Leukemia Research Reports最新文献

Introduction

Myelodysplastic syndrome (MDS) represents a group of malignant clonal hematological disorders characterized by dysplasia in one or more hematopoietic lineages in the bone marrow, leading to cytopenias and an increased risk of developing acute myeloid leukemia. The only treatment option that has shown benefit in PFS and OS for high-risk MDS is 5-azacitidine (5-AZA).

Methods

The aim of this study was to determine the impact of 5-AZA on the treatment outcome of patients with high-risk MDS from January 1, 2013, to December 31, 2021, at the Clinical Hospital Merkur in Zagreb, Croatia. Retrospective analysis was performed on data from patients with high-risk MDS. The study included 38 patients (M:F=25:13), at time of study conclusion, 34 patients died. Laboratory data and overall survival of the patients were analyzed. Data were analyzed using the Kaplan-Meier method, Log-rank test, and Mann-Whitney U test.

Results

A longer overall survival was observed in patients treated with more than 12 cycles of 5-AZA. The median survival of the group receiving more than 12 cycles of 5-AZA was 24 months, while the median survival of patients receiving less than 12 cycles was 11 months (p=0.023). Higher creatinine levels at diagnosis and lower LDH levels before the first cycle were observed in the group of surviving patients.

Conclusions

The results of this study highlight the efficacy of 5-AZA in the first-line treatment of high-risk MDS patients, with a statistically significant difference in overall survival observed in group of HR MDS patients receiving at least 12 cycles of 5-AZA.

A 67-year-old female came to Tampa General Hospital with Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) featuring an intriguing combination of mutations, including NPM1 and IDH2 mutations. Novel combination therapy with azacitidine, venetoclax and ponatinib allowed her to successfully achieve a complete response (CR) and undergo an allogeneic hematopoietic stem cell transplant (HSCT). This case report provides an overview of her clinical course, emphasizing the significance of integrated therapy and the challenges associated with balancing treatment for AML. It also underscores the importance of a multidisciplinary approach and careful monitoring of patients with complex hematologic conditions.

Both clonal plasma cell and myeloid disorders occur more frequently with age. Patients with concurrent clonal plasma cell and myeloid disorders (CPCMD) can present clinical and therapeutic challenges. In this single-institution cohort of patients with CPCMD (n = 18), we abstracted clinically relevant themes. A majority of patients (12/18) were treated with clone-directed therapies and three received treatment targeting both clones. Treatment of clones with targetable genetic lesions or those causing end-organ complications should be prioritized. Simultaneous treatment of both clones can be safe but is best done in a stepwise manner. Further study of patients with dual clonal processes is warranted.

Introduction

Germline DDX41 variants are implicated in late-onset myeloid neoplasms, accounting for the largest germline risk of the development of myeloid neoplasms. In typical cases, a germline loss-of-function allele is compounded by the somatic R525H mutation affecting the helicase domain in the remaining allele. The molecular mechanism by which DDX41 mutations lead to myeloid neoplasms remains to be elucidated.

Methods

To delineate the pathogenic mechanism of DDX41-mutated myeloid neoplasms, we generated mice models carrying the conditional Ddx41 knock-out and/or R525H knock-in alleles.

Results

In non-competitive bone marrow (BM) transplantation, most of the mice reconstituted with Ddx41^−/− or Ddx41^R525H/− BM died within a month due to severe BM failure. In competitive transplantation, Ddx41^−/− and Ddx41^R525H/− mice-derived cells showed markedly disadvantageous reconstitution, while Ddx41^+/− and Ddx41^R525H/+ mice-derived cells showed slightly reduced reconstitution compared to Ddx41^+/+ mice-derived cells. By contrast, the mice transplanted with Ddx41^+/− or Ddx41^R525H/+ BM showed significantly reduced WBC counts and anemia in long-term observation in both primary and serial transplantations. Some of the Ddx41^+/− or Ddx41^R525H/+ BM-transplanted mice exhibited MDS-like phenotypes, showing ineffective hematopoiesis with evidence of erythroid dysplasia. Transcriptome analysis of Ddx41^+/− and Ddx41^R525H/+ derived stem cells exhibited a significant deregulation of genes involved in RNA metabolism, ribosome biogenesis and apoptosis.

Conclusions

Monoallelic Ddx41 loss-of function or R525H knock-in alleles led to age-dependent impaired hematopoiesis and the development of myeloid malignancies, while compound biallelic loss-of function and R525 alleles showed a severely compromised function of hematopoietic stem cells.

