Ashley M. Perry

Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate.

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 (HR+) 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 patients serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ 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.

Presentation and outcomes among patients with isolated myeloid sarcoma: a Surveillance, Epidemiology, and End Results database analysis

Abstract 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.

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.

BACKGROUND Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. METHODS In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. RESULTS We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. CONCLUSION Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. IMPLICATIONS FOR PRACTICE Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.

Population-based disparities in survival among patients with core-binding factor acute myeloid leukemia: a SEER database analysis.

We performed a retrospective population-based study using the SEER database to assess survival trends in CBF-AML between 2000 and 2010. Median OS increased from 16 months in 2000-2002 to 25 months in 2006-2008 (P=0.002). The 3-year OS rate for patients with inv(16) was 57.3%, but in t(8;21) was only 35.5%. Patients aged 75-84 had worse survival than patients aged 15-44 (HR 5.61, P=0.0002). Black race was associated with higher mortality (HR 1.50, P=0.03). Compared to clinical trial outcomes, CBF-AML survival is poorer in the general population, particularly among African Americans and the elderly, and in t(8;21) compared to inv(16) AML.

New insights in AML biology from genomic analysis.

Advancements in sequencing techniques have led to the discovery of numerous genes not previously implicated in acute myeloid leukemia (AML) biology. Further in vivo studies are necessary to discern the biological impact of these mutations. Murine models, the most commonly used in vivo system, provide a physiologic context for the study of specific genes. These systems have provided deep insights into the role of genetic translocations, mutations, and dysregulated gene expression on leukemia pathogenesis. This review focuses on the phenotype of newly identified genes, including NPM1, IDH1/2, TET2, MLL, DNMT3A, EZH2, EED, and ASXL1, in mouse models and the implications on AML biology.

Association between insurance status at diagnosis and overall survival in chronic myeloid leukemia: A population-based study

Chronic myeloid leukemia (CML) can be treated effectively with tyrosine kinase inhibitor therapy directed at BCR‐ABL, but access to care, medication cost, and adherence may be barriers to treatment. This study was designed to determine whether the insurance status at diagnosis influences CML patient outcomes.

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring “5+2” reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68–96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33–81%) and 42% (90% CI 17–65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation

Cabozantinib, a tyrosine kinase inhibitor of FMS‐like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up‐regulation of multiple relevant pathways.

Early infectious complications among patients treated with induction compared to hypomethylating therapy for acute myeloid leukemia

The lethality of acute myeloid leukemia (AML) is often associated with infectious complications, caused either by direct disruption of normal hematopoiesis by the disease or by marrow suppression during its treatment [1,2]. Conventional upfront therapy frequently incorporates cytarabine and an anthracycline to induce remission, a common example being ‘7þ 3’ induction chemotherapy. Induction causes profound cytopenias and may carry unacceptably high treatment-related morbidity and mortality among certain populations, such as those with advanced age, significant comorbidity, or compromised functional status. In the last decade, the hypomethylating agents (HMAs) 5-azacytidine and decitabine have emerged as tolerable and effective therapies for less robust patients [3,4]. Although HMAs are felt to be better tolerated than conventional induction for these populations [4–7], few studies have directly compared these strategies in terms of safety and tolerability. Infectious complications are an important consideration for the tolerability of AML therapy, particularly given the rate of infection with standard induction. It is known that bacterial and fungal infections predominate [8–10], although the spectrum of these complications can vary according to choice and extent of antimicrobial prophylaxis [8–10], baseline immune status [2], and local flora. Less is known regarding how infectious complications may differ according to initial treatment with HMA therapy vs. induction. We performed a retrospective cohort study of patients with newly diagnosed AML to compare the incidence and timing of infectious complications among those receiving HMA vs. conventional 7þ 3 therapy. We identified adults aged 18 or older, newly diagnosed with AML, seen at Massachusetts General Hospital (MGH) between 1 January 2010 and 30 June 2014, and initially treated with either ‘7þ 3’-based induction (‘induction’ group) or HMA therapy (‘HMA’ group). We excluded patients with acute promyelocytic leukemia, those initially treated at a different institution, and those receiving supportive care alone or experimental treatments without an induction or HMA component. We collected relevant patient data from the electronic medical record. Secondary AML was defined as AML in a patient with a prior myeloid neoplasm or prior exposure to chemotherapy or radiotherapy. Cytogenetic risk was documented as per the National Cancer Research Institute Adult Leukaemia Working Group [11]. This study was approved by the institutional review board prior to initiation. Febrile neutropenia (FN) was defined as temperature over 38.0 C (100.4 F), with an absolute neutrophil count of less than 500/mm, regardless of culture data. Bacteremia and fungemia were identified by blood culture data and clinical findings. Pneumonias were identified by culture or imaging data, as per Infectious Diseases Society of America guidelines [12]. Cellulitis, neutropenic colitis or typhlitis, and mucositis were diagnosed as per the judgment of the treating physician based on clinical data. Clostridium difficile colitis and urinary tract infection (UTI) were diagnosed as per the treating physician according to stool and urine cultures. Grade IV infections were defined using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 [13]. Patients were considered at risk for infectious complications starting at the day of treatment initiation. Time to infection was calculated from day 1 of AML treatment to documentation of infection. Patients were censored at death, date last known alive (LKA), date of salvage therapy, or on the date of hematopoietic cell transplantation (HCT). The primary outcome was 30-day and 60-day infectious event rates. Continuous and ordinal variables were compared using Wilcoxon and Fisher’s exact test, as appropriate. The cumulative incidence of infection was performed

Chromosome 17p deletion in a case of T-cell acute lymphoblastic lymphoma

A 25-year-old, previously healthy female presented with pleuritic chest pain, dyspnea, and dry cough. Auscultation of the lungs demonstrated an absence of breath sounds on the left. Imaging with computed tomography (CT) and positron emission tomography (PET) modalities confirmed a large pleural effusion, but also revealed an anterior PET-avid mediastinal mass, measuring 11.2 cm by 6.0 cm, with a small pericardial effusion. There was also near-complete opacification of the left lung and a rightward mediastinal shift with displacement of adjacent structures. She was hospitalized and underwent placement of a left pleural chest tube. The pleural fluid was exudative and cellular, consisting of 12% atypical lymphoid cells expressing cytoplasmic CD3, CD7, CD34, but not surface CD3 or TdT. She then underwent a biopsy of a left internal mammary node, with pathological evaluation confirming a diagnosis of T-cell acute lymphoblastic lymphoma (Image 1A). Cytogenetic analysis revealed multiple abnormalities including a chromosome 17p deletion (Image 1B), which was confirmed by interphase fluorescence in situ hybridization (FISH) demonstrating p53 deletion in 88% of nuclei (Image 1C). An immunostain for p53 showed positive staining in approximately 2% of tumor