Search Results (504)

Background: Relapsed/refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge due to disease heterogeneity, resistance mechanisms, and poor tolerability to intensive regimens. Venetoclax (VEN), a BCL-2 inhibitor, has shown promise in combination with hypomethylating agents (HMAs), but data on response timing in the R/R setting are limited. The aim of this study was to assess the efficacy, safety, and kinetics of response to HMA-VEN therapy in a real-world cohort of R/R AML patients, with particular focus on early versus late responders. Methods: This prospective single-center study included 33 adult patients with R/R AML treated with VEN plus either azacitidine (AZA) or decitabine (DEC) from 2018 to 2021. The primary endpoint was the composite complete remission (cCR) rate and the rate of early and late response, respectively, occurring within two cycles of therapy or later; secondary endpoints included overall survival (OS), relapse-free survival (RFS), time to relapse (TTR), and safety. Results: The cCR was 58%, with complete remission (CR) or CR with incomplete recovery (CRi) achieved in 52% of patients. Median OS was 9 months. No significant differences in OS or TTR were observed between early (≤2 cycles) and late (>2 cycles) responders. Eight responders (42%) underwent allogeneic hematopoietic stem cell transplantation (HSCT), with comparable transplant rates in both groups of responders. Toxicity was manageable. Grade 3–4 neutropenia occurred in all patients, and febrile neutropenia occurred in 44% of patients. An Eastern Cooperative Oncology Group (ECOG) score >2 was associated with inferior response and shorter treatment duration. Conclusions: HMA-VEN therapy is effective and safe in R/R AML, including for patients with delayed responses. The absence of a prognostic disadvantage for late responders supports flexible treatment schedules and suggests that the continuation of therapy may be beneficial even without early blast clearance. Tailored approaches based on performance status and comorbidities are warranted, and future studies should incorporate minimal residual disease (MRD)-based monitoring to refine response assessment. Full article

Introduction: Medication adherence is essential for treatment and recovery following hematopoietic stem cell transplantation (HSCT). However, limited data exist on the most effective methods to measure adherence and the factors influencing it in HSCT patients. Materials and Methods: A prospective longitudinal study assessed immunosuppressant medication adherence in 150 patients with hematologic malignancies undergoing allogeneic HSCT. Adherence was assessed using pill counts, immunosuppressant medication levels, patient-reported medication logs, and the Medication Adherence Response Scale-5 (MARS-5) at 30, 100, and 180 days post-HSCT. We evaluated adherence rates, agreement between methods, and sociodemographic and clinical predictors. From patient-reported logs, we calculated dose adherence (comparing reported doses to expected doses) and timing adherence (comparing medication intake within ±3 h of the prescribed time). Kappa analysis assessed agreement among methods. Results: Of 190 eligible patients, 150 (78.9%) enrolled. The mean age was 57.5 years (SD = 13.5); 41.3% (n = 62) were female, 85.3% (n = 128) were non-Hispanic White, and 73.3% (n = 110) were married or living with a partner. Medication adherence varied across the three timepoints and by measurement type: 52–64% (pill counts), 18–24% (medication levels), 96–98% (medication log dose adherence), 83–84% (medication log timing adherence), and 97–98% (MARS−5). There was minimal agreement between measures (Kappa range: 0.008–0.12). Conclusions: Despite the feasibility of leveraging objective and patient-reported measures to assess medication adherence in HSCT patients, there was little agreement between these measures. Patient-reported measures showed high adherence, while objective measures like pill counts and medication levels revealed more modest adherence. The complexity of medication regimens likely contributes to this discrepancy. A rigorous approach to understanding medication adherence in the HSCT population may entail both objective and subjective measures of medication adherence. Full article

Background/Objectives: Pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by iron overload and hypomagnesemia, both contributing to immune dysfunction and post-transplant morbidity. The combined impact of these metabolic disturbances on pediatric allo-HSCT outcomes remains unexplored. This study aims to determine whether hypomagnesemia can serve as a prognostic biomarker for delayed immune reconstitution and explores its interplay with iron overload in predicting post-transplant complications and survival outcomes. Methods: A retrospective analysis was conducted on 163 pediatric allo-HSCT recipients. Serum magnesium levels were measured at defined intervals post-transplant, and outcomes were correlated with CD4+ T cell recovery, time to engraftment, incidence of graft-versus-host disease (GVHD), and survival within 12 months. Iron status, including siderosis severity, was evaluated using imaging and laboratory parameters obtained from clinical records. Results: Patients who died within 12 months post-transplant exhibited significantly lower magnesium levels. Hypomagnesemia was associated with delayed CD4+ T cell recovery, prolonged engraftment, and an increased risk of acute GVHD. A strong inverse correlation was observed between magnesium levels and the severity of siderosis. Iron overload appeared to exacerbate magnesium deficiency. Additionally, the coexistence of hypomagnesemia and siderosis significantly increased the risk of immune dysfunction and early mortality. No significant association was found with chronic GVHD. Conclusions: Hypomagnesemia is a significant, early predictor of poor outcomes in pediatric allo-HSCT, particularly in the context of iron overload, underscoring the need for early intervention, including iron chelation and MRI, to improve outcomes. Full article

