Leukemia Research Reports最新文献

Introduction

High-risk MDS & AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS & AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.

Methods

Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from > 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.

Results

A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental & Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 & MCL1 on treatment with the STAT3 degrader.

Conclusions

Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.

Real-world data on treatment patterns and outcomes of patients with acute myeloid leukemia unfit for intensive chemotherapy are lacking before the advent of precision medicine in this setting.

Herein, we present the Italian sub-analysis of the CURRENT study in AML patients unfit for first line intensive chemotherapy, evaluating patients’ outcomes between 2015 and 2018.

Among 74 evaluable patients, 62 received systemic treatments (most used therapy was hypomethylating agents), while 12 best supportive care.

Key results include both efficacy and safety data, as well as HCRU and treatment patterns. In first-line therapy cohort median OS was 13.4 months vs. 2.7 months for BSC.

Chimeric antigen receptor (CAR) T-cells have unveiled a promising therapeutic horizon for relapsed/refractory multiple myeloma (R/R MM). Nevertheless, immune impairment induced by cellular therapies, previous treatments and MM itself could promote infectious events. COVID-19 could evolve into a life-threating infection in R/R MM patients who often have suboptimal responses to SARS-CoV-2 vaccines. Here, we describe a case of severe and long-lasting COVID-19 pneumonia after CAR T-cell therapy for R/R MM requiring a complex clinical management. Long-term infectious complications in MM patients undergoing CAR T-cells should be taken into consideration as they could counteract the efficacy of this new treatment.

Plasma cell leukemia (PCL) is a rare aggressive variant of multiple myeloma. PCL is diagnosed when clonal plasma cells constitute more than 20 % of the total circulating leukocytes or when the absolute plasma cell count exceeds 2 × 10⁹ /L. Extramedullary involvement including cavity effusion is frequently seen at the time of diagnosis. However, soft tissue involvement is rarely encountered with only one published case in the English literature. We report a 74-year-old man, who presented with progressive shortness of breath over a few months. Laboratory studies showed leukocytosis (32 × 109 /L) with 26 % peripheral plasmacytoid cells and significantly elevated lactate dehydrogenase (> 2500 U/L). Serum protein electrophoresis detected a monoclonal IgG lambda band. A 7.4 cm left hilar mass, bilateral pleural effusion, and multiple fluorodeoxyglucose (FDG)-avid subcutaneous nodules in the pelvic and gluteal regions were demonstrated on imaging. Gluteal nodule biopsy revealed diffuse infiltrative CD138+ and MUM1+ cells with aberrant CD4, CD30, and BCL2 expression. The Ki-67 proliferation index was 70 %. Bone marrow biopsy showed sheets of atypical plasma cells with lambda-restriction and CD138 and MUM1 expression without cyclin D1 and CD20 expression. These cells comprise approximately 70–80 % of the bone marrow cellularity. A similar immunophenotype was demonstrated in peripheral and bone marrow flow cytometry. Molecular and cytogenetics showed an abnormal clone with a complex karyotype including monosomy 13 and 14q deletion. Overall, these findings are consistent with a plasma cell neoplasm. Our case study illustrates soft tissue involvement in PCL, which is rarely seen.

Introduction

Germline SAMD9 and SAMD9L mutations (SAMD9/9L^mut) cause a novel bone marrow failure and pediatric myelodysplastic syndrome. Despite >400 patients reported, evaluating variants remains challenging with >70% of germline SAMD9/9L^mut classified as variants of uncertain significance, mainly due to heterogenous phenotypes and lack of functional assays. Many patients acquire compensatory clones including secondary SAMD9/9L^mut and UPD7q with loss of the mutant allele, along with maladaptive, stress-induced monosomy 7. Monosomy 7 poses unique surveillance challenges as it may disappear spontaneously over time, precluding the need for HSCT.

