Leukemia最新文献

Aplastic anaemia (AA) is a disorder in which the bone marrow fails to produce enough blood cells [1]. For patients with severe aplastic anaemia (SAA) who are ineligible for haematopoietic stem cell transplantation (HSCT), intensive immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin A (CsA) is recommended [2]. However, the efficacy of IST alone is higher in children than in adults. Recently, eltrombopag (EPAG) has been proven to enhance the haematologic response to AA treatment [3, 4]. Whether the difference between adults and children still exists during treatment with IST + EPAG remains unclear. To date, no direct comparison of adults and children has been conducted. The aim of this study was to evaluate the differences in treatment efficacy and survival between adults and children treated with different regimens.

The haematologic response was evaluated in each patient. Among the patients receiving IST alone, the complete response rate (CRR) of adults was lower than that of children at 12 months (31% vs. 48%, P = 0.048), but there was no difference in the overall response rate (ORR) between adults and children at 3, 6, or 12 months (52% vs. 59%, P = 0.426; 69% vs. 74%, P = 0.599; 76% vs. 75%, P = 1.000, respectively). Relatedly, there was no difference in the CRR at 3 and 6 months between the adults and children (3% vs. 11%, P = 0.113; 21% vs. 22%, P = 0.849, respectively). The time to response was 4.3 (IQR 2.9–6.3) months in adults and 3.2 (IQR 2.5–4.0) months in children (P = 0.243), and the time to CR was 8.5 (IQR 6.8–11.0) months in adults and 7.5 (IQR 6.0–10.5) months in children (P = 0.113). Among the patients with IST + EPAG, there was no difference in the ORR between adults and children at 3 or 6 months (67% vs. 64%, P = 0.868; 83% vs. 76%, P = 0.567, respectively), but adults had a higher ORR at 12 months (89% vs. 73%, P = 0.027). There was also no difference in the CRR at 3, 6 and 12 months between the two groups (13% vs. 21%, P = 0.229; 25% vs. 38%, P = 0.124; 54% vs. 50%, P = 0.614, respectively; Fig. 1). The time to response was 3.0 (IQR 2.8–3.3) months in adults and 2.5 (IQR 1.9–3.9) months in children (P = 0.361). Moreover, the time to CR was 6.0 (IQR 3.0–8.3) months for adults and 3.9 (IQR 2.5–5.7) months for children (P = 0.478).

In 2022, leukemia ranked as the second most common hematological malignancy after non-Hodgkin lymphoma worldwide. However, updated global estimates of leukemia incidence by subtype are unavailable. We estimated leukemia incidences for different leukemia subtypes by country, world region, and human developmental index using data from the Cancer Incidence in Five Continents databases combined with the GLOBOCAN 2022 estimates of leukemia in 185 countries. We estimated sex-specific age-standardized rates (ASRs) per 100 000 for children (0–19 years) and adults (20+ years). In adults, the most common leukemia worldwide was AML (males: 38%, ASR = 3·1; females: 43%, ASR = 2·4), followed by CLL (males: 28%, ASR = 2·2; females: 24%, ASR = 1·3). In very high HDI countries, the ASR of CLL was higher than the ASR of AML among males (5·2 versus 4·3, respectively) and similar among females (2·9 and 3·0, respectively). In children, the most common leukemia was ALL (boys: 70%, ASR = 2·4; girls: 68%, ASR = 1·8) followed by AML (boys: 22%, ASR = 0·76; girls: 25%, ASR = 0·65). ALL proportions varied across world sub-regions from 57 to 78% among boys, and from 49 to 80% among girls. Our findings suggest clear geographical patterns of leukemia subtypes in adults and children. Further research into underlying causes that explain these variations is needed to support cancer control strategies for prevention and plan national healthcare needs.

Polycomb group (PcG) proteins play important roles in hematopoietic stem cell (HSC) self-renewal. Mel18 and Bmi1 are homologs of the PCGF subunit within the Polycomb repressive complex 1 (PRC1). Bmi1 (PCGF4) enhances HSC self-renewal and promotes terminal differentiation. However, the role of Mel18 (PCGF2) in hematopoiesis is not fully understood and how Mel18 regulates gene transcription in HSCs remains elusive. We found that acute deletion of Mel18 in the hematopoietic compartment significantly increased the frequency of functional HSCs in the bone marrow. Furthermore, we demonstrate that Mel18 inhibits HSC self-renewal and proliferation. RNA-seq studies revealed that HSC self-renewal and proliferation gene signatures are enriched in Mel18^−/− hematopoietic stem and progenitors (HSPCs) compared to Mel18^+/+ HSPCs. Notably, ATAC-seq revealed increased chromatin accessibility at genes important for HSC self-renewal, whereas CUT&RUN showed decreased enrichment of H2AK119ub1 at genes important for proliferation, leading to increased expression of both Hoxb4 and Cdk4 in Mel18^−/− HSPCs. Thus, we demonstrate that Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of genes important for HSC self-renewal and proliferation.

