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The Lancet Oncology

Monday, November 23, 2009

'Explore the Mystery of Blood' Teaches High School Students About Blood and Career Opportunities in the Field of Hematology

The American Society of Hematology (ASH), the world's largest professional society concerned with the causes and treatment of blood disorders, and Scholastic, the global children's publishing, education, and media company, are launching "Explore the Mystery of Blood," a dynamic science curriculum designed to spark interest in the fields of science and medicine, in addition to exposing students to exciting career opportunities in hematology.

"Many hematologists may remember watching a cartoon in grade school about Hemo the Magnificent, which made learning about blood really fun," stated Nancy Berliner, MD, ASH President. "Now ASH has the opportunity to convey this excitement to a new generation of high school students. We are really excited to have developed this quality program with Scholastic."

This hands-on, interactive learning experience will engage students in learning about blood functions as well as common disorders through colorful imagery and the actual examination of blood smears under a microscope. The program align with national education standards for science, technology, and life skills. It includes lesson plans built on themes from the hematology documentary "Blood Detectives" and information from 'Blood, The Vital Connection ", a website designed to educate the public about the importance of healthy blood.

As part of the program, students will watch "Blood Detectives" (a DVD is included with the materials) where they will see real-life hematologists at work in clinical and research settings helping to treat and cure hematology patients with life-threatening blood diseases . Follow-up activities allow students to see what it is like to be a hematologist by observing blood from an unhealthy patient and learning about how this information helps doctors and draw conclusions Determining accurate diagnoses.

"Scholastic is pleased to be working with The American Society of Hematology to provide resources to help high school core teachers foster their students in scientific investigation skills." Said Ann Amstutz-Hayes, Vice President of Scholastic InSchool.

This curriculum is being distributed to 50,000 high school science teachers and science club advisors nationwide, reaching more than 4 million students. It will also be available for download.

The program "Explore the Mystery of Blood" was made possible in part by the Wallace H. Coulter Foundation.

New NCCN Guidelines to Incorporate Approved New Treatment Options

Two recent FDA approvals have prompted the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world's leading cancer centers dedicated to improving the quality and effectiveness of care provided to patients with cancer, to update the NCCN Clinical Practice Guidelines in Oncology™ for Non-Hodgkin's Lymphomas to include ofatumumab (Azerra™, GlaxoSmithKline) and romidepsin (Istodax®, Gloucester Pharmaceuticals) as treatment options for select patients with two types of Non-Hodgkin's Lymphomas.

Ofatumumab was added to the NCCN Guidelines as a treatment option for relapsed/refractory disease in patients with chronic lymphocytic leukemia (CLL), with and without a 17p deletion. A 17p deletion refers to a chromosomal abnormality involving deletion of genetic material from chromosome 17. Ofatumumab was approved by the FDA on October 27, 2009 for patients with CLL, a slowly progressing cancer of the blood and bone marrow, whose cancer is no longer responding to other chemoimmunotherapy regimens.

In addition, the updated NCCN Guidelines now include romidepsin as a suggested systemic treatment option for patients with mycosis fungoides and Sezary syndrome, two of the most common types of cutaneous T-cell lymphoma (CTCL). On November 6, 2009, the FDA approved romidepsin, a histone deacetylase (HDAC) inhibitor, for the treatment of CTCL in patients who have received at least one prior systemic therapy.

These latest additions come shortly after another recent update to the NCCN Guidelines for Non-Hodgkin's Lymphomas that incorporated the FDA approval of pralatrexate (Folotyn™, Allos Therapeutics, Inc.) for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).

The NCCN Clinical Practice Guidelines in Oncology(TM) are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of physicians from NCCN Member Institutions.

First Patients Enrolled in Phase I/II Trial of CYT387, A Potent JAK1/JAK2 Inhibitor

Recruitment of participants for a New Phase I/II trial ‘Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)’ started today. The drug candidate is designed to treat various hematological disorders.

The new, open-label, dose-escalating, Phase I/II trial, which is being conducted at Mayo Clinic in Rochester, Minnesota, is designed to investigate the safety and tolerability of CYT387, an orally-administered ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases, administered as a daily oral capsule dose in 30-60 patients with myelofibrosis. The study will also allow preliminary assessment of the compound's activity in these patients including its effect on spleen size, hematological symptoms, quality-of-life and markers of aberrant JAK2 activity in blood. Dr. Ayalew Tefferi, Professor of Hematology at Mayo Clinic will be Study Chairman for the program with Dr. Animesh Pardanani acting as Lead Investigator. Initial safety data from the trial are expected in mid-2010.

