-derived myeloid/lymphoid neoplasm. To our knowledge, this appears to be the first reported case documenting sequential CSF3R and PTEN variant acquisition with complete follow-up through fatal AML transformation, and the first to describe treatment with a pediatric ALL induction protocol (PEDS AALL1231) in this setting. The characteristic histomorphologic pattern of eosinophil-rich T-ALL in lymph nodes with concurrent myeloproliferative neoplasm in bone marrow should prompt immediate molecular workup. Allo-HSCT must be pursued urgently at diagnosis, as complications rapidly narrow the transplant window and the disease is uniformly fatal without it. Full article

Cutaneous graft-versus-host disease (GVHD) is a common complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Despite established guidelines, discrepancies persist between clinical trial evidence and real-world practice, particularly for newer agents such as ruxolitinib. To characterize the phenotypic spectrum of cutaneous GVHD, evaluate real-world treatment strategies—with a specific focus on systemic and topical ruxolitinib—and assess adherence to national and international guidelines, we conducted a retrospective observational study of patients undergoing allo-HSCT between 2015 and 2025 who were referred to a dedicated dermato-haematology clinic. Clinical, histological, and therapeutic data were collected. Cutaneous manifestations were classified according to National Institutes of Health (NIH) and Italian Group for Blood and Marrow Transplantation (GITMO) criteria. Of 62 transplanted patients, 44 (71%) developed GVHD, with the skin as the most frequently involved organ. Acute GVHD predominantly presented with maculopapular eruptions, whereas chronic GVHD showed heterogeneous phenotypes, including sclerotic variants. First-line management was largely guideline-concordant. Systemic ruxolitinib was administered to 3% of patients in the aGVHD group and 3% in the cGVHD group. Steroid-refractory and steroid-dependent status was not systematically recorded; therefore, treatment eligibility could not be reliably determined, and the observed frequencies should not be interpreted as evidence of underuse. Topical ruxolitinib was not used and remains investigational for cutaneous GVHD. Interpretation should also consider that the study period encompassed changes in regulatory approval, reimbursement, and access to targeted therapies. Structured multidisciplinary assessment may support the management of complex cutaneous GVHD, although its effects on treatment decisions and patient outcomes require prospective evaluation. Full article

Background/Objectives: CAR T-cell therapy is a highly efficacious therapy option for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), but its widespread use is currently limited by safety concerns and high healthcare costs. Methods: We evaluated 66 patients with R/R LBCL treated with tisagenlecleucel or axicabtagene ciloleucel between 2016 and 2022 at a single institution to identify factors associated with increased healthcare utilization. Results: The median age of our cohort was 59.5 years, with 22.7% over the age of 70. The median length of stay (LOS) during the initial hospitalization was 12 days (range, 7–62 days). Longer initial hospital LOS was linked to higher age-adjusted HCT-CI score (IRR 1.08; 95% CI, 1.01 to 1.15; p = 0.0203), thrombocytopenia grade 3–4 (IRR 1.32; 95% CI, 1.07 to 1.63; p = 0.0091), and first ICU admission (IRR 1.81; 95% CI, 1.37 to 2.38; p < 0.00001). Thirty- and 90-day readmission rates post-discharge after receiving CAR T-cell therapy were 21.2% and 28.8%, respectively. Multiple readmissions within 90 days after initial hospital discharge were observed in 15% of patients. Longer 30-day readmission LOS was linked to initial hospital LOS (IRR 1.23; 95% CI, 1.11 to 1.35; p < 0.0001) but outpatient follow-up was associated with shorter 30-day readmission LOS (IRR 0.43; 95% CI, 0.26–0.69; p = 0.0005). Factors associated with longer 90-day readmission LOS included a greater number of ER visits within 60 days of CAR T-cell therapy (IRR 3.10; 95% CI, 2.15–4.46), prior 30-day readmission LOS (IRR 1.35; 95% CI, 1.14–1.60), and SUVmax at Day 30 (IRR 1.06; 95% CI, 1.03–1.09) (all p-values < 0.0001). Conclusions: Our findings identify key clinical and utilization variables associated with initial and repeat hospitalizations post-CAR T-cell therapy, emphasizing the need for targeted interventions to reduce readmissions and optimize post-discharge care. Full article

