Long-term follow-up of CD19 chimeric antigen receptor T cell therapy in acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation.

Human cytomegalovirus (HCMV) reactivation is a common and significant complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT), causing potentially life-threatening disease. Antiviral therapy approaches for HCMV are often limited by toxicities and the risk of developing antiviral drug resistance. This review article (Part 2) provides an overview of current antiviral pharmacotherapies for HCMV and the application of virus-specific adoptive T cell therapies for the prevention or treatment of HCMV reactivation in allo-HSCT recipients. The number of available antiviral drugs for HCMV is expanding, and letermovir primary prophylaxis is increasingly being adopted due to its favourable safety profile. Treatment resistant/refractory infections, end-organ disease, and late HCMV reactivations after antiviral therapy withdrawal continue to pose challenges. Adoptive HCMV-specific T cell therapies are a promising strategy for promoting immune-mediated control of HCMV reactivation in allo-HSCT recipients. The administration of HCMV-specific T cell products, generated through ex vivo expansion of donor-derived or partially HLA matched, third party HCMV-specific T cells, have demonstrated efficacy in combatting clinically significant HCMV infection in clinical trials. Adoptive HCMV-specific T cell therapies represent a powerful alternative approach for managing drug resistant HCMV infections in allo-HSCT recipients and reducing the reliance on antiviral pharmacotherapies.

Human cytomegalovirus (HCMV) is one of the most important opportunistic pathogens in immunocompromised individuals, including allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. In allo-HSCT, HCMV seropositivity of the recipient and donor is associated with inferior survival outcomes, and post-transplant HCMV reactivation is a frequent complication, necessitating close viral monitoring and pre-emptive and prophylactic antiviral therapies. We present a review in two parts that focuses on the risk factors, immunological responses and treatment strategies for HCMV infection in allo-HSCT recipients, and also explores current evidence surrounding HCMV reactivation in recipients of chimeric antigen receptor T cell (CAR T) therapies. In the current article (Part 1), the impact of HCMV infection in allo-HSCT and CAR T cell recipients is investigated. HCMV reactivation in allo-HSCT recipients is associated with increased mortality, graft-versus-host disease (GvHD) and other microbial infections. Prominent alterations in T cell and natural killer (NK) cell recovery represent distinct immune reconstitution features associated with HCMV reactivation. Immunological biomarkers to predict HCMV complications have been proposed and their adoption in future immune monitoring strategies may allow individualised risk assessment to guide antiviral treatment decisions. The clinical significance of HCMV reactivation after CAR T cell infusion is yet to be fully determined. Continued viral surveillance and investigation of viral dynamics with correlative studies of immune function are needed in this patient population. Current and emerging strategies for treatment and prevention of HCMV complications in allo-HSCT, including use of letermovir prophylaxis and adoptive HCMV-specific T cell therapies, are explored in the following article (Part 2).

SARS-CoV-2 spike-directed T cells and anti-receptor-binding-domain antibodies in hematological patients receiving three mRNA COVID-19 vaccine doses

Low-dose ruxolitinib as first-line therapy for acute graft-versus-host disease (aGVHD) increases the risk of Epstein-Barr virus (EBV) reactivation but not posttransplant lymphoproliferative disease (PTLD).

Allogeneic HSCT for consolidation in pediatric refractory or relapsed ALK-positive anaplastic large cell lymphoma.

