Waksal, Julian A.Harrison, Claire N.Mascarenhas, John O.
14页
查看更多>>摘要：Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.
查看更多>>摘要：High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or both, commonly called double-hit lymphoma (DHL), is an aggressive B-cell lymphoma that is molecularly distinct from diffuse large B-cell lymphoma (DLBCL) and is associated with poor outcomes. Recent advances in the molecular classification of DLBCL have identified distinct subsets, including genetic signatures which correlate with DHL and survival. DHL with concomitant TP53 mutation appears to be associated with a very poor prognosis. Standard chemo-immunotherapy is not an effective treatment for these patients and personalized, innovative strategies are needed. In this review, we summarize recent advances in the subclassification of DLBCL, with a focus on DHL. We also incorporate early, promising clinical trial data using CAR T and targeted therapies. Rationally designed clinical trials for DLBCL are needed to advance the care of patients with DHL and other adverse risk DLBCL subgroups.
查看更多>>摘要：Acute myeloid leukemia (AML) is a group of genetically complex and heterogeneous invasive hematological malignancies with a low 5-year overall survival rate of 30%, which highlights the urgent need for improved treatment measures. RNA-binding proteins (RBPs) regulate the abundance of isoforms of related proteins by regulating RNA splicing, translation, stability, and localization, thereby affecting cell differentiation and self-renewal. It is increasingly believed that RBPs are essential for normal hematopoiesis, and RBPs play a key role in hematological tumors, especially AML, by acting as oncogenes or tumor suppressors. In addition, targeting an RBP that is significantly related to AML can trigger the apoptosis of leukemic stem cells or promote the proliferation of stem and progenitor cells by modulating the expression of important pathway regulatory factors such as HOXA9, MYC, and CDKN1A. Accordingly, RBPs involved in normal myeloid differentiation and the occurrence of AML may represent promising therapeutic targets.
查看更多>>摘要：We report efficacy, safety and biomarker data from a phase-II study evaluating atezolizumab (eight 21-day cycle as induction therapy) in combination with obinutuzumab in patients with relapsed/refractory mantle cell lymphoma (MCL, n = 30) or Waldenstrom's macroglobulinemia (WM, n = 4), and in combination with rituximab in patients with marginal zone lymphoma (MZL, n = 21). All patients received atezolizumab monotherapy as maintenance for <= 10 cycles. Objective response rates at end of induction were 16.7% (MCL) and 42.9% (MZL), with no responses in WM. Median duration of response was 6.8 months (range 5.7-not estimable) for MCL and not reached for MZL. Treatment-emergent adverse events (TEAEs) occurred in 93.3%, 95.2% and 100% of MCL, MZL and WM patients, respectively. One fatal TEAE (pneumonia) occurred in each of the MCL and MZL groups. Biomarker analysis highlighted the importance of characterizing the immune environment to optimize efficacy of immunotherapy regimens.
Amaador, KarimaVos, Josephine M., IPals, Steven T.Kraan, Willem...
10页
查看更多>>摘要：Discrimination between Waldenstrom macroglobulinemia (WM) and marginal zone lymphoma (MZL) of the bone marrow (BM) can be difficult due to overlap in clinical, histopathologic, and immunophenotypic characteristics. We determined which characteristics can aid in the differential diagnosis of 'gray zone' cases. We compared clinical, histopathologic, immunophenotypic, and molecular features of 222 WM and 65 MZL patients. LASSO regression was employed for variable selection. The most distinguishing clinical features of WM compared to MZL were the presence of the B-symptom weight loss and IgM paraprotein. Histopathological findings were plasmacytoid differentiation, monoclonal plasma cells, and increased mast cells in the BM. Regarding flow cytometry, only CD10 and CD38 were distinguishing markers. Finally, as the expected presence of the MYD88(L265P) mutation showed to be of great value in the distinction between WM and MZL. Despite the great overlap, WM can often be distinguished from MZL by using a combination of characteristics. These characteristics should be weighed in complex, 'gray zone' cases.