Intestinal microbiome dysbiosis has been associated with transplant-related mortality and graft-versus-host disease in allo-HSCT patients. We assessed how pre-transplant antibiotic and antineoplastic exposures, together with multidrug-resistant colonization, are associated with baseline gut microbiome diversity at allo-HSCT. We conducted a prospective, single-center cohort study at Fundeni Clinical Institute (Bucharest, Romania) between August 2024 and June 2025, enrolling 52 allo-HSCT recipients and 27 healthy controls. Fecal samples were collected before conditioning. Gut microbiome composition was assessed via 16S rRNA gene sequencing and analyzed using QIIME2 and R. Associations were evaluated using Wilcoxon test, multivariable linear regression, and PERMANOVA. Shannon diversity was significantly lower in patients (median 4.71, IQR 3.97–5.44) than in healthy controls (median 6.09, IQR 5.87–6.28; p < 0.001). In bivariate analyses, carbapenem (p adj = 0.02) and oxazolidinone exposure (p adj = 0.005) were associated with reduced diversity, while immunotherapy was associated with higher diversity (p adj = 0.042). Broad-spectrum penicillin (p adj = 0.062) and ESBL colonization (p adj = 0.066) did not reach significance. In the multivariable antibiotic model, although the overall model was statistically significant (model p = 0.039), no individual antibiotic class remained significantly associated with Shannon diversity after adjustment for co-exposures. Beta diversity differed modestly with carbapenem exposure (R² = 0.033, p = 0.019). Pre-transplant antibiotic exposures were associated with lower gut microbiome diversity at allo-HSCT admission, with patterns consistent with a cumulative rather than a class-specific association. These findings support antibiotic stewardship in pre-transplant care. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes. Full article

Genetically modified hematopoietic stem cell therapy using gene-modified autologous hematopoietic stem cells has evolved over the last 30 years as an alternative approach to circumvent the limitations of donor availability, risks of excessive regimen related toxicity, prolonged immune suppression and graft-versus-host disease associated with allogeneic hematopoietic cell transplantation. Gene replacement therapy based on viral insertion of transgene into host genome was developed as one of the main methods for gene modification of autologous cells. Unfortunately, many cases of oncogenesis were directly caused by genetically modified hematopoietic stem cell therapy. The purpose of the present review is the description of cases of leukemogenesis in gene replacement therapy in hematopoietic stem cells, elucidation of the causes, and overview of the risk mitigation strategies. It aims to elucidate the main risk factors in gene replacement therapy in hematopoietic stem cells. The insertional mutagenesis leads to activation of proto-oncogenes, mostly LMO2 and MECOM-EVI1. γ-retroviral vectors are dangerous in this case, as they contain long terminal repeats with strong promotor activity and are prone to integration near transcription initiation sites. Therefore, safer self-inactivating lentiviral vectors were developed, with long terminal repeats modified to reduce their promoter activity and with safer integration pattern. Nevertheless, the risk of leukemogenesis remains because the promoter integrated into the transgene expression cassette may still influence nearby gene expression. Another risk factor is monosomy 7, either pre-existing or caused by MECOM-EVI1 activation, which may contribute directly to leukemogenesis. Thus, oncogenesis in HSPC gene replacement therapy does not have a single definitive cause; rather, multiple factors may contribute, and each may be sufficient under specific conditions. Full article