Venetoclax-based low-intensity regimens have improved the outcomes of older or unfit patients with acute myeloid leukemia (AML). This phase II study investigated the combination of cladribine plus low-dose cytarabine and venetoclax alternating with azacitidine plus venetoclax for older or unfit patients with newly diagnosed AML. A total of 190 patients were included; the median age was 68 years (range, 47-84 years; 13% ≥ 75 years). By the European LeukemiaNet 2022 classification, 16%, 20%, and 64% were stratified as favorable, intermediate, and adverse risk, respectively. The rates of complete remission (CR)/CR with incomplete blood count recovery (CRi) and minimal residual disease (MRD) negative CR/CRi were 84% and 75% overall and 91% and 77% among patients with TP53-wild type AML, respectively. The 4- and 8-week mortality rates were 1% and 3%, respectively. Among responders, 44% proceeded to allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) and event free survival (EFS) were 52 and 50 months, respectively. The 2- and 5-year OS rates were 60% and 45%, respectively. The 2-and 5-year EFS rates were 56% and 43%, respectively. Patients achieving MRD-negative CR had a median OS not reached and a 2-year OS rate of 70%. The median time to absolute neutrophil count recovery (> 1 × 109/L) and platelet count recovery (> 100 × 109/L) after induction was 27 and 24 days, respectively. Overall, the treatment was safe and most grade 3 and 4 adverse events were infectious complications. The combination produced a high rate of remissions, translating into favorable outcomes for older patients with newly diagnosed AML. Trial Registration: ClinicalTrials.gov idetifier: NCT03586609.

Chronic ocular graft-versus-host disease (oGVHD) is a debilitating complication of allogeneic hematopoietic stem cell transplantation (HSCT) that leads to persistent ocular surface damage, visual morbidity, and substantial treatment burden. Despite its prevalence, long-term outcome data remain limited. We conducted a retrospective cohort study of patients evaluated between 2012 and 2024 at a tertiary academic centre in Vancouver, Canada, with follow up of a year or more and recorded the outcomes of the first five years to characterise longitudinal ocular outcomes and therapeutic trajectories in patients with oGVHD. A total of 189 patients met inclusion criteria. At baseline, meibomian gland dysfunction (81.5%) and superficial punctate keratitis (49.7%) were highly prevalent. Over five years, these manifestations remained persistent in over half of patients, while vision-threatening complications including filamentary keratitis (3.7%), corneal neovascularisation (2.6%), and limbal stem cell deficiency (4.8%) emerged. Therapeutic escalation was common, with 92.1% of patients requiring artificial tears, 47.1% serum tears, 28.0% punctal cautery, 19.0% scleral lenses, and 7.4% topical cyclosporine by year five. Baseline NIH Eye Scores correlated with later complications and treatment intensity, while NIH Lung and Mouth Scores were also predictive of ocular surface disease. These findings underscore the progressive, treatment-resistant nature of oGVHD and highlight the value of early ophthalmic referral and multidisciplinary management to preserve vision and quality of life.

Safety and Efficacy of Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation for Salvage Therapy of Myelofibrosis.

β-thalassemia is a common inherited hemoglobin disorder caused by reduced or absent β-globin production, leading to ineffective erythropoiesis, chronic anemia, and, in severe cases, lifelong transfusion dependence. Although allogeneic hematopoietic stem cell transplantation can be curative, its use is limited by donor availability and transplant-related complications. In recent years, gene therapy has emerged as a promising alternative and has rapidly changed the treatment landscape for β-thalassemia. In this review, we summarize both established and emerging gene-based strategies, including lentiviral gene addition to restore HBB expression and gene editing approaches aimed at reactivating fetal hemoglobin. We discuss key targets such as the erythroid-specific BCL11A enhancer, repressor-binding sites in the HBG promoters, and other regulatory elements involved in globin switching. We also highlight the growing potential of newer technologies such as base editing and prime editing, which may offer greater precision and reduce the risks associated with double-strand DNA breaks. Finally, we address the major challenges that still need to be resolved, including safety, durability, technical complexity, and access to treatment. Overall, gene therapy is moving β-thalassemia closer to a broadly applicable curative approach.

