Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib.

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia.

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis.

Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities.

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib.

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy.

Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia.

Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML.

Unique amplification of BCR-ABL1 gene fusion in a case of T-cell acute lymphoblastic leukemia.

Background: ABL1 gene translocations can be seen in precursor T-acute lymphoblastic leukemia (T-ALL). The typical translocation partner is the NUP214 gene. BCR-ABL translocations are relatively rare in this entity.

Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone - A novel class of compounds with potent activity against acute myeloid leukemia cells.

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported.

Comparative Analysis of Methods for Detecting Isocitrate Dehydrogenase 1 and 2 Mutations and Their Metabolic Consequence, 2-Hydroxyglutarate, in Different Neoplasms.

Isocitrate dehydrogenase (IDH) mutations have been recognized in a few neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The direct methods to detect IDH mutations include DNA sequencing, immunohistochemistry (IHC), or by measuring its byproduct, 2-hydroxyglutarate (2-HG), in the blood or urine. Moreover, conventional magnetic resonance imaging can be modified to magnetic resonance spectroscopy (MRS) to measure 2-HG in tumor.

Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity.

Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors.

Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan.

Hydroxylated Dimeric Naphthoquinones Increase the Generation of Reactive Oxygen Species, Induce Apoptosis of Acute Myeloid Leukemia Cells and Are Not Substrates of the Multidrug Resistance Proteins ABCB1 and ABCG2.

Selective targeting of the oxidative state, which is a tightly balanced fundamental cellular property, is an attractive strategy for developing novel anti-leukemic chemotherapeutics with potential applications in the treatment of acute myeloid leukemia (AML), a molecularly heterogeneous disease. Dimeric naphthoquinones (BiQs) with the ability to undergo redox cycling and to generate reactive oxygen species (ROS) in cancer cells are a novel class of compounds with unique characteristics that make them excellent candidates to be tested against AML cells. We evaluated the effect of two BiQ analogues and one monomeric naphthoquinone in AML cell lines and primary cells from patients.

Perturbation of cellular oxidative state induced by dichloroacetate and arsenic trioxide for treatment of acute myeloid leukemia.

The incidence of acute myeloid leukemia (AML) is rising and the outcome of current therapy, which has not changed significantly in the last 40 years, is suboptimal. Cellular oxidative state is a credible target to selectively eradicate AML cells, because it is a fundamental property of each cell that is sufficiently different between leukemic and normal cells, yet its aberrancy shared among different AML cells. To this end, we tested whether a short-time treatment of AML cells, including cells with FLT3-ITD mutation, with sub-lethal dose of dichloroacetate (DCA) (priming) followed by pharmacologic dose of arsenic trioxide (ATO) in presence of low-dose DCA could produce insurmountable level of oxidative damage that kill AML cells.

First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors.

Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors. The pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of filanesib were also evaluated.

Disparities in black and white patients with multiple myeloma referred for autologous hematopoietic transplantation: a single center study.

Background: Racial disparity in the incidence of multiple myeloma is well established; however, to the authors' knowledge, little is known regarding the impact of racial differences on disease characteristics, response to therapy, and clinical outcome.

Methods: The authors studied 453 patients (174 of whom were black and 279 of whom were white) who underwent transplant between 2000 and 2013. The median follow-up was 4.

Treatment of catheter-related deep vein thrombosis in patients with acute leukemia with anticoagulation.

Patients with acute leukemia develop venous thrombosis (VT) related to central venous catheters (CVCs). Anticoagulation (AC) in these patients who are thrombocytopenic and often coagulopathic is challenging. To evaluate the safety and efficacy of AC in treating CVC-related VT, we retrospectively compared outcomes of patients with acute leukemia who were treated or not with AC during induction chemotherapy and post-discharge.

A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms.

Purpose: To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations.

Methods: Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels.

Asparaginase in the treatment of non-ALL hematologic malignancies.

Asparaginases are among the most effective agents against acute lymphoblastic leukemia (ALL) and are Food and Drug Administration-approved for the treatment of pediatric and adult ALL. However, the efficacy of these drugs for the treatment of other hematologic malignancies particularly acute myeloid leukemia is not well established. The mechanism of action of asparaginases has thought to be related to a swift and sustained reduction in serum L-asparagine, which is required for rapid proliferation of metabolically demanding leukemic cells.

Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy.

We retrospectively reviewed outcomes in 45 previously untreated patients with acute myeloid leukemia (AML) considered unfit for chemotherapy who were treated with 10-day courses of decitabine 20 mg/m(2) daily outside of a clinical trial, with no cut-offs for organ function or performance status (PS). Nineteen had Eastern Cooperative Group performance status (ECOG PS) ≥ 2, and 39 had ≥ 2 comorbidities. Fourteen patients (31%) achieved complete remission (CR) and five (11%) CR with incomplete count recovery, for an overall response rate of 42%, after a median of 2 (range, 1-4) courses.

PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer.

Purpose: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.

Schistocytes, echinocytes, iron deficiency anemia, and thrombocytopenia - hematologic manifestations of splenic angiosarcoma.

Splenic angiosarcoma is a rare and aggressive malignancy with an incidence of less than one per million and a fatality rate over 90%.  Early diagnosis is of great importance for optimal management.  Here, we report the case of a patient with splenic angiosarcoma who presented with prominent schistocytes, echinocytes, thrombocytopenia, and iron deficiency anemia, which in combination with radiographic evidence of a splenic mass, raised the suspicion for angiosarcoma and resulted in a prompt surgical intervention with curative intent.

A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors.

Purpose: Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2-10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study.

Methods: Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m(2) in week 1 of cycle 1 and 20, 27, or 36 mg/m(2) thereafter.

Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias.

Purpose: Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro.

Methods: Adults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m(2) given as a 2-h infusion every 21 days.