Leukemia research最新文献

The standard treatment for aggressive adult T-cell leukemia/lymphoma (ATL) is multi-agent chemotherapy, but the use of more intense cytotoxic anticancer agents is becoming more difficult with the aging of patients at the time of diagnosis. As a means of overcoming this hurdle, antibody drugs, which are supposed to be less toxic, have been developed for ATL. The advent of the anti-CC chemokine receptor 4 (CCR4) antibody mogamulizumab has significantly advanced ATL treatment. Real-world data and a phase 2 clinical trial suggest the efficacy and manageable safety profile of mogamulizumab with combination chemotherapy in elderly patients. Interestingly, mogamulizumab has performed well in cases with CCR4 mutations and cutaneous adverse events. In addition, emerging immunotherapies, including Tax peptide dendritic cell vaccines, immune checkpoint inhibitors, and Chimeric Antigen Receptor-T cell therapy, are under investigation. These innovative approaches aim to enhance immunogenic responses and offer hope for better outcomes in this challenging malignancy.

Adult T cell leukemia lymphoma (ATL) is a mature T cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). ATL is endemic in specific geographic regions of the world closely related to areas with high prevalence of HLTV-1 infection, including Southwestern Japan, the Caribbean Basin, Central Africa, South America, Northern and Central Australia. HLTV-1 is primarily transmitted through breastmilk in asymptomatic carriers with a long latency period before transformation into ATL in 3 - 5 % of carriers after acquisition of multiple leukemogenic mutations. The Shimoyama classification established by the Japanese Lymphoma Study Group more than three decades ago remains clinically relevant and practical for guiding treatment. Due to the rarity of this illness, prospective, large prospective clinical are challenging to perform and treatment recommendations are based upon limited evidence. Aggressive disease subtypes have median survival ranging in months and the only curative therapy remains achieving deep remission with induction therapy followed by consolidative allogeneic transplantation. The prognosis for relapsed disease remains dismal due to chemo-refractoriness and limited therapeutic options. Herein, we review the current landscape of novel therapeutic agents with a focus on relapsed and refractory ATL including their mechanisms of action, resistance, and clinical efficacy.

Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 are highly successful in chronic myeloid leukemia (CML). However, extensive interpatient variability in therapeutic responses and resistance supports the need to find new prognostic biomarkers. We have previously reported that TP53 SNP215 variant affects CML risk and clinical outcome. We aimed to evaluate the role of MDM2 genetic variants in CML susceptibility and treatment response to TKIs. We genotyped five MDM2 promoter variants (del1518, SNP309, SNP285, SNP288 and SNP344) in 135 CML patients and 136 healthy individuals. Our study showed that MDM2 variants alone or in combination had no effect on CML susceptibility. The analysis of MDM2 genotypes in relation to patients' clinical parameters revealed that individuals with SNP309 G/G genotypes were at a significantly increased risk of undergoing molecular response failure (p = 0.044). Improved overall survival was also observed for non-responders with the alternative MDM2 del1518 del allele (p = 0.017) as well as for MDM2 del1518-SNP309 combinations with alternative genotypes (p = 0.014). In addition, combinatorial analysis demonstrated that alternative MDM2 SNP309 and TP53 SNP215 genotypes together are associated with faster achievement of MR² (p = 0.029) and MMR (p = 0.042) in non-responders, suggesting a relationship with a favorable outcome. Overall, our study highlights the influence of MDM2 variants on clinical outcome, supporting that specific genotypes, alone or in combination, underlie the treatment-responsive phenotype.