Methods

We utilized our prospective somatic surveillance database to identify genetic patterns and evolution in SAMD9/9L^mut patients (median age 8 years). Using high-sensitivity myeloid gene panel and SNP array, we evaluated hematopoietic specimens of 23 patients with SAMD9/9L syndromes. For comparison, we analyzed a cohort of 132 patients with other BMF/MDS conditions. Serial analysis was performed in 39% (61/155) of patients for a median duration of 15.7 (1.4-53.2) months.

Results

We found 33 somatic SAMD9/9L^mut in 61% (14/23), UPD7q in 26% (6/23), and monosomy 7 in 48% (11/23) of patients with germline SAMD9/9L^mut. Somatic SAMD9/9L^mut and UPD7q were not identified in the comparative cohort, resulting in 100% specificity and positive predictive value to rule-in germline SAMD9/9L syndromes. Notably, no patient (including monosomy 7 cases) developed advanced MDS, leukemia, or cancer driver mutations with up to 4.4 years of follow-up.

Conclusions

Somatic SAMD9/9L^mut and UPD7q act as a “natural functional assay” confirming pathogenicity of germline SAMD9/9L^mut. Despite high rates of monosomy 7, leukemic progression is rare in SAMD9/9L syndromes.

Introduction

Tie2 is a receptor tyrosine kinase and regulates angiogenesis and vascular quiescence. Given that Tie2 modulates microvascular density in cancer, we hypothesized that deletion of Tie2 in blood cells can inhibit progression of myelodysplastic syndrome (MDS). We attempted to understand the role of Tie2 in development of MDS by using an Ezh2/Tet2 double knock out (DKO) mouse model.

Methods

We transplanted bone marrow (BM) cells isolated from Cre-ERT2 mice, Tie2^flox/wt; Cre-ERT2 mice, Ezh2^flox/flox; Tet2^flox/flox; Cre-ERT2 mice, Ezh2^flox/flox; Tet2^flox/flox; Tie2^flox/wt; Cre-ERT2 mice and Ezh2^flox/flox; Tet2^flox/flox; Tie2^flox/flox; Cre-ERT2 mice into lethally-irradiated Ly5.1⁺ recipient mice. Ezh2, Tet2 and Tie2 genes were deleted by administration of tamoxifen one month post the transplantation.

Results

We found that Ezh2^−/−Tet2^−/- DKO, Ezh2^−/−Tet2^−/- Tie2^+/− (DKOTie2^+/−) and Ezh2^−/−Tet2^−/- Tie2^−/− TKO mice all developed MDS and MDS/MPN, showing anemia and dysplastic cells in the peripheral blood (PB) and the BM; however, DKOTie2^+/− mice showed significantly longer survival than did DKO mice and TKO mice. While DKO mice showed deformed CD31⁺ endothelial cells and increased vascular density in the BM, DKOTie2^+/− mice mitigated the altered vascular formation in the BM. RNA-sequencing revealed that DKOTie2^+/− stem cells repressed expression of genes involved in interferon, cell cycles and angiogenesis, compared to DKO stem cells, suggesting that the haploinsufficiency of Tie2 impaired the property of MDS cells to drive angiogenesis in the BM, resulting in the delayed development of MDS.

Conclusions

We are now working on the molecular mechanism of how the Tie2 gene in blood cells modulates the angiogenesis to drive the progression of MDS.

Introduction

Fanconi Anemia (FA) gene is a congenital bone marrow failure (BMF) disorder caused by impaired replication stress (RS) associated DNA damage repair. We previously described FA fetal liver (FL) hematopoietic stem cell (HSC) exhibited high mitochondrial oxidative phosphorylation (OXPHOS) and mitophagy when it was under RS. Thrombopoietin (TPO) signaling is known to modulate mitochondria metabolism in HSC. While TPO agonists are utilized for the treatment of BMFs such as aplastic anemia, whether and how these drugs can affect FA and its progression to hematopoietic malignancy is unknown.

Methods

To clarify the TPO signal of response in FA, we analyzed FA mice [an1] treated with TPO agonists or crossed with TPO-deficient mice.

