Nelarabine in the Treatment of Refractory T-Cell Malignancies

Nelarabine is a nucleoside analog indicated for the treatment of adult and pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that is refractory or has relapsed after treatment with at least two chemotherapy regimens. After being first synthesized in the late 1970s and receiving FDA approval in 2005, the appropriate use of nelarabine for refractory hematologic malignancies is still being elucidated. Nelarabine is the prodrug of 9-β-D-arabinofuranosylguanine (ara-G) which when phosphorylated intracellularly to ara-G triphosphate (ara-GTP), preferentially accumulates in cancerous T-cells. Dose-dependent toxicities, including neurotoxicity and myelosuppression, have been documented and may, in turn, limit the ability to appropriately treat the diagnosed malignancy. This article will summarize the pharmacologic properties of nelarabine and will address the current place in therapy nelarabine holds based upon the results of the available clinical trials to date

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

RECQL5 suppresses JAK2V617F-induced replication stress and genomic instability

JAK2V617F is the most common oncogenic lesion in patients with myeloproliferative neoplasms (MPNs). Despite the ability of JAK2V617F to instigate DNA damage in vitro, MPNs are nevertheless characterized by genomic stability. In this study, we address this paradox by identifying the DNA helicase RECQL5 as a suppressor of genomic instability in MPNs. We report increased RECQL5 expression in JAK2V617F-expressing cells and demonstrate that RECQL5 is required to counteract JAK2V617F-induced replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F mutant cells to hydroxyurea (HU), a pharmacological inducer of replication stress and the most common treatment for MPNs. Using single-fiber chromosome combing, we show that RECQL5 depletion in JAK2V617F mutant cells impairs replication dynamics following HU treatment, resulting in increased double-stranded breaks and apoptosis. Cumulatively, these findings identify RECQL5 as a critical regulator of genome stability in MPNs and demonstrate that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F mutant cells through RECQL5-targeted synthetic lethality.This work was supported by the NIH (K08 HL109734 to AM) and the MPN Research Foundation (AM). A.M. receives support from the Jeanne D. Housman Fund for Research on Myeloproliferative Disorders and is a recipient of a Damon Runyon clinical investigator award. EC is a recipient of a Lady Tata Memorial Trust Award.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.celrep.2015.11.03

Chronic myeloid leukemia 2011: Successes, challenges, and strategies-Proceedings of the 5th annual BCR-ABL1 positive and BCR-ABL1 negative myeloproliferative neoplasms workshop.

This report is based on the presentations and discussions at the 5th annual BCR-ABL1 positive and BCR-ABL1 negative myeloproliferative neoplasms (MPN) workshop, which took place immediately following the 52nd American Society of Hematology (ASH) meeting in Orlando, Florida on December 7th-8th, 2011. Relevant data which was presented at the ASH meeting as well as all other recent publications were presented and discussed at the workshop. This report covers front-line therapies of BCR-ABL1-positive leukemias, in addition to addressing some topical biological, pre-clinical and clinical issues, such as new insights into genomic instability and resistance to tyrosine kinase inhibitors (TKIs), risk stratification and optimizing molecular monitoring. A report pertaining to the new therapies and other pertinent preclinical and clinical issues in the BCR-ABL1 negative MPNs is published separately

Dividend Policy in Switzerland

Dividends, Payout policy, Signaling, Expected earnings, G14, G35,

A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias

Background: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonineto- isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph-positive ALL). Methods: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. Results: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. Conclusions: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440.)J.E. Cortes, D.-W. Kim, J. Pinilla-Ibarz, P. le Coutre, R. Paquette ... Timothy Hughes ... et al