Bosutinib is a tyrosine kinase inhibitor approved for the management of chronic myeloid leukemia (CML). Interstitial lung disease and pleural effusion are pulmonary side effects of TKIs rarely ...associated with bosutinib treatment.
Bosutinib is a tyrosine kinase inhibitor approved for the management of chronic myeloid leukemia (CML). Interstitial lung disease and pleural effusion are pulmonary side effects of TKIs rarely associated with bosutinib treatment.
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of ...pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
subspecies
is a beta-haemolytic, group C streptococcal bacterium. Although it is an opportunistic pathogen commonly found in horses, transmission to human can lead to severe infections. Here, we ...present a patient with
subspecies
bacteraemia and consequent development of mycotic aneurysms.
Introduction
Thromboses are a common complication in patients with myeloproliferative neoplasms (MPN) and are reported to occur at a rate of 15- 20% at sea level. In the MPN-Thromboses spectrum which ...includes both arterial and venous thrombosis, cardiovascular disease (CVD) is noted to be the most common thrombotic event. JAK2 V617F is reported to be the most common driver mutation in MPNs and is associated with increased risk of thromboses. CALR and MPL are other mutations whose contribution to the thrombotic phenotype is not known. Chronic hypoxia from living in moderate or high altitude is reported to be an independent prothrombotic risk factor. The average elevation of New Mexico is 5,700 feet (1,740 meters) above sea level. The goal of this study is to evaluate the frequency of thromboses and prothrombotic risk factors in patients with MPN in patients in this distinct population.
Methods
We reviewed 134 patients, who were diagnosed with MPN in University of New Mexico Comprehensive Cancer Center between 2001 to 2019. A retrospective chart review was conducted to identify demographics, clinical and molecular risk factors for both arterial and venous thromboses. The mutation analyses for Janus Kinase 2 (JAK2), myeloproliferative leukemia (MPL) gene and calreticulin (CALR) gene were performed by polymerase chain reaction (PCR). Contingency table and logistic regression methods were applied to analyze and compare the distribution of the prothrombotic risk factors between the patients with and without thrombosis.
Results
In this study, 62 patients (47%) were diagnosed with ET, 47 patients (35%) with PV, and 22 patients (17%) with primary myelofibrosis (PMF). Seventy-five patients (56%) were females. Mean age at diagnosis was 62 years. 102 patients (77%) were living in the Albuquerque metropolitan area with an average elevation of 5312 feet above sea level and others were in areas with an elevation of 6000 feet or higher in New Mexico. Forty-four patients (33%) experienced either arterial (29) or venous thromboses (11) or both (4). A significant percentage (70.4%) of thrombotic events were either ischemic stroke or myocardial infarction.
The patients with thromboses were predominantly males (21/36, 57%) while most patients without thromboses were females (56/90, 62%) with p=0.003. Twenty-one (53%) patients with thromboses had ET; however, a higher proportion of patients with PV (20/47, 42.5%) developed thromboses compared to ET or PMF (32.2% and 9% respectively). Also, a significant number of patients (32/44, 76%) with thromboses have JAK2 mutations while only 4 patients (9%) have CALR gene mutation. Although not statistically significant, CALR mutation was associated with lesser thrombotic events than other MPN patients.
In univariate logistic regression analysis, PV and ET were significantly associated with increased thrombotic events. Patients with PV showed a 7.7-fold increase and patients with ET have a 5.1-fold increase in odds for thrombosis compared to patients with PMF (p=0.0365). Female gender was associated with decreased thrombotic risk with an odds ratio of 0.46 (p=0.0387). There was no significant difference between patients with and without thromboses, regarding other clinical characteristics such as age, previous aspirin use, leukocytosis, diabetes, hypertension, hyperlipidemia, obesity, and smoking.
Conclusion
An increased frequency of thromboses was observed among patients with Ph negative MPN in New Mexico which is significantly higher than previously reported studies. This strongly suggests the role of mild to moderate hypoxia as a contributing prothrombotic risk factor for MPN. The role of chronic hypoxia and its influence in thrombotic events in MPN need to be further evaluated in prospective studies. The decreased risk of thrombosis in females and patients harboring CALR mutations compared to other common mutations was consistent with other published studies. JAK2 mutation was not associated with an increased risk of thrombosis. Other genetic factors in this population were not evaluated in this study.
Display omitted
Arana Yi:Jazz Pharmaceuticals: Other: Advisory Board.
Comparative Analysis for Effectiveness of Azacitidine versus Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes with Marrow Fibrosis: A Single Institution Experience
Ala Ebaid, MD1, ...Shashank Cingam, MD1, Quiying Liu, MD2, Khine Z Win3, MD, Daniel Babu, MD4, Tawny Boyce, MS, MPH4, Cecilia Arana-Yi, MD1
Department of Internal Medicine, Hematology/Oncology, University of New Mexico, Albuquerque, NM.
Department of Internal Medicine, University of New Mexico, Albuquerque, NM.
University of California San Francisco.
University of New Mexico and Tricore Reference Laboratories
Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, NM.
Introduction
The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DEC) are used clinically for the management of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML); however, treatment responses and survival outcomes are very limited. Bone marrow fibrosis (MF) is present in 10-20% of MDS/AML and is predictor of poor responses to azacitidine and dismal survival outcomes. Genetic abnormalities including TP53 accumulation, WT1 gene expression, increased CXCL9 and CXCL10 among others contribute to the etiology of MF. The impact of MF in therapeutic responses and survival to AZA versus DEC has not been previously assessed.