Clonal isotype switch (CIS) in multiple myeloma (MM) refers to the emergence of new immunoglobulin bands distinct from those present at diagnosis. CIS often appears after high-dose chemotherapy and autologous stem cell transplantation (ASCT), reflecting post-transplant immune recovery. However, its prognostic significance remains unclear. In this study, CIS was observed (CIS-positive) in 31.7 % (26/82) of patients undergoing ASCT. Patients receiving bortezomib-containing induction therapy showed a higher prevalence of CIS compared to those treated with vincristine-doxorubicin-dexamethasone chemotherapy (37.9 % vs. 16.7 %, p = 0.061). Median overall survival (OS) was not estimable (NE) in the CIS-positive group, while it was 47 months in the CIS-negative group (hazard ratio [HR]: 0.27, 95 % CI: 0.11-0.67; p = 0.005). Median progression-free survival (PFS) was also NE in the CIS-positive group versus 26 months in the CIS-negative group (HR: 0.25, 95 % CI: 0.11-0.58; p = 0.001). These findings suggest that CIS is an independent biomarker associated with favorable outcomes in MM patients undergoing ASCT.

Background: Hematopoietic stem cell transplantation (HCT) is a pivotal treatment modality for primary plasma cell leukemia (pPCL). We aimed to examine the outcomes of allogeneic (allo) and autologous (auto) HCT in adult pPCL patients.

Methods: Following PRISMA guidelines, a comprehensive literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov using relevant MeSH terms and keywords. Twelve original articles reporting outcomes of auto-HCT or allo-HCT in adult pPCL patients were included. The pooled analysis was performed using the 'meta' package in the R program (version 4.3.0).

Results: Our analysis included 1757 pPCL patients (1535 with auto-HCT, 222 with allo-HCT), and 49 % were males. The pooled 3 years overall survival (OS), progression-free survival/event-free survival (PFS/EFS), and relapse rate (RR) in auto-HCT were 51 % (95 % CI 0.4-0.61, I²=92 %, p = <0.01), 36 % (95 % CI 0.24-0.52, I 2 =97 %, p < 0.01), and 68 % (95 % CI, 0.65-0.71, I2=0 %, p = 0.42), respectively. Among allo-HCT recipients, the reported OS varied from 71 % at 2.3 years to 31 % at 4 years and EFS/PFS from 29 % at 2.5 years to 19 % at 4 years. The pooled treatment-related mortality (TRM) was 12 % (95 % CI 0.05-0.25, I ²=35 %, p = 0.22) at a median of 6 months. The pooled incidence of acute and chronic graft versus host disease was 27 % (0.19-0.36, I²= 30 %, p = 0.21) and 36 % (0.27-0.45, I²= 24 %, p = 0.26), respectively.

Conclusion: HCT remains pivotal in treating primary plasma cell leukemia. However, higher relapse rates warrant novel agents and clinical trials to improve transplant-related outcomes in this challenging subgroup.

Objective: The primary methods for defining the prognostic risk of AML patients are cytogenetic and molecular analysis at the time of diagnosis. However, the prognosis of intermediate-risk patients is still not well assessed for biomarkers. The main objective of this meta-analysis is to evaluate the relationship between circRNAs and AML prognosis, to provide a theoretical basis for finding effective prognostic indicators in intermediate-risk patients, and to provide an important scientific basis for the development or revision of WHO practice guidelines and ELN risk classification, and to highlight the importance of continuing to focus on and evaluate the prognostic impact of circRNAs on AML in future studies.

Methods: We performed a comprehensive literature search across PubMed, the Cochrane Library, and Web of Science databases for studies published up to September 15, 2024. Articles were selected based on inclusion criteria. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of studies. The outcome measure of overall survival (OS) was used, and hazard ratios (HR) and 95 % confidence intervals (CI) were pooled to estimate the relationship between circRNA expression and prognosis in AML using STATA 17.0 software.

Results: A total of 13 studies involving 1401 AML patients were included. The studies showed a significantly increased hazard ratio (HR) of upregulated CircRNA expression for OS (HR=1.87, 95 % CI=1.51-2.32, P < 0.001). The results of subgroups analysis showed a significant increase in the hazard ratio (HR) for upregulation of CircRNA expression in EFS and circ_0012152（HR= 1.66, 95 % CI= 1.19-2.32, P < 0.005 and HR= 2.26,95 % CI= 1.27-4.00, P < 0.005), respectively. No significant heterogeneity or publication bias was detected.

