Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in mar- IntroductionMutations in genes encoding isocitrate dehydrogenase (IDH1/2) were recently discovered in acute myeloid leukemia (AML). 1,2 Their prognostic significance remains under investigation. [3][4][5][6][7][8][9] IDH proteins catalyze the oxidative decarboxylation of isocitrate to ␣-ketoglutarate (␣-KG). IDH mutations reside in the active site 10 and include missense alterations affecting arginine-132 (R132) in IDH1, and the analogous arginine residue (R172), or one at arginine-140 (R140), in IDH2. [1][2][3]5,6,8,11 The altered IDH proteins instead catalyze reduction of ␣-KG to the metabolite 2-hydroxyglutarate (2-HG). 12 2-HG is normally present at low levels in cells, 13 readily interconverted by 2-HG dehydrogenase to ␣-KG, 14,15 but IDH mutations promote its accumulation in myeloblasts and sera of affected patients. 10 No prior studies have prospectively measured 2-HG in IDHmutant AML during treatment. We focused on the utility of 2-HG as a potential biomarker of disease burden and sought to assess the effect of treatment on the trajectory and kinetics of 2-HG levels. To accomplish this, we serially measured serum, urine, marrow aspirate, and myeloblast 2-HG during conventional therapy for newly diagnosed AML. MethodsAdult patients at Massachusetts General Hospital, eligible for treatment of newly diagnosed AML, as defined by World Health Organization criteria, were enrolled. Samples were obtained through a protocol approved by our institution, Dana-Farber Harvard Cancer Center, its institutional review board, and the scientific review committees, with the approved protocol number 11-121. Informed consent was obtained per the Declaration of Helsinki.Serum, urine, and marrow samples were obtained for 2-HG measurement before therapy. Mononuclear cells from blood and marrow aspirate were isolated using density gradient centrifugation with Ficoll-Hypaque (GE Healthcare). 2-HG measurement was performed by Agios Pharmaceuticals, with methods previously described. 13,16 Serum and myeloblast 2-HG levels were considered elevated if Ͼ 1000 ng/mL or 1000 ng/2 ϫ 10 6 cells, respectively, as per previous reports. 10 In those with elevated baseline 2-HG, serum and urine were serially obtained for 2-HG measurement, at days 7, 14, 30, 60, and re...
Isolated myeloid sarcoma (MS) is a rare extramedullary presentation of acute myeloid leukemia (AML). Little is known about MS outcomes due to its rarity. A population-based analysis of MS using the Survival, Epidemiology, and End Results (SEER) database was performed. We identified 345 patients, aged 15 or older, diagnosed with isolated MS between 1973 and 2010. Overall survival (OS) was calculated and compared between MS and non-MS AML using the log-rank test. Survival was also evaluated based upon the primary site of disease presentation. The 3-year survival rate for MS (0.319; 95% confidence interval [CI]: 0.267-0.371) was greater than for non-MS AML (0.172; 95% CI: 0.168-0.175). There was variation in survival based on the site of involvement. The survival rates for isolated MS involving the pelvis/genitourinary organs, eyes/gonads and gastrointestinal mucosa appeared to be slightly improved when compared to primary sites of soft tissues, lymphatic/hematopoietic tissues or nervous system.
Key Points AE induces hematopoietic self-renewal through a COX/prostaglandin E2/β-catenin signaling pathway. Clinically available COX inhibitors may target AML stem cells and suppress AML of various karyotypes.
Objective: Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data. Design: Population-based cohort study in Alberta, Canada from 2012 to 2019. Methods: Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100,000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated. Results: A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5,196,368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100,000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60 to 79 years (8.85 and 14.68 cases per 100,000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >2-fold or normetanephrine >3-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100,000 people per year. Conclusion: The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.
Acute Myeloid Leukemia (AML) is more common and more lethal among patients over the age of 60. Increased body mass index (BMI) has been associated with a higher incidence of various malignancies, including AML. We sought to determine whether patient BMI at the time of AML diagnosis is related to overall survival among elderly patients. We identified 97 patients with AML diagnosed after the age of 60 and treated with cytarabine-based induction chemotherapy. The median age was 68 years (range 60-87); 52% of patients were male, and our study population was predominantly white (89% of patients). The median overall survival (OS) for all patients was 316 days (95% CI 246-459). The hazard ratio for mortality was increased among patients with a BMI < 25 compared to BMI ≥ 30 (HR 2.14, P=0.009, 95% CI 1.21-3.77), as well as with older age (HR 1.76, P=0.015, 95% CI 1.12-2.79) and with secondary versus de novo disease (HR 1.95, P=0.006, 95% CI 1.21-3.14). After multivariable analysis, we did not find a significant association between OS and other potential confounders such as coronary artery disease or diabetes among these patients. We conclude that increased BMI was independently associated with improved OS among older AML patients at our institution.
Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR1) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR1 breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme. The Oncologist 2014; 19:602-607 Implications for Practice: Isocitrate dehydrogenase (IDH) mutations have been identified in various hematologic and solid-tumor malignancies. To date, there are no published reports of these mutations in breast cancer. With this article, we describe a case of hormone receptor-positive adenocarcinoma of the breast with an IDH1 (p.R132L) mutation. The impacted patient had markedly elevated levels of serum and urine 2-hydroxyglutarate, an oncometabolite that accumulates as a result of the neomorphic activity of the altered IDH enzyme. IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, and these findings may carry future therapeutic implications, given the emergence of targeted therapies against the altered IDH protein.
• Infiltrating FLT3-ITD neutrophils identified in skin confirms terminal differentiation of FLT3-ITD blasts after FLT3 inhibitor therapy.• Neutrophilic dermatosis after FLT3 inhibition may be a manifestation of a differentiation syndrome associated with this treatment.The FLT3-ITD mutation is associated with poor outcomes in acute myeloid leukemia. Multiple FMS-like tyrosine kinase 3 (FLT3)-inhibitors have been studied in clinical trials. Recently, potent FLT3 inhibition was shown to induce terminal differentiation of FLT3-mutant myeloblasts. In 3 patients who developed characteristic skin nodules on initiation of FLT3-inhibition, we conducted dermatopathologic evaluation of skin samples, as well as FLT3 and NPM1 mutational analysis and fluorescence in situ hybridization. All 3 patients demonstrated characteristically deep dermal and subcutaneous neutrophilic infiltrates without evidence of myeloblasts. Discovery of FLT3-ITD and NPM1 mutations in 2 of the samples, as well as the presence of FLT3-ITD and deletion of 7q in the other, confirmed the ancestry of the differentiated neutrophils as that of the original FLT3-mutant myeloblasts. FLT3 inhibition can lead to clinically distinct dermatoses, which suggests the effect of FLT3 inhibition on myeloid differentiation and a manifestation of a broader "syndrome" associated with this therapy. (Blood. 2013;122(2):239-242)
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