Invasive aspergillosis (IA) is a potentially life-threatening complication of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We conducted a systematic review and meta-analyses of studies on acute leukemia in children aged 0-17 years since 2000. Findings were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We included 24 studies with 3,661 ALL patients and 1,728 AML patients. IA cumulative incidence varied (0%-10% for ALL and 0%-18% for AML) across the studies. Pooled cumulative IA incidences were estimated at 3.2% (95% CI: 1.8% - 5.8%) in ALL and 5.2% (95% CI: 3.1% - 8.6%) in AML, with corresponding case-fatality-rates of 13.3% (95% CI: 6.3% - 25.9%) and 7.8% (95% CI: 0.7% - 51.2%), respectively. Our analysis highlights the impact of IA in childhood leukemia, underscoring the need to address strategies for prevention, early detection, and treatment of IA in pediatric leukemia.

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Eosinophilic esophagitis (EoE) is an immune/antigen-mediated disease with an increasing incidence over the last decade. Clinicopathological remission can be achieved through different treatment options but often requires chronic therapy. To our knowledge, this is the first report of EoE wherein the patient (a 54-year-old man) achieved histological remission after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia. Overall, despite the success of EoE treatment in this case, further studies are needed to establish allogeneic HSCT as a curative option for EoE.

The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized.

The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS-directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post-HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post-HCT. We analyzed a publicly available dataset derived from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission (CR) between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplants and noncalcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. The Cox regression model and Fine-Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n = 136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0 to 3 years, patients who were in the second CR, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio: 0.50, 95% confidence interval: 0.33 to 0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (P = .10 and 0.20, respectively) in the two cohorts. The entire TBI-treated cohort showed an association with increased risks of grade 2 to 4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of nonrelapse mortality and a trend of higher grade 3 to 4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

UNASSIGNED: Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised.
UNASSIGNED: This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010-31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation.
UNASSIGNED: In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5-348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P = .85) or by center (P = .92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P = .004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1-3; range, 1-8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression.
UNASSIGNED: AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression.

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Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

BACKGROUND: Acute myeloid leukemia (AML) is a clonal malignant disorder which originates from a small number of leukemia-initiating cells or leukemic stem cells (LSCs)-the subpopulation that is also the root cause of relapsed/refractory AML. Chimeric antigen receptor (CAR)-T cell therapy has proved successful at combating certain hematologic malignancies, but has several hurdles that limit its widespread applications. CAR-natural killer (NK) cells do not carry the risk of inducing graft-versus-host disease (GvHD) frequently associated with allogeneic T cells, thereby overcoming time-consuming, autologous cell manufacturing, and have relatively safer clinical profiles than CAR-T cells. The present study aimed to generate anti-TIM3 CAR-NK cells targeting LSCs from a clonal master induced pluripotent stem cells engineered with the third-generation anti-TIM3 CAR.
METHODS: A clonal master umbilical cord blood NK-derived induced pluripotent stem cell (iPSC) line, MUSIi013-A, was used as a starting cells for engineering of an anti-TIM3 CAR harboring TIM3 scFv fragment (clone TSR-022), CD28, 4-1BB, and CD3ζ signaling (CAR-TIM3). The established CAR-TIM3 iPSCs were further differentiated under serum- and feeder-free conditions into functional CAR-TIM3 NK cells and tested for its anti-tumor activity against various TIM3-positive AML cells.
RESULTS: We successfully established a single-cell clone of CAR-TIM3 iPSCs, as validated by genomic DNA sequencing as well as antibody and antigen-specific detection. We performed thorough iPSC characterization to confirm its retained pluripotency and differentiation capacity. The established CAR-TIM3 iPSCs can be differentiated into CAR-TIM3 NK-like cells, which were further proven to have enhanced anti-tumor activity against TIM3-positive AML cells with minimal effect on TIM3-negative cells when compared with wild-type (WT) NK-like cells from parental iPSCs.
CONCLUSIONS: iPSCs engineered with CARs, including the established single-cell clone CAR-TIM3 iPSCs herein, are potential alternative cell source for generating off-the-shelf CAR-NK cells as well as other CAR-immune cells. The feasibility of differentiation of functional CAR-TIM3 NK cells under serum- and feeder-free conditions support that Good Manufacturing Practice (GMP)-compliant protocols can be further established for future clinical applications.

Anthracycline- and cytarabine-based intensive combination chemotherapies are considered the backbone therapy for patients with acute myeloid leukemia (AML). Although chemotherapy leads to long-term remission and cures many patients with AML, it can induce DNA damage/stress due to acute/chronic toxicities, acquired resistance, relapse, and therapy-related malignancies. Introduction of molecularly targeted agents with less systemic toxicities has considerably improved the scope of treatment, particularly in elderly and frail patients. However, outcomes of TP53-mutated myelodysplastic syndrome (MDS) and AML, a distinct group of myeloid disorders, have not improved irrespective of the treatment used (median overall survival, 5-10 months). In this review, we discuss the biological and clinical significance of TP53 mutations in malignancies, while particularly focusing on MDS/AML, and emerging therapies for TP53-mutated MDS/AML. Rationally designed novel treatment strategies are expected to improve the clinical outcomes of TP53-mutated MDS/AML.