Paroxysmal nocturnal hemoglobinuria (PNH) clones are detected in up to 60% of patients with aplastic anemia (AA); however, their prognostic impact remains incompletely defined, particularly in the context of frontline immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 207 patients with AA treated between 2004 and 2024 at a single institution. PNH clones were identified at diagnosis in 64 patients (30.9%). Treatment modalities included IST (n = 104) and HSCT (n = 103). Clinical outcomes, including overall survival (OS), event-free survival, graft-versus-host disease (GVHD), relapse, and non-relapse mortality, were compared between the PNH-positive and PNH-negative cohorts. At 5 years, PNH-positive patients treated with IST had significantly improved OS compared with PNH-negative patients (100% vs. 72.4%, p = 0.004). In the HSCT group, OS was 100% in PNH-positive patients versus 90% in PNH-negative patients (p = 0.09). The incidence of chronic GVHD after HSCT was significantly lower in the PNH-positive group (4% vs. 27%, p = 0.01), whereas the rates of acute GVHD, graft failure, and relapse were comparable. Clone size (small vs. large) did not affect survival or GVHD outcomes. The presence of a PNH clone in AA was associated with superior survival following IST and a lower incidence of chronic GVHD following HSCT. These findings suggest that PNH positivity may serve as a prognostic and immunomodulatory biomarker in AA and support its integration into therapeutic decision-making and risk stratification algorithms.

Abstract Cytomegalovirus (CMV) infection is common in people who are immunocompromised; however, cutaneous manifestations are rare compared with internal organ involvement. The clinical findings of cutaneous CMV infection typically include perioral or perianal ulcerations. Here, we present a case of a 66-year-old woman who underwent allogeneic haematopoietic stem cell transplantation, developed graft-versus-host disease and persistent skin lesions during her treatment course, and was eventually diagnosed with cutaneous CMV infection.

Bronchiolitis obliterans syndrome (BOS) is a rare non-infectious bronchopulmonary complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with an unfavorable prognosis. This article presents a case of effective BOS treatment after allo-HSCT with therapeutic response achievement in a short time.

Discordance between estimated glomerular filtration rate (eGFR) based on serum creatinine (eGFRcr) versus cystatin C (eGFRcys) is associated with adverse outcomes in patients with and without cancer. We hypothesized that eGFR discordance is associated with acute kidney injury (AKI) and death following hematopoietic stem cell transplant (HSCT) or receipt of adoptive T-cell therapies. We conducted a multicenter study of adults receiving allogeneic HSCT and adoptive T-cell therapies who had paired serum creatinine and cystatin C values obtained in the 30 days preceding conditioning or lymphodepleting chemotherapy. The primary exposure was eGFR discordance, defined as eGFRcys ≥30% lower than eGFRcr. The primary outcome was a composite outcome of AKI (≥50% increase in serum creatinine or receipt of kidney replacement therapy) or death within 90 days following HSCT or adoptive T-cell infusion. Secondary outcomes included time-to-platelet engraftment in HSCT and prolonged cytopenia in adoptive T-cell recipients. We used multivariable logistic regression and cause-specific Cox regression with inverse probability weighting to adjust for confounders. Of 274 patients receiving HSCT (median age 65 years, interquartile range [IQR] 52-71]; 43% female), 86 (31%) had an eGFR discordance. Among 236 adoptive T-cell recipients (median age 67 years, IQR [60-74]; 59% female), 78 (33%) had a discordance in eGFR. eGFR discordance was associated with higher odds of AKI or death in HSCT (odds ratio [OR] 1.75; 95% confidence interval [CI] 1.03-3.02) and adoptive T-cell recipients (OR 2.37; 95% CI 1.12-4.94). However, adjustment for eGFRcr-cys attenuated these associations in both cohorts. eGFR discordance was also associated with slower time-to-platelet engraftment in HSCT recipients and prolonged cytopenia following adoptive T-cell therapy. A pre-treatment eGFR discordance was associated with AKI or death in HSCT and adoptive T-cell recipients; however, this association was attenuated after adjusting for eGFRcr-cys.

