FDA approves additional medical indication for Sprycel

The U.S. Food and Drug Administration today approved a new indication for Sprycel (dasatinib) for the treatment of a rare blood cancer when it is first diagnosed. The cancer, called Philadelphia chromosome positive chronic phase chronic myeloid leukemia (Ph+ CP-CML), is a slowly progressing blood and bone marrow disease linked to a genetic abnormality.

Sprycel, an oral kinase inhibitor, is believed to inhibit the activity of certain proteins responsible for the growth of cancer cells. The action allows bone marrow to begin reproducing normal red and white blood cells.

In June 2006, the FDA granted accelerated approval for Sprycel to treat adults with CP-CML with resistant disease or who were intolerant to prior therapy, including Gleevec (imatinib). The agency converted Sprycel to a regular approval in May 2009, after 24-month follow-up data from earlier clinical studies confirmed the treatment’s safety and effectiveness.

Other FDA-approved drugs to treat various forms of CML include Gleevec, approved in May 2001, and Tasigna (nilotinib), approved in October 2007.

The FDA granted Sprycel a priority review for Ph+ CP-CML.

This is the third drug approved for Ph+ CP-CML under accelerated approval, a process allowing the FDA to approve a drug to treat a serious disease with an unmet medical need based on an endpoint thought to reasonably predict clinical benefit. A company is required to collect additional long term efficacy and safety information data confirming the drug’s benefit. The accelerated approval program provides earlier patient access to promising new drugs while confirmatory clinical trials are being conducted.

“These drugs have dramatically changed the lives of patients with CML,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “Results from additional CML studies continue to demonstrate the importance of studying cancer drugs in the earlier stages of a disease.”

In CML, too many blood stem cells develop into a type of white blood cell called granulocytes. These granulocytes are abnormal and do not become healthy white blood cells. These cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or unexpected bleeding may occur.

One open-label, randomized clinical trial in patients with CP-CML evaluated the safety and effectiveness of Sprycel. The trial measured complete cytogenetic response (CCyR) and cytogenetic response (MCyR), gene-based indicators of how well the malignant cells respond to the treatment. The most commonly reported side effects of Sprycel included decreased bone marrow activity resulting in fewer red and white blood cells and platelets (myelosuppression), fluid retention, diarrhea, headache, musculoskeletal pain, and rash.

Sprycel is marketed by New York City-based Bristol-Myers Squibb. Tasigna and Gleevec are marketed by East Hanover, N.J.-based Novartis Pharmaceuticals.

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FDA Approves New Indication for Tasigna

The U.S. Food and Drug Administration on June 17 approved a new indication for Tasigna (nilotinib) for the treatment of a rare blood cancer when it is first diagnosed. The cancer, called Philadelphia chromosome positive chronic phase chronic myeloid leukemia (Ph+ CP-CML), is a slowly progressing blood and bone marrow disease linked to a genetic abnormality.

Tasigna is believed to work by blocking a signal that leads to leukemic cell development. The new indication expands the use of Tasigna to adult patients in earlier stages of the disease. The FDA originally approved Tasigna in October 2007 for the treatment of Ph+CP-CML in adult patients whose disease had progressed or who could not tolerate other therapies, including Gleevec (imatinib).

When Tasigna was originally approved in October 2007, the FDA identified that the therapy placed patients at risk of an abnormal heart rhythm called QT prolongation. In March 2010, the FDA approved a Risk Evaluation and Mitigation Strategy (REMS) for Tasigna to help patients and health care professionals to better understand this risk. The REMS includes an updated Medication Guide and a communication plan to help reduce medication errors involving drug-food interactions and incorrect dosing intervals.

“It’s important for companies to continue developing oncology drugs for earlier stages of the disease once they have demonstrated clinical effectiveness in resistant forms of cancer,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products, part of the FDA’s Center for Drug Evaluation and Research. “This approach has the potential to increase the availability of an effective treatment to more patients.”

In CML, too many blood stem cells develop into a type of white blood cell called granulocytes. These granulocytes are abnormal and do not become healthy white blood cells. These cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or unexpected bleeding may occur.

The FDA granted Tasigna a priority review for Ph+ CP-CML. The agency completed the review in six months. The new indication for Tasigna was approved under the FDA’s accelerated approval program, which allows FDA to approve a drug to treat serious diseases with an unmet medical need based on an endpoint thought to reasonably predict clinical benefit. The company is required to collect additional long term efficacy and safety information data confirming the drug’s benefit. The accelerated approval program provides earlier patient access to promising new drugs while the confirmatory clinical trials are being conducted.

The safety and effectiveness of Tasigna were evaluated in a single clinical trial enrolling 846 patients with newly diagnosed Ph+ CP-CML. Patients received either Tasigna or Gleevec until the disease worsened, or until unacceptable side effects developed. The study was designed to measure a significant reduction in the surrogate endpoint of the number of CML cancer cells in the blood stream (i.e., major molecular response) at 12 months. About 44 percent of patients who received Tasigna experienced a major molecular response, compared with 22 percent of patients receiving Gleevec.