In patients diagnosed with B-acute lymphoblastic leukemia (B-ALL) or B-non-Hodgkin’s lymphoma (B-NHL) relapsing after allogeneic stem cell transplantation (allo-HCT), it is a standard practice to perform anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. When collected from the patient after allo-HCT, the produced CAR-T cells are likely to be donor T-cell-derived, creating unknown safety risks due to their potential allo-reactivity. We therefore performed an EBMT registry-based study on the incidence of graft-versus-host disease (GvHD) in this setting. We included 257 allo-HCT patients (n = 172 ≥ 18 years) with B-ALL or B-NHL, treated with anti-CD19 CAR T-cells (tisagenlecleucel n = 184, brexucabtagene autoleucel n = 43 and axicabtagene ciloleucel n = 30), between 2018 and 2022. Three patients developed aGvHD, whereas 6 patients developed cGvHD after CAR T-cell. The 100-day cumulative incidence (CI) of new aGvHD was 1.6% and the 12-month CI of new cGvHD was 2.8%. The 1-year GvHD relapse-free survival and non-relapse mortality were 52.1% and 4.7%, respectively. Last, with a median follow up of 18.8 months, the 1-year overall survival was 76.8%. In summary, the GvHD rate in allo-HCT patients treated with CAR T-cell therapy is relatively low. Our data support the view that GvHD is not a major safety issue in this setting.

Patients with myelodysplastic neoplasms (MDS) who progress on hypomethylating agents have poor outcomes [1,2,3]. There are no standard treatment approaches in this setting; while high-dose chemotherapy followed by allogeneic stem cell transplant remains a curative option for higher-risk MDS, advanced age and significant comorbidities preclude this approach for many patients [4]. In these cases, novel therapies are urgently needed.

Programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) are upregulated in hypomethylating agent failure MDS [5]. PD-L1 on the surface of MDS cells binds to PD-1 on T cells, facilitating immune evasion [6]. Similarly, CTLA4 on T cells binds to B7 on MDS cells, stifling T-cell receptor activation and contributing to immune escape [7]. These findings provide a rationale for assessing PD-1 and CTLA4 blockade in MDS following hypomethylating agent exposure [7]. Ipilimumab and nivolumab are fully human IgG1k monoclonal antibodies that target CTLA4 and PD-1, respectively [8, 9]. Both monotherapy and combination immunotherapy approaches are safe and effective in solid tumors and lymphomas; however, their safety and efficacy in relapsed or refractory MDS remains unclear.

Immunotherapy has demonstrated promise as a treatment for acute myeloid leukemia (AML). However, there is still an urgent need to identify new molecules that inhibit the immune response to AML. Most prior research in this area has focused on protein-protein interaction interfaces. While carbohydrates also regulate immune recognition, the role of cell-surface glycans in driving AML immune evasion is comparatively understudied. The Siglecs, for example, are an important family of inhibitory, glycan-binding signaling receptors that have emerged as prime targets for cancer immunotherapy in recent years. In this study, we find that AML cells express ligands for the receptor Siglec-9 at high levels. Integrated CRISPR genomic screening and clinical bioinformatic analysis identified ST3GAL4 as a potential driver of Siglec-9 ligand expression in AML. Depletion of ST3GAL4 by CRISPR-Cas9 knockout (KO) dramatically reduced the expression of Siglec-9 ligands in AML cells. Mass spectrometry analysis of cell-surface glycosylation in ST3GAL4 KO cells revealed that Siglec-9 primarily binds N-linked sialoglycans on these cell types. Finally, we found that ST3GAL4 KO enhanced the sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages. This work reveals a novel axis of immune evasion and implicates ST3GAL4 as a possible target for immunotherapy in AML.

Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline NOTCH3 ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related NOTCH3^C455R exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of NOTCH3^C455R and Dnmt3a^R878H, homologous to a frequent human CH mutation, increased the fitness of NOTCH3^C455R HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of NOTCH3^C455R hematopoietic cells supported the expansion of Dnmt3a^R878H HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to DNMT3A^R882H-driven CH. Considering that CADASIL-related NOTCH3 mutations are more frequent in the general population than anticipated (~1 carrier in 400 people), the effect of these NOTCH3 mutations on CH development should be considered.

Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy with overlapping features of myelodysplastic neoplasm (MDS) and myeloproliferative neoplasms characterized by peripheral blood monocytosis [1]. There is a predisposition for transformation to acute myeloid leukemia (AML), termed CMML with blast transformation (CMML-BT) [2, 3]. Hypomethylating agents (HMAs) are the sole FDA approved therapy for CMML albeit without established efficacy in terms of prolonging overall survival (OS) and halting disease evolution [4,5,6]. In order to improve response rates, venetoclax (VEN) has been combined with HMAs extrapolating data from AML and MDS [7, 8]. Single centers have offered varied results on the added benefit of VEN to HMA therapy in CMML and CMML-BT [9,10,11], but these studies lack control cohorts and are limited by small sample sizes of patients evaluated in each treatment setting and disease category.

To clarify the role of upfront HMA + VEN in patients with CMML and CMML-BT, we performed a multicenter retrospective cohort study utilizing a propensity score matched (PSM) cohort of patients treated with HMA alone.