Advances in Hemophilia A Management.

Hemophilia A is an inherited insufficiency of Factor VIII (FVIII), one of the critical clotting factors. The gold standard for the management of moderate-to-severe hemophilia A is prophylaxis using regular replacement therapy with clotting factor concentrates. Compared with conventional treatment, extended half-life products reduce the burden of frequent factor replacement injections. Of note, up to 30% of patients with hemophilia A receiving prophylactic factor infusions develop "inhibitors," neutralizing anti-FVIII autoantibodies. Therapeutic options for patients with hemophilia A and inhibitors include the immune tolerance induction (ie, eradication of inhibitors) and the management of acute bleeds with bypassing agents and/or emicizumab. Emicizumab is a biphasic monoclonal antibody mimicking activated FVIII, approved for patients with hemophilia A with/without inhibitors. Gene therapy is an emerging therapy for hemophilia A, essentially curing patients with hemophilia A or transforming them to a milder phenotype by establishing continuous endogenous expression of FVIII after one-time treatment.

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

BACKGROUND: 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. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. RESULTS: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells. CONCLUSIONS: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.

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

BACKGROUND: 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. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 5784 patients, aged 15 years or older, who were diagnosed with CML between 2007 and 2012 and whose insurance status was documented at diagnosis. The primary outcome was 5-year overall survival (OS). Covariates of interest included the age at diagnosis, race, ethnicity, sex, county-level socioeconomic status, and marital status. OS was evaluated with a log-rank test and Kaplan-Meier estimates. RESULTS: Among patients aged 15 to 64 years, insurance status was associated with OS (P < .001): being uninsured or having Medicaid was associated with worse 5-year OS in comparison with being insured (uninsured patients, 72.7%; Medicaid patients, 73.1%; insured patients, 86.6%). For patients who were 65 years old or older, insurance had less of an impact on OS (P = .07), with similar 5-year OS rates for patients with Medicaid and those with other insurance (40.2% vs 43.4%). In a multivariate analysis of patients aged 15 to 64 years, both uninsured patients (hazard ratio [HR], 1.93; P < .001) and Medicaid patients (HR, 1.83; P < .001) had an increased hazard of death in comparison with insured patients; patients younger than 40 years, female patients, and married patients also had a lower hazard of death. CONCLUSION: These findings suggest that CML patients under the age of 65 years who are uninsured or have Medicaid have significantly worse survival than patients with other insurance coverage. Cancer 2017;123:2561-69. © 2017 American Cancer Society.

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).

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.

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

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.

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.

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.