Invasive fusariosis (IF) is a rare but often fatal mold infection in immunocompromised patients, particularly after allogeneic hematopoietic stem cell transplantation (HSCT). Despite antifungal prophylaxis and treatment, mortality remains high. We retrospectively reviewed all allogeneic HSCT recipients for hematological malignancies at our center (2010-2024) and identified proven IF cases. Species identification was based on multigene sequencing, and antifungal susceptibility testing was performed. Among 2359 allogeneic HSCTs, 17 proven IF cases (7.2/1000) were identified. Patients more often had prior HSCT (58.8% vs. 19.8%, p=0.002) and were transplanted in non-complete remission (94.1% vs. 75.8%). Median onset was 19 days (range, 2-1011) posttransplant, with a median neutrophil count of 1/µL (range, 1-7097) at diagnosis; 64.7% were pre-engraftment. Prophylaxis included micafungin (n=10), posaconazole (n=4), and voriconazole (n=3). Species: Fusarium solani complex (n=11), Fusarium dimerum complex (n=4), and Fusarium fujikuroi complex (n=2). All isolates had high micafungin MECs (>16 µg/mL); the median amphotericin B MIC was 4µg/mL, voriconazole MIC >8 µg/mL. Median overall survival was 8 days; mortality reached 82.4% by Day 84. In univariate analysis, combination liposomal amphotericin B (L-AMB) plus voriconazole (p=0.013) and neutrophil recovery (p=0.008) were associated with improved survival. No clear trends were noted in antifungal susceptibility between survivors and non-survivors. IF after allogeneic HSCT is rare but highly lethal. Despite the small sample size, outcomes were not clearly associated with MIC values. Early L-AMB plus VRCZ and neutrophil recovery may be associated with improved survival.

Long-read KIR genotyping reveals donor KIR/HLA polymorphisms linked to posttransplant relapse in T-cell malignancies.

Philadelphia-negative myeloproliferative neoplasms (MPNs) can progress to blast phase (MPN-BP), a biologically distinct and highly lethal entity with a median survival typically under six months. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative approach, yet relapse and non-relapse mortality limit durable benefit. We retrospectively analyzed post-transplant outcomes in 51 consecutive adults undergoing 53 allo-HSCTs for MPN-BP. Median age was 62 years; most cases evolved from myelofibrosis, and JAK2 was the predominant driver mutation. Neutrophil engraftment occurred in all but two patients (median 12 days). At 1-year, cumulative incidences were 35.8% for grade II-IV acute GVHD, 7.5% for moderate-severe chronic GVHD, 44.3% for relapse, and 25.8% for non-relapse mortality. One-year overall survival (OS) and disease-free survival were 43.4% and 37.7%, respectively; relapse was the leading cause of death. In multivariable analysis, TP53 mutations and higher peripheral blast burden adversely affected OS, while CALR mutations appeared to be associated with improved OS, peripheral blasts also independently predicted relapse. These data underscore the cure rate of approximately one-third of MPN-BP and highlight peripheral blasts and TP53 as actionable risk markers for transplant strategies.

A comprehensive retrieval, evaluation, selection, and integration of literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for transfusion-dependent thalassemia (TDT) published over the past decade was conducted. For 10 clinical questions related to allo-HSCT in TDT, 26 recommendations were developed. The guideline aims to guide and standardize clinical diagnosis and treatment practices of allo-HSCT for TDT in China.