Importance of JAK
Hyperactivity of the JAK2 enzyme is known to cause a number of heterogeneous hematological conditions known as myeloproliferative neoplasms (MPN), a group of diseases including myelofibrosis, polycythemia vera (PV) and essential thrombocythemia.

Myeloproliferative neoplasms were initially thought to include four different diseases: chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF). However, recently hypereosinophilic syndrome (HES) and chronic neutrophilic leukemia (CNL) were included in the classification of MPNs.

These disorders are hematological malignancies that arise from the transformation of a multipotent hematopoietic stem cell. Clonal hematopoiesis is characteristics of chronic myeloid leukemia, polycythemia vera , chronic idiopathic myelofibrosis and, at least, some cases of essential thrombocythemia . Except for IMF, all MPNs are generally characterized by increased levels of blood cell production with predominance of one myeloid cell lineage and no marked alterations in cellular maturation.

Each of the MPNs has a predisposition to progress towards acute leukemia, yet they differ with respect to the rate of transformation to blast crisis. Many complications of the MPNs, such as thrombosis in essential thrombocythemia and polycythemia vera, are characterized by cytokine hypersensitivity and overproduction of mature blood cells.

Clinical evidence suggests that JAnus Kinase 2 or JAK2 is involved in the pathogenesis of PV because it is implicated in the intracellular signaling following the exposure to cytokines to which PV progenitors display hypersensitivity (Epo, GM-CSF, IL-3,TPO and more or less SCF and IGF-1).

Dual JAK1/JAK2 inhibition is likely to increase the clinical benefit in these disease indications and broaden the therapeutic opportunities for CYT387. JAK kinase inhibitors with similar profiles are also being trialed in inflammatory diseases such as rheumatoid arthritis. CYT387 possesses optimized JAK1/JAK2 inhibition while minimizing unwanted activity seen with other JAK2 inhibitors in clinical development.

CYT387 is a pyrimidine derivative, with low nanomolar activity against JAK1/2 in biochemical assays and a very narrow scope of additional targets. Studies have shown that it inhibits the growth of JAK2-dependent cell lines in the high nanomolar – low micromolar dose range.

Studies have shown that CYT387 is active in a murine model of JAK2-V617F-positive MPD, with normalization of blood counts and spleen size, without apparent toxicity. However, residual disease remained detectable and relapse occurred upon discontinuation of drug, reminiscent of preliminary data from studies of JAK2 inhibitors in humans.

"The utility of JAK2 inhibitors may be broadly applicable and is not limited to myelofibrosis. Additional potential indications include other MPNs, graft-vs-host disease, solid tumors and inflammatory conditions. To suitably address this large potential requirement, the development of multiple JAK2 inhibitor candidates may be warranted," said Dr. Ayalew Tefferi. "Patient safety is very important with this class of compounds and can be reliably predicted only by testing in humans. It is premature to select the best JAK2 inhibitors in clinical development as there is a need for longer follow-up data on safety and efficacy than is currently available. As such, the results of this study could yield important data on the potential for this molecule and possibly the entire class."

The trials are sponsored by Cytopia, an Australian biotechnology company focused on the discovery and development of new drugs to treat cancer and other diseases

"Given the broad potential of JAK inhibitors, the human clinical safety data generated from this first clinical trial could be pivotal to the further development of CYT387 and its differentiation within the class. Limited data is available on the use of JAK 2 inhibitors in this patient population but a strong rationale exists to pursue this approach," said David Allan, Chairman and CEO of YM BioSciences, a life sciences product development company, currently awaiting the results of a merger proposal with Cytopia which pending approval by Cytopia shareholders, Australian court and other regulatory approvals.

"This program has also been an opportunity for productive collaboration between the YM and Cytopia teams to further advance Cytopia's pipeline," Allan noted.

Debilitating conditions
CYT387 is reported to potently inhibit the JAK2 enzyme, a mutated form of which has been implicated in a variety of MPNs including myelofibrosis, polycythemia vera and essential thrombocythemia. CYT387 has reportedly demonstrated the ability to attenuate MPN symptoms in preclinical models and disrupt JAK2 hyperactivity in cells from patients with MPNs. These data suggest that the compound may exert a profound effect on the human diseases. Over-activity of the JAK2 enzyme has also been noted in certain cancers and in inflammatory conditions, such as rheumatoid arthritis and psoriasis.

Myelofibrosis is a chronic, debilitating condition where the patient's bone marrow is replaced by scar tissue. This compromises the ability of patients to produce sufficient blood cells and creates a reliance on organs other than the bone marrow, including the liver and spleen, to produce blood cells. Typical symptoms include an enlarged spleen, progressive anemia and poor overall survival.