查看更多>>摘要：BCOR is a component of a variant Polycomb repressive complex 1 (PRC1.1). PRC1 and PRC2 complexes together constitute a major gene regulatory system critical for appropriate cellular differentiation. The gene is upregulated in germinal center (GC) B cells and mutated in a number of hematologic malignancies. We report BCOR inactivating alterations in 4/7 classic Hodgkin lymphoma (cHL) cell lines, subclonal somatic mutations in Hodgkin and Reed-Sternberg (HRS) cells of 4/10 cHL cases, and deletions in HRS cells of 7/17 primary cHL cases. In mice, conditional loss of Bcor driven by AID-Cre in GC B cells resulted in gene expression changes of 46 genes (>2-fold) including upregulated Lef1 that encodes a transcription factor responsible for establishing T-cell identity and Il9r (interleukin-9 receptor), an important member of the cytokine network in cHL. Our findings suggest a role for BCOR loss in cHL pathogenesis and GC-B cell homeostasis.
Abrahao, RenataBrunson, Ann M.Kahn, Justine M.Li, Qian W....
11页
查看更多>>摘要：We compared secondary primary malignancy risk (SPM) in HIV-uninfected and HIV-infected Hodgkin lymphoma (HL) survivors. We used data from the California Cancer Registry on patients diagnosed with HL from 1990 to 2015 (all ages included), and standardized incidence ratios (SIRs) and multivariable competing risk models for analyses. Of 19,667 survivors, 735 were HIV-infected. Compared with the general population, the risk of SPM was increased by 2.66-fold in HIV-infected and 1.92-fold in HIV-uninfected survivors. Among HIV-infected survivors, median time to development of SPM was shorter (5.4 years) than in HIV-uninfected patients (8.1 years). Additionally, the highest risk of SPM was observed <2 years after diagnosis in HIV-infected survivors (SIR = 4.47), whereas risk was highest >= 20 years after diagnosis (SIR = 2.39) in HIV-uninfected survivors. The risk of SPMs persisted for decades and was higher among HIV-infected survivors, suggesting that these patients should benefit from long-term surveillance and cancer prevention practices.
查看更多>>摘要：Carfilzomib (Cfz) is widely used to treat multiple myeloma. However, real-world data of the incidence of thrombotic microangiopathy (TMA) caused by Cfz is inconsistent (<1-5%). We evaluated 96 consecutive patients who received Cfz to evaluate the incidence of TMA in clinical practice. TMA developed in five patients (5.2%) who were mainly receiving high-dose Cfz (>= 56 mg/m(2)). Based on a literature review, precaution should be taken for Cfz-induced TMA in male patients receiving high-dose Cfz irrespective of the combination therapy, Cfz administration period, and complement level. In conclusion, Cfz-induced TMA might be underestimated in clinical practice, and early intervention should be considered.
查看更多>>摘要：This multi-centric prospective study (InPOG-HL-15-01) assessed epidemiological, clinical and outcome data of advanced stage Hodgkin Lymphoma (IIB, III and IV) in children and adolescents (N = 262). Chemotherapy regimen was ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and radiotherapy (RT) was restricted to patients with bulky disease at diagnosis or with suboptimal response at early response assessment (ERA). ERA revealed complete response in 175 (68.1%), partial response in 77 (29.9%), stable disease in 2 (0.8%), and progressive disease in 3 (1.2%) patients. RT was administered to 111 (97 bulky disease, 14 suboptimal response) patients. Five-year event free (EFS) and overall survival for the whole cohort was 81.1% and 90.8% respectively. On multivariate analysis, the only statistically significant predictor of EFS was use of RT (89% versus 74.2%; p-value <0.001). This study reinforces the benefit of consolidative RT in bulky disease and in those with suboptimal response at ERA on an ABVD backbone.
NSTL
Taylor & Francis