In patients with newly diagnosed CP-CML, the most commonly reported non-blood-related adverse drug reactions were rash, itching (pruritus), headache, nausea, fatigue, and muscle pain (myalgia). Serious blood-related drug reactions included decrease in bone marrow activity (myelosuppression), low level of platelets in the blood (thrombocytopenia), decrease in infection-fighting white blood cells (neutropenia), and anemia.

Other FDA-approved drugs to treat CML include Gleevec in May 2001 and Sprycel (dasatinib) in June 2006. Tasigna and Gleevec are marketed by East Hanover, N.J.-based Novartis Pharmaceuticals. Sprycel is marketed by New York City-based Bristol-Myers Squibb.

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A Better Genetic Test for Autism

/PRNewswire/ -- A large study from Children's Hospital Boston and the Boston-based Autism Consortium finds that a genetic test that samples the entire genome, known as chromosomal microarray analysis, has about three times the detection rate for genetic changes related to autism spectrum disorders (ASDs) than standard tests. Publishing in the April issue of Pediatrics (and online March 15), the authors urge that CMA become part of the first-line genetic work-up for ASDs.

Expectant parents who have family members with ASDs, as well as families who already have an affected child, often request genetic testing. However, there is still only limited knowledge about actual causative genes. The currently recommended tests (karyotyping to look for chromosomal abnormalities and testing for Fragile X, the single largest known genetic cause of ASDs) often come up negative. Chromosomal microarray analysis (CMA) is a genome-wide assay that examines the chromosomes for tiny, sub-microscopic deletions or duplications of DNA sequences, known as copy-number variants.

CMA offers about 100-fold greater resolution than standard karyotyping. However, since it is new, it is often considered a second-tier test. Depending on where a person lives, or what insurance they have, CMA may not be covered by health insurance. "Based on our findings, CMA should be considered as part of the initial clinical diagnostic evaluation of patients with ASDs," says Bai-Lin Wu, PhD, Director of Children's DNA Diagnostic Lab in the Department of Laboratory Medicine, which has offered CMA to families since 2006.

The research team, led by co-senior authors Wu (heading the Children's team), and David Miller, MD, PhD, of Children's Division of Genetics and Department of Laboratory Medicine (heading the Autism Consortium team), assessed the diagnostic value of CMA in the largest cohort to date - 933 patients with a clinical diagnosis of ASD (by DSM-IV-TR criteria) who received clinical genetic testing in 2006, 2007 and 2008.

Half were Children's patients who had their samples submitted to the hospital's DNA Diagnostic Laboratory, and the others were recruited through the Autism Consortium, a research and clinical collaboration of five Boston-area medical centers. Nearly half of the patients were diagnosed with autistic disorder, nearly half with PDD-NOS (pervasive developmental disorder - not otherwise specified) and about 3 percent with Asperger disorder. Ages ranged from 13 months to 22 years.

Testing included the two currently used tests (G-banded karyotype and fragile X), as well as CMA. When the researchers compared the tests' diagnostic yield, they found:

-- Karyotyping yielded abnormal results in 2.23 percent of patients
-- Fragile X testing was abnormal in 0.46 percent
-- CMA results were judged to be abnormal in 7.3 percent of patients when
the entire length of the chromosomes (the whole genome) was sampled.


Extrapolating from these results, the researchers estimate that without CMA, genetic diagnosis will be missed in at least 5 percent of ASD cases. CMA performed best in certain subgroups, such as girls with autistic disorder, and past studies indicate that it also has a higher yield in patients with intellectual disability (who constituted only 12 percent of this sample).

"CMA clearly detects more abnormalities than other genetic tests that have been the standard of care for many years," says Miller. "We're hoping this evidence will convince insurance companies to cover this testing universally."

In all, roughly 15 percent of people with autism have a known genetic cause. Establishing a clear genetic diagnosis helps families obtain early intervention and services for autism, and helps parents predict the possibility of having another child with autism.

In addition, by pinpointing bits of chromosomes that are deleted or duplicated, CMA can help researchers zero in on specific causative genes within that stretch of DNA. They can also begin to classify patients according to the type of deletion or duplication they have, and try to find specific treatment approaches for each sub-type of autism.

"Just in the last two years, a number of studies have revealed the clinical importance of ever smaller chromosome deletions and duplications found with advanced microarray technology," says Wu. "These new, highly-efficient tests can help in the evaluation or confirmation of autism spectrum disorders and other developmental disorders, leading to early diagnosis and intervention and a significantly improved developmental outcome."