Over the past two decades, the treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a profound transformation. Once considered the subtype with the worst prognosis, Ph+ ALL is now associated with the possibility of long-term survival in a significant proportion of patients. This dramatic improvement has been driven by the advent of tyrosine kinase inhibitors (TKIs) and, more recently, by the incorporation of blinatumomab, a bispecific T-cell engager antibody, into frontline therapeutic strategies. In this evolving context, two major areas have become the focus of clinical investigation: on the one hand, the identification of high-risk patients who truly benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT); on the other, the characterization of patients who can achieve durable responses without transplantation and who may be candidates for treatment discontinuation of TKIs. This review aims to summarize the current evidence supporting the concept of treatment-free remission (TFR) in Ph+ ALL. Full article

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

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

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease (SOS/VOD) is a severe complication of hematopoietic cell transplantation (HCT). Furthermore, emerging evidence suggests the potential role of complement activation and endothelial injury in SOS/VOD pathogenesis. In this study, we aimed to identify potential distinct pathogenic genetic variants between SOS/VOD and other endothelial injury syndromes following HCT, such as transplant-associated thrombotic microangiopathy (TA-TMA). For this aim, genomic DNA from 30 SOS/VOD patients and 30 controls with TA-TMA was analyzed. Using Next-Generation Sequencing (NGS), variants in complement-related genes (CFH, CFI, CFB, CFD, C3, CD55, C5, CD46, and thrombomodulin/THBD) and ADAMTS13 were examined. Out of 426 detected variants, 20 were classified as pathogenic. In SOS/VOD patients, variants were identified in ADAMTS13 (4), CFH (3), C3 (2), and CFB (1) genes. One of the variants has been recognized as the strongest genetic predictor of ADAMTS13 activity. Controls exhibited more variants in complement-related genes, particularly CFH, CFI, and C3. The genetic differences between SOS/VOD and TA-TMA highlight different pathogenic mechanisms, offering the potential for targeted risk assessment and therapy in HCT recipients. Full article

Background: Advanced home care is becoming increasingly common for cancer patients and serves as a viable alternative to inpatient hospital care. The transition to home care is driven by both the rising costs of healthcare and evidence indicating better quality of care. This study aims to compare the costs of hospital-at-home treatment and in-hospital care for patients undergoing allo-HSCT. Methods: The cost analysis was conducted as a case–control study comparing the costs of allo-HSCT at home (HaH) to the costs of allo-HSCT for patients receiving in-hospital care (INH). The cost evaluation was conducted from the hospital’s perspective, which means that costs incurred outside the hospital setting were not included. Post-procedural costs for the first year after allo-HSCT included all readmissions and outpatient visits at Oslo University Hospital. Results: The cost for the peritransplant period could be reduced by up to 33% by treating allo-HSCT recipients at home instead of in the hospital. During the study period, 24% of the allo-HSCT recipients were treated at home, but our data from 2021 and 2022 indicate that at least a third of the patients scheduled for allo-HSCT are candidates for HaH. Conclusions: The findings demonstrate that patients in advanced home care experience significantly lower total costs compared to those receiving in-hospital treatment. Full article