Background/Objectives: This study describes body composition, bone mineral density (BMD), and dietary intake in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation compared to healthy children. Methods: In this prospective observational study, dual-energy X-ray absorptiometry was used to assess appendicular lean mass index (ALMI), fat mass index (FMI), fat mass percentage (FM%), and BMD, and a 4-day dietary record was used to assess dietary intake at 3 months and 1 year post-transplant. Healthy children were assessed once by the same methods. Results: We included 28 patients (mean 10.3 years, SD 4.0) and 50 healthy children (mean 10.0 years, SD 3.6). At 1 year, median Z-scores were lower for ALMI (−1.34 vs. 0.40, p < 0.001), higher for FMI (0.34 vs. −0.33, p < 0.012) and FM% (0.59 vs. −0.98, p < 0.001), lower for BMD total body less head (−1.0 vs. 0.3, p = 0.006), but similar for BMD spine compared to healthy children. At 1 year, 9/15 (60%) had ALMI Z-score ≤ −1, 6/15 (40%) had FMI Z-score ≥ 1, 5/15 (33%) had FM% Z-score ≥ 1, and 8/18 (53%) had BMD total body less head Z-score ≤ −1, and 3/15 (20%) had BMD spine Z-score ≤ −1. Dietary intake improved, and at 1 year, energy and protein intakes were comparable, fat, calcium, and vitamin D intakes were higher, but fiber intake remained lower in patients than in healthy children. Conclusions: Patients had a more unfavorable body composition and bone health. Dietary intake improved from 3 months to 1 year post-transplant. However, the results indicate a need for nutritional follow-up, particularly targeting protein, fat, fiber, calcium, and vitamin D. Full article

Pediatric acute myeloid leukemia (AML) is biologically heterogeneous, and genomic profiling increasingly informs risk stratification and treatment. We evaluated the relationship between induction response, genomic risk, transplant allocation, and survival in pediatric AML. We retrospectively analyzed 38 pediatric patients with newly diagnosed AML, treated between 2020 and 2025. Clinical, cytogenetic, molecular, treatment, and outcome data were collected. Genomic alterations were assessed using cytogenetics, fluorescence in situ hybridization (FISH), molecular testing, and next-generation sequencing (NGS). Survival was estimated by Kaplan–Meier analysis, and prognostic factors for event-free survival (EFS) were assessed using univariable Cox regression. This study is exploratory given the limited sample size and should be interpreted accordingly. Complete remission (CR) after the first course of induction was achieved in 25/38 patients (65.8%), partial remission (PR) in 3/38 (7.9%), and refractory disease in 10/38 (26.3%). Twenty-four patients underwent allogeneic hematopoietic stem cell transplantation; 17/24 (70.8%) were alive at last follow-up, with a 2-year overall survival rate of 72.9%. Both induction response and genomic risk stratification showed suggestive associations with outcome; descriptively, induction response showed the strongest prognostic discrimination, with achievement of CR associated with markedly improved survival. High cytogenetic risk and FLT3-ITD were significantly associated with inferior EFS. Post-induction measurable residual disease (MRD) positivity was detected in 16 of 38 patients (42.1%) and was associated with suboptimal induction response; MRD negativity did not uniformly preclude adverse outcomes, particularly in the high-risk genomic subgroup. Genomic profiling refined biological risk and post-remission treatment allocation. Integrated assessment of genomic risk, induction response, and MRD status may improve therapeutic stratification in pediatric AML. Full article

Membranous nephropathy (MN) and minimal change disease (MCD) are the most common causes of nephrotic syndrome following hematopoietic stem cell transplantation (HSCT), a complication conventionally attributed to chronic graft-versus-host disease (GVHD). Paraneoplastic MCD is well described in lymphoid malignancies but is rarely reported in myeloid neoplasms. We report two cases of biopsy-confirmed MCD presenting as the initial manifestation of acute myeloid leukemia (AML) relapse following allogeneic HSCT. Both patients were White men in their sixties with relapsed/refractory AML who developed nephrotic-range proteinuria and acute kidney injury after matched unrelated donor HSCT without histologic evidence of GVHD. Renal biopsies confirmed MCD in both cases. Corticosteroid therapy was ineffective in halting renal deterioration; renal function improved only after initiation of leukemia-directed therapy, with one patient achieving dialysis independence. These cases highlight a rare paraneoplastic presentation of AML relapse. Nephrotic syndrome due to MCD may signal post-HSCT leukemia recurrence, and evaluation for AML relapse warrants consideration in steroid-refractory cases or those without concurrent GVHD. In such cases, control of the underlying malignancy, rather than escalation of immunosuppression, may be central to renal recovery. Full article