Introduction

About 40% - 50% of Myelodysplastic syndromes (MDS) patients present with a normal karyotype whereas 50% - 60% of patients are of low risk, however, they tend to have worse outcomes and a higher chance of disease progression. Hence, we aim to study the genomic pathophysiology of disease and their association with overall survival in MDS.

Methods

The study cohort included 200 MDS patients. The molecular cytogenetic and mutation profiling was carried out in all MDS patients. The patients were clinically followed up. The Kaplan-Meier survival and multivariate analysis was performed using GraphPad Prism 5.00

Results

The WHO 2016 classification revealed a high frequency of MDS – MLD (33%) followed by MDS – SLD (25%), MDS – EB-1/2 (24%). The chromosomal aberrations were identified in 35% of MDS patients by CK/FISH. The NGS identified gene mutations in 75% of the cohort. The survival analysis revealed that the mutations in TP53, JAK2/3, KRAS, NRAS, and ASXL1 are significantly (P < 0.05) associated with poor survival. SNP array analysis (n=77), revealed, patients with chromosome 2 aberrations have a poor prognosis. SNP array combined with NGS confirmed the biallelic loss of function of the TP53 gene (3/7), a clinically relevant biomarker and new genetic-based MDS entity i.e. MDS-biTP53 as per the new WHO classification 2022. The univariate and multivariate analysis suggested that genetic lesions (mutations/CNVs/LOH) with IPSS-R could be prognosticating markers in MDS patients.

Conclusions

Our study strongly supports that the genome profiling by combined CGH+SNP array and NGS improves prognostication and hence personalized disease management.

Introduction

Chronic Myelomonocytic Leukemia (CMML) is a rare, malignant hematopoietic system tumour whose pathogenesis remains unclear. This primarily affects elderly males and may transform into acute myeloid leukemia. Elevated innate immune and inflammation-related pathways were found in CMML patients' monocytes. Activation of type I interferon signalling pathway was significant and correlated with prognosis. Strong expression of interferon-regulated genes in patients pointed to type 1 interferon signalling's role in CMML's pathogenesis. TET2 and SRSF2 mutations, affecting gene expression and cellular function, are common in CMML, with a synergistic effect shown in mouse model experiments.

Methods

We studied 14 untreated CMML patients, analysing their peripheral blood monocytes and 13 inflammatory cytokines via transcriptome sequencing and Cytometric Bead Array. SRSF2-P95H/TET2 mutation cell lines were also created.

Results

Exome and transcriptome sequencing in 14 CMML patients revealed frequent TET2, ASXL1, and SRSF2 mutations. Compared to controls, CMML cells displayed activated innate immune and inflammation pathways, including elevated levels of IL-10, IFN-α2, IL-8, IL-12p70, IL-6, and IL-17A. Higher 1-IFN scores, indicating the activation level of the type 1 interferon pathway, were seen in MP-CMML patients, suggesting a link with poor prognosis. In vitro, interferon pathway inhibition induced apoptosis in CMML monocytes and reduced protein P38 phosphorylation, inhibiting cell proliferation in THP-1/U937. TET2 loss-of-function mutations and SRSF2-P95H mutations overexpressed type 1 interferon pathway genes, leading to increased culture supernatant interferon levels in HEK-293T cells.

Conclusions

Study shows TET2 loss-of-function/SRSF2-P95H mutations in CMML trigger type I interferon pathway activation, promoting P38 and PI3K phosphorylation, potentially partly causing CMML.

Introduction

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized with chromosomal instability and a high propensity to myeloid malignancy. Although causative genes have been identified in most patients, the genetic background of the leukemic transformation in FA has not been fully understood.

Methods

We studied 2 acute myeloid leukemia (AML) and 7 myelodysplastic syndromes (MDS) developed in patients with FA using whole-genome sequencing and analyzed somatic mutations, structural variants and copy number alterations.

Results

The number of somatic mutations and copy number alterations (CNAs) in AML were 1,071 mutations and 4 CNAs per patient on average, which tended to be higher than those in MDS (265 mutations and 2.3 CNAs per patient). For mutational signatures, three known signatures were identified, which included SBS1 and SBS5 caused by endogenous mutational processes, and SBS3 related to defective homologous recombination. Mutations and structural variants affected known driver genes in myeloid malignancies, such as RUNX1 (n = 3), ASXL1 (n = 1), CBL (n = 1), NRAS (n = 1) and KDM6A (n = 1). Recurrent copy number alterations were more frequently detected, including +3q (n = 6), +1q (n = 4) and -7q (n = 2). The majority of these CNAs were clonal and all but one patient harbored either of +3q or +1q, indicating the early acquisition of copy number changes and their driver role in leukemic transformation.