Background: Allogeneic hematopoietic stem cell transplant (Allo-HSCT) recipients are still at increased risk of severe COVID-19 infection. Vaccination is a critical strategy to protect this population. This real-world prospective cohort study aimed to evaluate the immune response and clinical outcomes of COVID-19 vaccines in Allo-HSCT recipients. Methods: Allo-HSCT recipients (median age: 48 years) who received either the BNT162b2 or CoronaVac vaccines were included. Antibodies against the SARS-CoV-2 spike protein were quantitatively measured using the chemiluminescent microparticle immunoassay. Patient- and vaccine-related factors affecting antibody responses were analyzed. Adverse events, including graft-versus-host disease (GVHD) and post-vaccine infections, were recorded. Results: Among 95 Allo-HSCT recipients, 86.3% achieved adequate antibody responses following COVID-19 vaccination. Patients receiving ≥3 vaccine doses showed significantly higher antibody titers compared to those with only 2 doses (OR: 0.11; 95% CI: 0.02–0.53; p = 0.006 **). The use of Ruxolitinib or Ibrutinib was associate with increased odds of low antibody response (OR: 38.39; 95% CI: 3.14–468.95; p = 0.004 **). Hypogammaglobulinemia (low serum IgG levels) was associated with a reduced antibody response (OR: 0.17; 95% CI: 0.03–0.96; p = 0.045 *), while no significant correlation was found between serum IgA levels and antibody responses (p = 0.672). Three cases of post-vaccine GVHD were observed, and no fatalities related to COVID-19 occurred during the study. Conclusions: COVID-19 vaccination is safe and effective in Allo-HSCT recipients, with stronger responses especially following ≥3 vaccine doses. Patients receiving GVHD treatment or with hypogammaglobulinemia exhibited impaired responses, emphasizing the need for tailored vaccination strategies and close monitoring in this population. Full article

Graft-versus-host disease (GVHD) remains a significant barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), contributing to long-term morbidity and non-relapse mortality in both pediatric and adult populations. Central to GVHD pathophysiology is the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, where JAK2 mediates key pro-inflammatory cytokines, including IL-6, IFN-γ, and GM-CSF. These cytokines promote donor T cell activation, effector differentiation, and target organ damage. The introduction of ruxolitinib, a selective JAK1/2 inhibitor, has transformed the treatment landscape for steroid-refractory acute and chronic GVHD, leading to improved response rates and durable symptom control. However, its limitations—such as cytopenias, infectious complications, and incomplete responses—have catalyzed the development of next-generation agents. In 2024, the FDA approved axatilimab, a CSF-1R inhibitor that targets monocyte-derived macrophages in fibrotic chronic GVHD, and remestemcel-L, an allogeneic mesenchymal stromal cell therapy, for pediatric steroid-refractory acute GVHD. Both agents offer mechanistically distinct and clinically meaningful additions to the therapeutic armamentarium. In parallel, emerging combination strategies involving JAK2 inhibitors and novel biologics show promise in enhancing immune tolerance while preserving graft-versus-leukemia (GvL) effects. Recent advances in biomarker development, such as the MAGIC Algorithm Probability (MAP), are enabling early risk stratification and response prediction. The integration of these tools with organ-specific and personalized approaches marks a shift toward more precise, durable, and tolerable GVHD therapy. This review highlights the current state and future direction of JAK2 inhibition and complementary therapies in the evolving GVHD treatment paradigm. Full article

Purpose: To profile tear cytokine changes in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) patients after instillation of daily topical cyclosporine-A 0.1% cationic emulsion. Methods: Participants in a longitudinal study were given cyclosporine eyedrops daily from 3 to 5 weeks before and 3 months, 6 months, and 12 months post-HSCT. The outcomes included tear cytokine concentration assayed by the Proximity Extension Assay O-linked target 96 platform. The patients were divided into two groups: Group 1 (n = 8 conjunctival CD4 cells responding to cyclosporine) and Group 2 (n = 5 conjunctival CD4 cells not suppressed after cyclosporine, where patients were non-compliant with cyclosporine). All participants had a standardized clinical examination, including meibomian gland evaluation and tear breakup times. Results: The levels of 38 cytokines/chemokines showed significant changes (p < 0.05) over time, and in many, the elevation was marked at one year. These include gamma-interferon, CXCL9, CCL3, and CCL4 (all p < 0.0001). For gamma-interferon, there was significant interaction between group and time at 1 year (p = 0.022), where the cytokine was significantly suppressed in Group 1. Four other cytokines showed significant group and time interaction at 1 year: FGF23, FGF5, LIFR, and Enrage (all p < 0.05). All patients had either withdrawal or a reduction in systemic immunomodulation between 6 months and 1 year. We found several cytokines to be associated with changes in tear osmolarity or symptom scores. Conclusions: HSCT induces significant elevation of 38 tear cytokines/chemokines even without the occurrence of ocular graft-versus-host disease when systemic immunosuppression is reduced within the first year. Topical daily cyclosporine eyedrops can reduce some pro-inflammatory tear cytokines. Full article