"The commencement of our CYT387 clinical study is another significant milestone delivered by Cytopia and we look forward to its progress under the guidance of Dr. Tefferi and his colleagues," said Mr. Andrew Macdonald, CEO of Cytopia. "The combination of JAK1 and JAK2 inhibitory activity in this compound represents a potential advantage over JAK2 inhibitors. JAK1 is hypothesized to have an effect on cytokines and cachexia, and thus may improve the quality of life in patients with JAK2 mediated diseases. Cytopia will seek to demonstrate the activity of CYT387 in other diseases where JAK1 and JAK2 activity may be important."

Commercial interest
There has been considerable commercial interest in the JAK2 target with no selective JAK inhibitors having yet successfully completed late stage clinical trials and few compounds in development that meet a desirable product profile. A similar JAK2 inhibitor in clinical development was recently licensed by Onyx Pharmaceuticals for $550 million including a $25 million up-front payment and double-digit royalties.

For more information, please review these PubMed Abstracts:

Friday, November 13, 2009

Romidepsin (Istodax) approved for the treatment of Cutaneous T-cell Lymphoma (CTCL)

The U.S. Food and Drug Administration has approved romidepsin (Istodax), an injectable medication, for treatment of patients with a rare form of cancer known as Cutaneous T-cell Lymphoma (CTCL).

Cutaneous T-cell lymphoma is a slow-growing cancer of infection-fighting white blood cells called T-lymphocytes. Most cases start with dry skin, red rash, and itching that can become severe. The skin may develop tumors that can become ulcerated, causing infection. In some cases, CTCL spreads to the blood, lymph nodes, or internal organs. There are about 1,500 new cases of CTCL every year in the United States.

Patients with localized CTCL on the skin are treated with topical agents or phototherapy, but chemotherapy may be used if the cancer advances.

Romidepsin interferes with processes required for cell replication. It is intended to be used in patients when CTCL gets worse or comes back after at least one other type of chemotherapy has been used.

“This approval demonstrates FDA’s commitment to the development and approval of drugs for rare and uncommon diseases,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. The FDA approved Istodax on Nov. 6, 2009.

Previous drug treatment approvals for CTCL included vorinostat (Zolinza, Merck & Co., Inc), denileukin difitox (Ontak, Eisai Inc), and bexarotene (Targretin, Eisai Inc).

Romidepsin was evaluated based on two clinical studies involving a total of 167 patients. About 35 percent of patients in both of the trials experienced tumor responses, indicating a reduction of the size of tumors. Responses lasted a median of 15 months in one study and 11 months in the other study. Six percent of those studied had complete responses, indicating no apparent evidence of the tumor on physical, laboratory, and X-ray examinations.

Common side effects include nausea, fatigue, infections, vomiting, decreased appetite, decreased red blood cell count, decreased platelet count, and decreases in the components of white blood cells.
Romidepsin may cause changes in an electrocardiogram (ECG). Periodic blood tests should be done to monitor electrolytes, and periodic ECG monitoring should be considered in patients at risk for certain heart rhythm abnormalities. Romidepsin may harm a fetus and women should not become pregnant while taking the drug.

Romidepsin is marketed by Gloucester Pharmaceuticals Inc. of Cambridge, Mass.

First Rapid Test for Bacterial Contamination in Pooled Platelets Cleared by FDA

The U.S. Food and Drug Administration today cleared for marketing the Platelet PGD Test System, the first rapid test for the detection of bacterial contamination in pooled platelets derived from whole blood.

Platelets are used to prevent or treat bleeding in individuals with dangerously low platelet counts, including those undergoing chemotherapy for cancer, following major trauma, during or after surgery, and in individuals who do not produce adequate numbers of platelets. Platelets have the potential to be contaminated with bacteria and it is important to detect and interdict such contamination before transfusion. Patients who are transfused with contaminated platelets are at risk of developing serious and potentially life-threatening infections.

The Platelet PGD Test System consists of a single-use test strip that, in fewer than 60 minutes, produces a signal that indicates the presence of bacteria. The test is intended for use mainly by hospital transfusion services as a quality control test for the detection of bacteria after platelets derived from whole blood have been pooled, just prior to a patient blood transfusion.

“Bacterial contamination of platelets is the leading infectious cause of patient fatalities associated with platelet transfusions,” said Karen Midthun, M.D., acting director of the FDA’s Center for Biologics Evaluation and Research. “A rapid test for pooled platelets is an important step in improving safety for patients who are transfused with platelets.”

Clinical studies showed that the Platelet PGD Test System improved the sensitivity for detecting bacterial levels by 100 to 1000-fold over existing methods used to test pooled platelets prior to transfusion.

The Platelet PGD Test System is manufactured by Verax Biomedical, in Worcester, Mass.