The management of acute myeloid leukemia (AML) remains characterized by high relapse rates despite advances in induction and consolidation therapy. Relapse prevention represents a major unmet need, particularly in patients ineligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT) or at high risk of post-transplant recurrence. This review examines current evidence supporting maintenance strategies following intensive chemotherapy or allo-HSCT, with emphasis on measurable residual disease (MRD)-guided approaches and targeted therapies. We summarize data from randomized and phase II/III trials evaluating hypomethylating agents, FLT3 inhibitors, IDH inhibitors, and immunotherapeutic strategies in post-remission settings. Oral azacitidine (CC-486) demonstrated overall survival benefit in older patients in first complete remission who were not transplant candidates, establishing a standard of care in this population. In FLT3-mutated AML, post-transplant maintenance with sorafenib and gilteritinib reduces relapse risk, with emerging evidence supporting MRD as a predictive biomarker for benefit. Other targeted agents and immunotherapies have shown promising early-phase results, although confirmatory data are limited. Ongoing phase III studies will clarify optimal patient selection, treatment duration, and integration with transplantation, aiming to transform post-remission management from passive surveillance to precision-based relapse prevention. Full article

Background: Toxic epidermal necrolysis (TEN) is a rare but life-threatening complication that may occur in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in the context of extensive drug exposure. In this population, TEN can closely resemble severe acute graft-versus-host disease (GVHD), making diagnosis and management challenging. Case presentation: We report the clinical course of an allo-HSCT recipient who developed a rapidly progressive skin rash early after transplantation, and we analyzed the clinical features, histopathology, treatment and outcome. Results: The patient developed rapidly progressive epidermal detachment with severe oral, ocular, and genital mucosal involvement shortly after exposure to trimethoprim/sulfamethoxazole (TMP-SMX). Disease severity was reflected by a SCORTEN score of 5, corresponding to a very high predicted mortality risk. The clinical picture raised concern for both TEN and severe acute GVHD, while histopathological findings favored TEN but were not definitive. Management included systemic corticosteroids, intravenous immunoglobulin, ruxolitinib, and intensive supportive care. The patient gradually re-epithelialized and recovered without long-term sequelae. Conclusions: This case underscores the diagnostic difficulty of distinguishing TEN from severe acute GVHD in the early post-transplant period. Careful assessment of drug exposure, clinical evolution, and multidisciplinary evaluation are essential to guide timely and appropriate management. Full article

Sickle Cell Disease (SCD) is a pervasive monogenic disorder characterized by chronic hemolytic anemia, unpredictable vaso-occlusive crises, and progressive multi-organ damage, representing a significant global health burden. Driven by a point mutation in the β-globin gene, the resulting abnormal Hemoglobin S (HbS) polymerizes under deoxygenated conditions, leading to erythrocyte sickling and systemic endothelial dysfunction. While supportive therapies such as hydroxyurea and transfusions manage symptoms, the mandate for definitive curative therapies is urgent. Historically, allogeneic hematopoietic stem cell transplantation (HSCT) utilizing matched sibling donors (MSD) has been the sole curative option, offering high survival rates but constrained by limited donor availability and the risk of graft-versus-host disease (GVHD). Consequently, alternative donor sources, including matched unrelated donors, umbilical cord blood, and haploidentical donors, have expanded patient access, particularly with the integration of post-transplant cyclophosphamide (PTCy) to mitigate alloreactivity. Concurrently, the advent of autologous gene therapy, encompassing lentiviral gene addition (Lyfgenia) and CRISPR-Cas9 gene editing (Casgevy) offers a revolutionary donor-independent approach that eliminates GVHD risk. Lyfgenia employs a lentiviral vector to introduce an anti-sickling βT87Q hemoglobin variant into autologous hematopoietic stem cells, while Casgevy employs CRISPR-Cas9 to disrupt the erythroid-specific enhancer of the BCL11A transcription factor, derepressing γ-globin expression and elevating fetal hemoglobin. This review synthesizes the pathophysiological mechanisms of SCD, evaluates the clinical outcomes and limitations of both allogeneic HSCT and autologous gene therapies, and outlines the clinical decision-making paradigms and future innovations required to achieve equitable global access to these transformative treatments. Full article