Post-transplant lymphoproliferative disorders (PTLD) represent a life-threatening complication following solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in patients with relapsed or refractory (R/R) disease, where therapeutic options are limited and prognosis is poor. Among emerging strategies, adoptive cellular immunotherapy—specifically Epstein–Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)—significantly improved outcomes in this challenging patient population. EBV-CTLs restore virus-specific immunity and induce sustained remissions with minimal toxicity, even in heavily pretreated individuals. The most promising cellular product to date is tabelecleucel, an off-the-shelf, allogeneic EBV-specific T-cell therapy, which is currently the only cellular therapy approved by the European Medicines Agency (EMA) for the treatment of R/R EBV-positive PTLD following SOT or allo-HSCT. This review aims to provide an overview of PTLD treatment with a specific focus on adoptive cellular immunotherapy. We highlight the most robust clinical outcomes reported with EBV-CTLs, particularly those achieved with tabelecleucel, and explore emerging cellular approaches such as CAR T-cell therapy, which may further broaden therapeutic strategies in the near future. Full article

While allogeneic hematopoietic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, its applicability is limited both by the high morbidity and mortality associated with the procedure and by the fact that only a minority of patients are eligible due to age or comorbidities. Ruxolitinib, a JAK1/JAK2 inhibitor, is the standard first-line therapy for intermediate- and high-risk MF, offering symptom relief and splenic volume reduction but lacking a clear survival benefit. Its use may be limited by hematologic toxicities, increased infection risk, and an inability to prevent disease progression. Ruxolitinib failure remains a significant clinical challenge, with resistance mechanisms not fully elucidated. The approval of other JAK inhibitors—fedratinib, pacritinib, and momelotinib—has expanded treatment options, particularly for patients with cytopenias or transfusion dependence. Moreover, many other targeted agents are in development in clinical trials, as monotherapy or in combination with ruxolitinib. This review provides an update on the use of JAK inhibitors and novel agents, with a focus on treatment options for ruxolitinib-resistant or refractory patients. As therapeutic strategies evolve, optimizing treatment sequencing and incorporating next-generation sequencing will be critical for improving patient outcomes. Full article

Background/Objective: Bullous Pemphigoid (BP) is a well-recognized autoimmune subepidermal blistering disease. However, its occurrence following allogeneic hematopoietic stem cell transplantation (HSCT) is extremely rare. The objective of this study is to systematically review the available data on BP following an allogeneic HSCT with focus on treatment options. Methods: A systematic review of studies evaluating BP following allogeneic HSCT, incorporating a highly treatment-resistant case from our graft-versus-host disease (GvHD) dermatology clinic, of a 47-year-old patient, notable as the only reported instance of BP following HSCT in a patient with chronic lymphocytic leukemia (CLL) that transformed into diffuse large B-cell lymphoma (DLBCL) and GvHD due to HSCT. The review yielded 15 publications that met the eligibility criteria. Including our case, a total of 16 cases were analyzed. Results: Nearly all patients (14/16) in this review had chronic GvHD due to their HSCT. Twelve patients were males, and six were of Japanese origin. The mean age for BP diagnosis was 38 years (a range of 5–67). On average, BP developed one year post-HSCT. The most common treatment for BP in these patients was prednisolone, with the majority experiencing complete resolution of symptoms. Conclusions: BP following HSCT is an exceptionally rare condition with an unclear underlying mechanism. Full article

Humanized mice generated by hematopoietic stem cell (HSC) transplantation are limited by the immune system developed being allogeneic to the tumor. We have innovated a platform to reconstitute an autologous human immune system (HIS) in immunodeficient NOG-EXL mice from mobilized peripheral blood (MPB)-CD34 cells, along with PDX generated from the same patient’s tumor tissue. Patients consented under an IRB-approved protocol for tumor biopsy and HSC apheresis at Emory University. HSC collection included mobilization with G-CSF and plerixafor, immunomagnetic bead isolation with CliniMACS, and cryopreservation of CD34⁺ cells. PDX were established from biopsies or surgical specimens by passaging into immunodeficient mice. Irradiated NOG-EXL mice were engrafted with HSCs by intravenous transplantation of CD34⁺ HSC. Engraftment of human T cells, B cells, and myeloid cells in peripheral blood was assessed by serial flow cytometry of blood samples, with final assessment of immune components in spleen and bone marrow at 30 weeks. Twenty-eight PDX models were generated from 43 patients with HNSCC; 1 patient underwent apheresis. HSC engraftment in blood was observed in 100% of NOG-EXL mice at 8 weeks post-transplant, with 5–20% hCD45⁺ cells present in the periphery. B-cell development was predominant at early time points and declined over time. Human T-cell and subset development of CD4⁺ and CD8⁺ T cells were observed in blood from 15 weeks post-transplant. Strong development of the myeloid lineage (CD33⁺) was observed starting at 8 weeks and persisted throughout the study. These data demonstrate that mobilization and apheresis of HNSCC patients is technically and clinically feasible and may allow the establishment of autologous HIS-PDX mice. Full article