Results

Embryonic mice FA fetal liver HSCs were rescued with TPO agonist administration. TPO deficiency no rescued FA FL HSC phenotype.

Conclusions

TPO signal confers developmental FA HSC deficit. Further investigation is needed to describe the mechanism and efficiency.

Introduction

In addition to direct cytotoxic effect of hypomethylaging agents (HMAs) on myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) cells, HMA upregulates effector T-cell function by demethylating T-cell exhaustion-associated genes (Hazem, Cell 2017) or trafficking effector T-cells to bone marrow (BM) by Th1-type chemokines activation (Peng, Nature 2019). We tried to elucidate dynamic changes of immune cells profile and gene expression after HMA treatment in patients with MDS or AML.

Methods

We performed scRNAseq on consecutive BM samples from an high-risk MDS (HR-MDS) patient treated with azacitidine: we categorized cell clusters based on immune-cell types, assessed changes in immune-cell proportions following treatment, and conducted a differentially expressed genes (DEG) analysis. In addition, changes in immune-cells proportions before vs. after HMA treatment in HR-MDS patients were evaluated, and the association between the immune-cell proportions changes and response to HMA were analyzed from seuqential BM aspirates from HR-MDS/AML patients.

Results

In the scRNAseq data, the NK-cell cluster exhibited the most significant increase in the relative proportion up to response, whereas the effector T-cells clusters showed only a modest increase of proportion upon HMA response. DEG revealed an overexpression of CXCR4 in the NK-cell cluster at the timepoint of response, suggesting the recruitment of NK cells to BM. The trafficking of NK cells to BM after HMA response were reproduced in serial BM aspirates from patients with HR-MDS/AML.

Conclusions

NK-cells recruited into BM through CXCR4 overexpression and anti-leukemic cytotoxicity exerted by NK cells may represent a crucial immunological mechanism of action for HMAs in patients with HR-MDS/AML.

Introduction

We report the full analysis of the COMMANDS trial assessing efficacy and safety of luspatercept versus epoetin alfa (EA) in ESA-naive patients with LR-MDS.

Methods

363 patients (aged ≥18 y, with transfusion-dependent LR-MDS, serum erythropoietin <500 U/L) were randomized 1:1 to luspatercept or EA. Primary endpoint was achievement of red blood cell transfusion independence (RBC-TI) ≥12 wk with concurrent mean hemoglobin increase ≥1.5 g/dL (wk 1–24). Secondary endpoints included achievement of RBC-TI ≥12 and 24 wk, hematologic improvement–erythroid (HI-E) ≥8 wk (wk 1–24), RBC-TI ≥12 wk duration, and safety.

Results

As of 31Mar2023, 110/182 (60.4%) luspatercept-treated versus 63/181 (34.8%) EA-treated patients achieved the primary endpoint (P<0.0001). Primary endpoint achievement favored luspatercept in most subgroups including region. Median (range) treatment duration was 51.3 (3–196) and 37.0 (1–202) wk for luspatercept versus EA. 68.1% and 48.6% of luspatercept- versus EA-treated patients, respectively, achieved RBC-TI ≥12 wk; 47.8% and 30.9% achieved RBC-TI 24 wk; 74.4% and 53.0% achieved HI-E ≥8 wk. Median (95% CI) duration of RBC-TI ≥12 wk was 128.1 wk (108.3–not estimable [NE]) with luspatercept versus 89.7 wk (55.9–157.3) with EA (HR, 0.534; Figure). 2.7% and 3.3% of luspatercept- and EA-treated patients, respectively, progressed to AML; 97.8% and 92.2% reported any-grade treatment-emergent adverse events (TEAEs); 58.5% and 49.2% reported grade 3/4 TEAEs. Death rates on- and post-treatment were similar between arms.

Conclusions

RBC-TI duration and erythroid responses achieved with luspatercept were superior to EA. Luspatercept safety results were consistent with previous MDS studies.