This update is in follow-up to the FDA Drug Safety Communication: FDA investigating leukemia drug Iclusig (ponatinib) after increased reports of serious blood clots in arteries and veins issued on October 11, 2013.

Josephs DH, Fisher DS, Spicer J, Flanagan RJ.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Oct. 18, 2013-- ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) today announced that it is discontinuing the Phase 3 EPIC (Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia) trial of Iclusig® (ponatinib) in patients with newly diagnosed chronic myeloid leukemia. ARIAD and the U.S. Food and Drug Administration mutually agreed that the trial should be terminated because arterial thrombotic events were observed in patients treated with Iclusig. This decision was made in the interest of patient safety based on a recent assessment of data in the clinical trial.

Iclusig (Ponatinib): Drug Safety Communication - Increased Reports Of Serious Blood Clots In Arteries And Veins
[Posted 10/11/2013]

AUDIENCE: Health Professional, Oncology

ISSUE: FDA is investigating an increasing frequency of reports of serious and life-threatening blood clots and severe narrowing of blood vessels (arteries and veins) of patients taking the leukemia chemotherapy drug Iclusig (ponatinib). Data from clinical trials and postmarket adverse event reports show that serious adverse events have occurred in patients treated with Iclusig, including heart attacks resulting in death, worsening coronary artery disease, stroke, narrowing of large arteries of the brain, severe narrowing of blood vessels in the extremities, and the need for urgent surgical procedures to restore blood flow. FDA is actively working to further evaluate these adverse events and will notify the public when more information is available.

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced results of its review of updated clinical data from the pivotal PACE trial of Iclusig® (ponatinib) and actions that it is taking following consultations with the U.S. Food and Drug Administration (FDA).

Treatment of chronic myeloid leukemia (CML) has evolved considerably in recent years. Chemotherapy with hydroxyurea and busulfan were the main options for many years, and although these agents can control hematologic manifestations of CML, they rarely if ever induce the cytogenetic responses required to change the natural history of the disease. [Interferon] then became the standard therapy for most patients because of its ability to induce cytogenetic responses in 40% to 60% of patients, including 5% to 30% with a complete cytogenetic response.

J E Kim1,7, S Yoon1,7, B-R Choi1, K P Kim2, Y-H Cho3, W Jung4, D-W Kim5, S Oh6 and D-E Kim1

The BCR–ABL fusion transcript encodes the BCR–ABL tyrosine kinase (TK), which causes chronic myelogenous leukemia (CML). Although the TK inhibitor imatinib mesylate, which targets the BCR–ABL protein, has been proven to be effective in controlling leukemic growth, imatinib resistance has been observed with disease relapse because of point mutations in the ABL gene that inhibit imatinib efficacy. In this study, we designed oligodeoxyribozymes (DNAzymes) that specifically target and cleave both the junction sequence and the site of the point mutation (T315I), conferring imatinib resistance in BCR–ABL mRNA. DNAzymes significantly induced apoptosis and inhibited proliferation in wild-type and T315I-mutant BCR–ABL-positive cells. Selective cleavage of T315I-mutant ABL mRNA by DNAzyme (T315I Dz) led to cell cycle arrest in G0/G1 phase, with induction of caspase-3/-7 in imatinib-resistant BCR–ABL-positive cells harboring the T315I mutation. Moreover, cotreatment with the DNAzyme targeting the T315I mutation and imatinib resulted in enhanced inhibition of proliferation and induction of apoptosis in T315I leukemic cells as compared with imatinib alone, thereby antagonizing imatinib resistance in CML cells bearing T315I-mutant BCR–ABL. Therefore, cleavage of T315I-mutant ABL mRNA by DNAzyme combined with imatinib treatment may be an alternative approach to overcoming imatinib resistance in leukemic cells.

Ahmad Hamad, Zeyad Sahli, Maya El Sabban, Maha Mouteirik, and Rihab Nasr
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon

13 June 2013

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML.

By Dave Levitan
June 14, 2013

Almost half of patients with chronic-phase chronic myeloid leukemia (CML) who discontinued imatinib(Drug information on imatinib) treatment did not relapse, according to results of a prospective study. Those who did relapse showed continued sensitivity to imatinib when treatment started again.

By Michael Mauro, MD1, Jerald Radich, MD2
July 25, 2013

1Memorial Sloan-Kettering Cancer Center, New York
2Fred Hutchinson Cancer Research Center, Seattle

Interviewed by Anna Azvolinsky, PhD

Chronic myeloid leukemia (CML) is now seen as a classic example of a malignancy driven by a mutation, the BCR-ABL fusion gene on the Philadelphia chromosome. This fusion gene produces a continuously active tyrosine kinase that is thought to drive CML. The first small molecule inhibitor against BCR-ABL approved by the US Food and Drug Administration (FDA) was imatinib(Drug information on imatinib), or Gleevec. There are now several newer BCR-ABL inhibitors that can treat CML patients resistant to this earlier targeted therapy. Today, we are speaking with Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York and formerly of the Knight Cancer Institute in Portland, Oregon, and Dr. Jerald Radich, of the Fred Hutchinson Cancer Research Center in Seattle.