Methods
Retrospective chart review of cases from 2000-2019 at UNM Cancer Center to identify clinical characteristics, cytogenetic, molecular status, treatment and overall survival. AML patients were risk stratified according to ELN risk category, and MDS patients based on their IPSS-R scoring system. 142 bone marrow samples were analyzed for marrow fibrosis with hematoxylin and eosin-stained slides and confirmed with trichrome staining at Tricore Reference lab. 92 AML patients had a complete cytogenetics analysis.
The goal of this study is to evaluate the clinical, pathologic characteristics and survival outcomes of AML and MDS patients with and without MF treated with AZA compared to DEC at the University of New Mexico Comprehensive Cancer Center.
Results
142 patients with MDS (n=45, 31.7%) and AML (n=97, 68.3%) treated with AZA (n=85) 59.9%, and DEC (n=57) 40.1%. 45 patients have MF (31.7%) vs. 97 patients without MF (68.3%).
39.4% (n=56) were females, 31.7% had MDS (n=45), 68.3% had AML (n=97) and 31.7% (n=45) had MF.
The median age at diagnosis was 69.5 years for the AZA group and 68 years for the DEC group. In AML group there was 20 (20.8%) patients with high-risk cytogenetics and 38 (39.6%) with diploid cytogenetics. There was no statistical difference between the MF degree and the cytogenetics of the patients.
In the MDS group 9 patients (20%) with very low risk IPSS, 16 (35.6%) low risk, 13 (28.9%) intermediate and 13 (15.5%) patients with high and very high risk IPSS. In the fibrosis group 21 patients (46.7%) had low grade and 24 patients (53.3%) had high grade (MF2 and MF3). There were no significant differences in MF degree and IPSS or ELN categories.
Median duration of treatment was 3.2 months and median number of treatment cycles was 4 for AZA and 3 for DEC. There was no significant difference in median overall survival between two groups (AZA 18 months vs DEC 17 months, p=0.3355). Median overall survival was not significant in AZA group with de novo AML patients (AZA 19 months versus DEC 15 months, p=0.3013).
There were no OS differences in AML and MDS patients with MF. (Figure 1) Patients with MF on AZA had a trend toward better OS compared to DEC. (Figure 2) In MDS and AML, younger than 65 years old had better OS compared to older than 65 years. (p=0.011) In AML, TP53 mutation was associated with worsening survival outcomes. (median OS 2m vs 18m, p=0.0238)
Conclusions
The frequency of MF was 46.7% in MDS and 24.7 % of AML cases, higher than reported in other studies. However, MF did not affect survival outcomes of MDS/AML treated with AZA or DEC. Although non-statistically significant, MF cases had a trend towards better survival on AZA compared to DEC. The presence of TP53 was associated with decreased survival in AML patients with fibrosis.
Our study confirms that MF is a common feature in MDS/AML in New Mexico, but does not influence survival outcomes in patients treated with AZA or DEC.
Display omitted
Arana Yi:Jazz Pharmaceuticals: Other: Advisory Board.
In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive ...monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective small-molecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors. This sensitivity was observed in samples with varying genetic and clinical backgrounds, although higher white cell count and monocyte cell percentage was associated with increased sensitivity. Depleting CD14-expressing monocytes preferentially decreased viability in samples sensitive to CSF1R inhibitors, and treating samples with CSF1R inhibitors eliminated the presence of NLCs in long-term culture conditions. These results indicate that CSF1R small-molecule inhibitors target CD14-expressing monocytes in the CLL microenvironment, thereby depriving leukemia cells of extrinsic support signals. In addition, significant synergy was observed combining CSF1R inhibitors with idelalisib or ibrutinib, two current CLL therapies that disrupt tumor cell intrinsic B-cell receptor signaling. These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination.
Type B lactic acidosis is a rare metabolic complication of malignancy, more commonly in haematological malignancies. Due to the lack of formal prospective trials, treatment of lactic acidosis ...associated with malignancy is based on case reports. Given the poor prognosis, early recognition of type B lactic acidosis and prompt treatment are crucial. We report the first case of type B lactic acidosis in metastatic melanoma, followed by a brief literature review on the proposed pathophysiology and treatment.
Despite significant therapeutic progress in multiple myeloma, drug resistance is uniformly inevitable and new treatments are needed. Our aim was to identify novel, efficacious small-molecule ...combinations for use in drug resistant multiple myeloma.
A panel of 116 small molecule inhibitors was used to screen resistant myeloma cell lines for potential therapeutic targets. Agents found to have enhanced activity in the bortezomib or melphalan resistant myeloma cell lines were investigated further in combination. Synergistic combinations of interest were evaluated in primary patient cells.
The overall single-agent drug sensitivity profiles were dramatically different between melphalan and bortezomib resistant cells, however, the bromodomain inhibitor, CPI203, was observed to have enhanced activity in both the bortezomib and melphalan resistant lines compared to their wild-type counterparts. The combination of bortezomib and CPI203 was found to be synergistic in both the bortezomib and melphalan resistant cell lines as well as in a primary multiple myeloma sample from a patient refractory to recent proteasome inhibitor treatment. The CPI203-bortezomib combination led to enhanced apoptosis and anti-proliferative effects. Finally, in contrast to prior reports of synergy between bortezomib and other epigenetic modifying agents, which implicated MYC downregulation or NOXA induction, our analyses suggest that CPI203-bortezomib synergy is independent of these events.
Our preclinical data supports a role for the clinical investigation of the bromodomain inhibitor CPI203 combined with bortezomib or alkylating agents in resistant multiple myeloma.
PDF