Two known chromosome locations - on chromosome 16 (16p11.2) and chromosome 15 (15q13.2q13.3) accounted for 17 percent of abnormal CMA findings. Both chromosome abnormalities were initially linked with ASDs by Children's Hospital Boston and collaborators in The New England Journal of Medicine and the Journal of Medical Genetics, respectively, in 2008. Children's now offers specific tests targeting both of these "hot spots."

However, the researchers note that most copy-number changes were unique or identified in only a small number of patients, so their implications need further study. Many of them are presumed to be related to ASDs because they involve important genes, cover a large region of the chromosome, or because the child is the first person in that family to have the change.

"Some deletions and duplications are rare and specific to one individual or one family," says Miller. "Learning about them is going to be an evolving process. There won't be one single test that finds all genetic changes related to autism, until we completely understand the entire genome."

The paper's co-first authors were Autism Consortium members Yiping Shen, PhD, of Children's Department of Laboratory Medicine and the Center for Human Genetic Research at Massachusetts General Hospital, and Kira Dies, ScM, LGC, of the Family Research Network of the Autism Consortium and Children's Multi-Disciplinary Tuberous Sclerosis Program. A number of specialists from Children's Departments of Neurology, Developmental Medicine and Clinical Genetics and physicians from other medical centers in greater Boston were also authors on the study. The research was supported by the Nancy Lurie Marks Family Foundation, the Simons Foundation, Autism Speaks and the National Institutes of Health.

Families interested in scheduling an appointment at Children's may call the Developmental Medicine Center (617-355-7025) or the Department of Neurology (617-355-2711).

Citation: Shen Y; et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 2010 Apr; 125(4):e1-e17. (Published online March 15)

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UGA Researchers Discover Mechanism that Explains How Enzyme Crucial to Cancer Growth Winds Up on Ends of Chromosomes

Human cancer cells divide and conquer. Unless physicians can control that division with surgery, chemotherapy or radiation, the wildly dividing cells will eventually destroy a person’s life.

Researchers have known for some time that an enzyme called telomerase is crucial to cancer’s progress. Now, for the first time, researchers at the University of Georgia’s Franklin College of Arts and Sciences have shown a mechanism that explains how two essential components of human telomerase—normally active only in early prenatal development but turned back on during cancer growth—are “recruited” from distinct sites in the cell to the telomere, an area at the end of a chromosome that normally protects it from destruction.

“Telomerase is reactivated in more than 90 percent of human cancers,” said Michael Terns, professor of biochemistry and molecular biology and genetics at UGA, “and the fact that telomerase keeps these telomeres growing when it should be inactive is crucial for the proliferation of cancer. That makes telomerase a very promising target for a potential drug to stop cancers from spreading.”

The research was just published in the journal Molecular Biology of the Cell. Other authors on the paper were Rebecca Terns, a senior research scientist also in UGA’s department of biochemistry and molecular biology (Michael and Rebecca Terns are a husband-wife team); Rebecca Tomlinson, a former doctoral student in the Terns Lab; Eladio Abreu, a current graduate student in the Terns lab; Tania Ziegler, also a former member of the Terns lab, now pursuing an M.D. degree; Hinh Ly of Emory University; and Christopher Counter of Duke University Medical Center. Rebecca and Michael Terns are also members of the University of Georgia Cancer Center.

The two essential components of human telomerase are telomerase RNA and telomerase reverse transcriptase. They are “recruited” to telomeres during what is called the “S phase” (for synthesis) of the cell cycle when DNA replication or synthesis occurs.

“What we have found is that during the remainder of the cell cycle, telomerase RNA is found primarily in rather mysterious and, until recently, little-understood structures called Cajal bodies,” said Rebecca Terns. “Though science has known about Cajal [pronounced Ca-HAHL] bodies for more than a hundred years, what we have discovered is that the localization of telomerase RNA to Cajal bodies and telomeres is specific to cancer cells where telomerase is active.”

The new research shows for the first time that the trafficking of telomerase RNA to both telomeres and Cajal bodies depends on the presence of telomerase reverse transcriptase.

The Terns lab took advantage of the differences between normal and cancer cells of many kinds to better understand the trafficking of telomerase RNA.

“We examined a variety of factors that differ between normal and cancer cells in order to identify factors that impact human telomerase localization,” said Michael Terns. “Our results indicate that human reverse transcriptase is a key determinant in human telomerase trafficking and is essential for the localization of telomerase RNA both to Cajal bodies and telomeres.”

While all this jargon-filled science may sound difficult to understand, the discovery could lead to new ways to attack cancers by blocking their ability to grow. While that is years down the road, the new understanding of how this crucial biological action in the human body takes place will at the very least open new avenues of investigation into why and how cancer cells continue to grow and take the human toll they do every day.

The research was primarily supported by grants from the National Cancer Institute of the National Institutes of Health.

By Philip Lee Williams