Conclusion: Upregulated circRNA expression is significantly associated with poor prognosis in AML patients and may serve as a prognostic marker for AML.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by Human T-cell leukemia virus type 1 (HTLV-1) infection. Although the 5th Edition of the WHO classification (WHO-5) did not make drastic changes regarding the disease concept of ATLL from the revised 4th Edition of the WHO classification (WHO-4R), WHO-5 newly introduced the essential and desirable diagnostic criteria, namely, "neoplastic lymphoid cell proliferation with mature T-cell phenotype; proven HTLV-1 carriership" and "identification of monoclonal integration of HTLV-1", respectively. To satisfy the desirable criteria, a new diagnostic method using a combination of HBZ-ISH and tax-PCR was introduced for the identification of the HTLV-1 in addition to the conventionally used Southern blot hybridization, especially in the case when only FFPE specimens are available. Morphologically, pleomorphic- and anaplastic large cell-type, account for most cases, while minor variants, ATLL with dermatopathic reaction, angioimmunoblastic T-cell lymphoma-like variant, and classic Hodgkin lymphoma-like variant, should also be noted as diagnostic pitfalls. Phenotypically, about 80 % of ATLL cases show a typical phenotype of CD3 + CD4 +CD25 +CCR4 + , while about 10 % show atypical phenotypes such as T follicular helper cell-like one. Many genetic abnormalities, mainly associated with the TCR signaling pathway, are observed, and most are more frequent in the aggressive type than in the indolent type, except for STAT3, indicating the heterogeneous pathogenic process of ATLL. In this review, we present the latest findings on molecular pathogenesis and histopathological findings of ATLL in the era of the new classification of lymphomas, serving as a basis for future research and classification.

Human T-cell leukaemia virus type-1 (HTLV-1) causes the highly aggressive malignancy adult T-cell leukaemia-lymphoma (ATL) in approximately 5 % of chronically infected carriers. HTLV-1 persists in the host by enhancing survival of infected-T-cells despite the presence of a strong immune response. Therefore, asymptomatic HTLV-1 carriers have a lifelong balance between infected cell proliferation and the host antiviral immune response. However, this immunological balance is lost in patients with ATL. Reliable treatment options are lacking and there is urgent need for new treatment strategies to improve the dismal prognosis of ATL. In this review, we present a summary of the current knowledge on the immunological aspects of HTLV-1 persistence and the immune alterations observed in ATL, and discuss how the recent emerging advances in adoptive immunotherapy may offer a prevention and treatment option for ATL.

Acute myeloid leukemia (AML) is a complex hematological malignancy predominantly affecting the elderly, with a median diagnosis age of 68 years. Despite advances in treatment, elderly AML patients face suboptimal survival outcomes, with an estimated 5-year survival rate below 20 %. Epigenetic dysregulation, notably DNA methylation, is a key factor in the progression of myelodysplastic syndromes (MDS) to AML. This review examines various combination regimens involving azacitidine (AZA), including those with lenalidomide, histone deacetylase inhibitors (HDACi), kinase inhibitors, metabolic enzyme inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and anti-apoptotic protein inhibitors. Notable among these are the combinations with venetoclax, which has demonstrated remarkable efficacy in phase III trials, and the emerging IDH inhibitors ivosidenib and enasidenib, which have shown significant clinical benefits in patients with IDH mutations. While combination therapies with AZA hold great promise, challenges persist, including translating in vitro synergies to in vivo efficacy and identifying optimal regimens for specific patient populations. Cumulative toxicities may also offset clinical benefits, necessitating rigorous clinical trial design. Future research must focus on refining combination strategies, optimizing dosages and sequences, and thoroughly evaluating therapeutic efficacy and safety to advance the treatment of AML and improve patient outcomes.