Introduction. Acute myeloid leukemia (AML) is the second most prevalent type of blood malignancy in children that accounts for 15–20% of all pediatric leukemia cases. Before 2018, large-scale prospective studies of AML in children in the Russian Federation were constrained by the absence of both a central pathology review system and centralized monitoring of minimal residual disease (MRD). To address these issues, the national protocol AML-MRD-2018 (NCT03846362) was developed and initiated by the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Materials and methods. This study included 631 patients from 54 clinical facilities across 48 regions of the Russian Federation. Central pathology review was performed at two institutions: the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow) and Yekaterinburg Regional Children's Clinical Hospital. Risk group stratification was performed in two steps: initially it was based on molecular and genetic characteristics of blast cells, and then (for intermediate risk group) – on response to treatment assessed by MRD testing. Criteria for primary refractoriness and the transfer of patients to a high-risk group were blast cell count (assessed morphologically and immunophenotypically) 5% after induction and MRD ≥ 0.1% after the first course of consolidation. The final stratification was as follows: 67 standard-risk patients, 251 intermediate-risk patients, and 313 high-risk patients. Results. Response to induction therapy was assessable in 580 patients; complete remission was achieved in 84.3% of the cases (n = 489). Treatment effectiveness varied significantly across the risk groups: it was 100% in the standard-risk group (all the patients achieved MRD-negative remission), 91.5% in the intermediate-risk group and 72.9% in the high-risk group (which had the highest proprotion of refractory and MRD positive patients). The first cycle of consolidation therapy according to the protocol was given to 385 patients from the intermediate- and high-risk groups; MRD assessment was performed in 348 cases. MRD-negative remission was achieved in 196 (96%) out of 204 MRD-assessed patients in the intermediate-risk group and in 129 (90%) out of 144 MRD-assessed patients in the high-risk group. The 3-year treatment outcomes in the whole cohort of patients (n = 631) were the following: the overall survival (OS) reached 71% (95% confidence interval (CI) 68–76), the event-free survival (EFS) was 44% (95% CI 40–48), the cumulative risk of relapse (CRR) was 36% (95% CI 31–41). There were significant differences in these parameters between the risk-groups: standard-risk group (n = 67): OS – 84%, EFS – 66%, CRR – 24%; intermediate-risk group (n = 251): OS – 77%, EFS – 50%, CRR – 38%; high-risk group (n = 313): OS – 64%, EFS – 34%, CRR – 37%. Over the period of observation, a total of 255 allogeneic hematopoietic stem cell transplantations (HSCT) were performed. The most common HSCTs were from haploidentical related donors (n = 180; 70%), the graft sources were peripheral blood stem cells (n = 138) and bone marrow (n = 87). The median time from start of therapy to HSCT was 5 months. The 2-year EFS after HSCT was 65% and the 2-year OS post-HSCT was 75%. Conclusion. To date, the potential of universal chemotherapy protocols for AML has been exhausted. Further improvements in treatment outcomes are only possible through the implementation of individualized treatment strategies based on molecular genetic profiling. Promising approaches include the addition of FLT3 inhibitors, gemtuzumab ozogamicin, venetoclax; the inclusion of menin inhibitors in leukemias with KMT2A rearrangements; the integration of hypomethylating agents in the treatment of patients with CBF-AML.

Myelodysplastic neoplasms, also known as myelodysplastic syndromes (MDS), are a heterogeneous group of myeloid malignancies characterized by ineffective haematopoiesis, cytopenias and a variably increased risk of progression to acute myeloid leukaemia. MDS primarily affect older adults with a median age at diagnosis of 76 years among patients in the USA. Despite major advances in our understanding of the genetic landscape and pathophysiology of MDS over the past 20 years, few disease-modifying therapies have been approved. Allogeneic haematopoietic stem cell transplantation remains the only potentially curative option. This slow therapeutic progress likely reflects the complex and widely heterogeneous pathophysiology of MDS, including a multifaceted interplay of somatic and germline mutations, a dysfunctional immune system, and an inflamed bone marrow microenvironment. Despite improvements in diagnostic tools, classification systems and prognostic models, these changes have introduced challenges for clinical trial design and epidemiological reporting. In this Review, we provide an update on the epidemiology, diagnosis, risk stratification, classification and expanding therapeutic armamentarium for the management of MDS. We also provide an overview of the current challenges to further progress and discuss future directions of research, which will hopefully lead to the development and approval of novel and effective therapies.