Conclusions

Myeloid neoplasms related with FA were characterized by a unique pattern of CNAs and common driver mutations in myeloid malignancies.

Orbital plasmacytoma is rare and has only been reported in the context of the initial diagnosis of multiple myeloma. Moreover, isolated orbital plasmacytoma without any signs of multiple myeloma is extremely rare.

We report the case of a 59-year-old female patient diagnosed with IgA Kappa multiple myeloma. It was stage I ISS (International Staging System) and stage I R-ISS (Revised ISS). According to the Tunisian national protocol, the patient was included in the standard-risk group and was eligible for four cycles of CTD (Cyclophosphamide, Thalidomide, Dexamethasone) followed by autologous stem cell transplantation. Taking into account the partial response after the CTD cycles, the patient has benefited from two VTD cycles (Bortezomib, Thalidomide, Dexamethasone). Thus, complete remission was obtained. The patient refused autologous stem cell transplantation. Therefore, maintenance treatment based on Thalidomide only was started and received over a twelve-month period.

Five months after the end of maintenance treatment, she reported frontal headaches that were resistant to symptomatic treatment, with ptosis in the right eye in physical examination. Brain MRI revealed the presence of a right cranio-orbital tissue mass with intra-orbital and extra-axial cerebral components. The mass measured 32/36 mm on axial sections and 47 mm in height. The patient underwent a complete resection of the cranio-orbital mass with cranioplasty. The histopathological examination of the mass with Immunohistochemistry staining confirmed the diagnosis of orbital plasmocytoma.

An update of the multiple myeloma assessment did not reveal any biological, cytological or radiological signs in favor of multiple myeloma. Therefore the diagnosis of isolated orbital plasmacytoma without signs of multiple myeloma was made.

Post-operative brain MRI showed complete disappearance of the right cranio-orbital tissue lesion. There was only a persistent meningeal enhancement of the dura mater at the surgical site, suggestive of post-operative changes. The patient was then referred for cranio-orbital radiotherapy.

This case report discusses a 95-year-old man diagnosed with two types of lymphomas. He was hospitalized for erysipelas in September 2018. The lymph node revealed high-grade B-cell lymphoma with Myc and Bcl-2 rearrangement. Bone marrow biopsy revealed hairy cell leukemia, a rare type of indolent B-cell lymphoma. We found that the bone marrow and left inguinal lymph node were non-homologous. There are no known reports of super-aged patients with two types of lymphoma simultaneously. The toxicity of R-CHOP in elderly people limited its usage, so we first chose rituximab. However, this approach was not successful. We then considered the Bruton tyrosine kinase (BTK) inhibitor, but its use was limited due to high blood pressure. Finally, we administered venetoclax, which the patient took for 2 years. The results of the routine blood examination were close to normal and no enlarged superficial or abdominal lymph nodes were observed.This is the oldest reported patient with two types of malignant lymphatic diseases. Additionally, this rare case suggests that targeted therapy can be more effective and safe for super-aged individuals. To summarize, a 95-year-old man diagnosed with two types of lymphomas, high-grade B-cell lymphoma and hairy cell leukemia, was successfully treated with venetoclax after other treatments failed. This case suggests that targeted therapy can be effective and safe for super-aged patients with multiple malignant lymphatic system diseases.

In the context of chronic lymphocytic leukemia (CLL), Hyperviscosity Syndrome (HVS) typically arises from hyperleukocytosis, although it infrequently stems from IgM hyperparaproteinemia. We present a distinctive case of HVS induced by IgM hyperparaproteinemia in a patient experiencing relapsed CLL, marked by bulky disease and cytopenias upon progression. The patient exhibited new symptoms, including headache, dizziness, and confusion. Laboratory analysis revealed an elevated total protein level, and serum electrophoresis identified an elevated M spike at 4 g/dL with IgM on immunofixation. Suspecting HVS, prompt plasmapheresis was initiated, resulting in symptom resolution within two days.

A comprehensive literature review suggests that CLL patients with an elevated IgM level often face a poor prognosis, though HVS symptoms are not commonly observed. Our case underscores the significance of swiftly identifying HVS when IgM hyperparaproteinemia is detected in CLL patients. Notably, our patient not only achieved successful treatment for the acute presentation but also initiated second-line therapy for relapsed disease. In conclusion, effective management and stabilization of CLL patients with IgM-associated HVS are attainable, emphasizing the crucial role of prompt recognition.