A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia.

This phase I trial evaluated two schedules of escalating vorinostat in combination with decitabine every 28 days: (i) sequential or (ii) concurrent. There were three dose-limiting toxicities: grade 3 fatigue and generalized muscle weakness on the sequential schedule (n = 1) and grade 3 fatigue on the concurrent schedule (n = 2). The maximum tolerated dose was not reached on both planned schedules. The overall response rate (ORR) was 23% (three complete response [CR], two CR with incomplete incomplete blood count recovery [CRi], one partial response [PR] and two morphological leukemic free state [MLFS]). The ORR for all and previously untreated patients in the sequential arm was 13% (one CRi; one MLFS) and 0% compared to 30% (three CR; one CRi; one PR; one MLFS) and 36% in the concurrent arm (p = 0.26 for both), respectively. Decitabine plus vorinostat was safe and has clinical activity in patients with previously untreated acute myeloid leukemia. Responses appear higher with the concurrent dose schedule. Cumulative toxicities may limit long-term usage on the current dose/schedules.

Hepatic ALECT-2 amyloidosis causing portal hypertension and recurrent variceal bleeding: a case report and review of the literature.

OBJECTIVES: To examine laser microdissection and mass spectrometry (LMD-MS), which has emerged as a new tool to aid in typing amyloid proteins. RESULTS: ALECT-2 is a potential cause of hepatic amyloidosis best detected by LMD-MS. METHODS: One of the more recently reported proteins is ALECT-2 (leukocyte cell-derived chemotaxin 2) amyloid, found in renal specimens of Hispanic patients. Here we report the first case of hepatic ALECT-2 amyloidosis diagnosed by LMD-MS from a liver biopsy specimen of a 52-year-old Hispanic man and causing portal hypertension with recurrent esophageal variceal bleeding. CONCLUSIONS: ALECT-2 can cause amyloidosis in organs other than the kidneys. It should be strongly considered in Hispanic patients and in those with a globular pattern of amyloid deposition. The incidence of ALECT-2 amyloidosis is likely underreported.

Comprehensive analysis and identification of the human STIM1 domains for structural and functional studies.

STIM1 is a Ca(2+) sensor within the ER membrane known to activate the plasma membrane store-operated Ca(2+) channel upon depletion of its target ion in the ER lumen. This activation is a crucial step to initiate the Ca(2+) signaling cascades within various cell types. Human STIM1 is a 77.4 kDa protein consisting of various domains that are involved in Ca(2+) sensing, oligomerization, and channel activation and deactivation. In this study, we identify the domains and boundaries in which functional and stable recombinant human STIM1 can be produced in large quantities. To achieve this goal, we cloned nearly 200 constructs that vary in their initial and terminal residues, length and presence of the transmembrane domain, and we conducted expression and purification analyses using these constructs. The results revealed that nearly half of the constructs could be expressed and purified with high quality, out of which 25% contained the integral membrane domain. Further analyses using surface plasmon resonance, nuclear magnetic resonance and a thermostability assay verified the functionality and integrity of these constructs. Thus, we have been able to identify the most stable and well-behaved domains of the hSTIM1 protein, which can be used for future in vitro biochemical and biophysical studies.

Influence of FLT3-internal tandem duplication allele burden and white blood cell count on the outcome in patients with intermediate-risk karyotype acute myeloid leukemia.

BACKGROUND: In patients with acute myeloid leukemia (AML), testing for fms-like tyrosine kinase-3 (FLT3)-internal tandem duplication (FLT3-ITD) and nucleophosmin-1 (NPM1) mutations can allow for further prognostic subclassification, but less is known about the effects of FLT3-ITD allele burden and presenting white blood cell count (WBC) within molecular subgroups. METHODS: The authors retrospectively assessed 206 adult patients who had AML with an intermediate-risk karyotype and who received treatment on a uniform induction and consolidation chemotherapy regimen. RESULTS: The presenting WBC was a prognostic factor for survival only in patients who had an FLT3-ITD mutation. On multivariate analysis, after correcting for age, WBC, secondary AML, and blast percentage, nucleophosmin-1 (NPM1)-mutated/FLT3-ITD-negative patients had superior overall survival compared with patients in the other molecular subgroups. Patients who had FLT3-ITD mutations had an inferior overall survival compared with patients who had NPM1 wild-type/FLT3-negative disease, and patients who had low or intermediate levels of the FLT-ITD of mutant allele had overall and disease-free survival similar to those in patients who had high-level mutations. CONCLUSIONS: NPM1 and FLT3-ITD status, age, WBC, and secondary AML were identified as important prognostic variables that can help to risk stratify patients with AML who have intermediate-risk cytogenetics. FLT3 allele burden had no significant influence on outcomes after correcting for other variables.

ENMD-2076 for hematological malignancies.

INTRODUCTION: Aurora kinases are key regulators of mitosis and inhibition of Aurora kinase activity is a rational therapeutic strategy in the treatment of solid tumors and hematological malignancies. AREAS COVERED: This paper will provide an updated summary of preclinical and clinical experience with ENMD-2076 in hematological malignancies. The MEDLINE (OVID) (1980 through 31 January 2012) was searched with the term combinations including Aurora, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome and myeloproliferative neoplasms. In addition, the American Society of Clinical Oncology (ASCO) (1997 - 2011) and the American Society of Hematology (ASH) (1997 - 2011) conference proceedings were searched for reports of new or ongoing trials. EXPERT OPINION: ENMD-2076 is a multi-kinase inhibitor, with activity against Aurora A kinase, FLT3, c-KIT, c-FMS and VEGFR-2 and -3. It appears to be tolerable, exhibits favorable pharmacokinetic profiles and has activity in patients with acute myeloid leukemia and multiple myeloma. Further evaluation with cytotoxic chemotherapy and targeted agents, which affect different pathways and have non-overlapping toxicities, in patients with hematological malignancies are warranted.