Drugs to treat anemia in cancer patients linked to thromboembolism

Medications frequently given to cancer patients to reduce their risk of anemia are associated with an increased risk of deep vein thrombosis or pulmonary embolism, according to new research led by Dawn Hershman, M.D, M.S., co-director of the breast cancer program at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center. The findings will be published online on Nov. 10, 2009 in the Journal of the National Cancer Institute .

The anemia-reducing medications, known as erythropoiesis-stimulating agents (i.e., erythropoietin and darbopoietin) or ESAs, stimulate red blood cell production and are intended to reduce the number of blood transfusions required during chemotherapy. However, concerns about the risks of deep vein thrombosis or pulmonary embolism (manifestations of venous thromboembolism) and mortality exist.

"This research answers important questions about outcomes of ESAs when used in long-term clinical practice with oncology patients," said Dr. Hershman, the Florence Irving Assistant Professor of Medicine and Epidemiology at Columbia University Medical Center, whose research is dedicated to examining cancer survivorship. "While ESAs were given to reduce the need for blood transfusions, a substantial reduction in the use of blood transfusions was not observed. However, an increase risk of deep vein thrombosis or pulmonary embolism was confirmed."

"This analysis confirms the association between ESAs and venous thromboembolism, which was observed in previous meta-analysis," said Dr. Hershman. "This new finding is significant because where the meta-analysis looked at pooled data from randomized clinical trials, this data is from community practice -- real-life clinical settings -- where you can often see things that wouldn't necessarily show-up in a short-term, 12-week study. Additionally, this analysis included data from more than 50,000 patients? including those with more advanced cancer or high-risk status, who therefore might not have been candidates for clinical trials."

Based on previous findings, in the spring of 2007, the FDA required a black-box warning on ESAs about the potential for venous thromboembolism, tumor promotion, and decreased survival in ESA users. The warning suggested limiting the use of ESAs to specific tumor types, durations, doses, and targeted hemoglobin levels. In addition, the Center for Medicare and Medicaid Services proposed eliminating or limiting coverage for ESAs as treatment for some cancers.

"But what is reassuring about our findings are that they don't show an increased risk of mortality when ESAs are given with chemotherapy," said Dr. Hershman.

Dr. Hershman and colleagues analyzed the association between use of ESAs and venous thromboembolism and overall survival in patients who were 65 years or older and diagnosed with colon, non-small cell lung, or breast cancer or diffuse large B-cell lymphoma, between 1991-2002. These cancers were chosen because they were thought to be common cancers for which ESAs were frequently used. Patients were identified in the Surveillance, Epidemiology, and End Results?Medicare database, which at the time contained records of patients diagnosed with cancer in regions that represented approximately 14 percent of the U.S. population.

Results demonstrated that more patients who received an ESA developed deep vein thrombosis or pulmonary embolism, as compared to patients who did not. Overall survival was similar in both groups. The number of patients receiving ESAs increased approximately 10-fold from 1991 through 2002, with approximately 50 percent of patients with advanced cancer undergoing chemotherapy receiving ESAs by 2002. The rate of blood transfusion per year during the same time period, however, remained constant at 22 percent.

"Further efforts at monitoring use and long-term toxicity of expensive oncology drugs should be put in place to ensure that for any drug the benefits outweigh the risks in community practice," the authors write in the paper.

In the JNCI paper, the authors note that ESAs may be of particular interest from a public policy perspective because of the costs associated with their use. Total U.S. sales of ESAs were $10 billion in 2006, accounting for a greater Medicare Part B expenditure than any other drug.

The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital encompasses pre-clinical and clinical research, treatment, prevention and education efforts in cancer. The Cancer Center was initially funded by the NCI in 1972 and became a National Cancer Institute (NCI)?designated comprehensive cancer center in 1979. The designation recognizes the Center's collaborative environment and expertise in harnessing translational research to bridge scientific discovery to clinical delivery, with the ultimate goal of successfully introducing novel diagnostic, therapeutic and preventive approaches to cancer.

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New research strategy for understanding drug resistance in leukemia

UCSF researchers have developed a new approach to identify specific genes that influence how cancer cells respond to drugs and how they become resistant. This strategy, which involves producing diverse genetic mutations that result in leukemia and associating specific mutations with treatment outcomes, will enable researchers to better understand how drug resistance occurs in leukemia and other cancers, and has important long-term implications for the development of more effective therapies.

Findings are reported in the Advance Online Publication of the journal “Nature” and are available at http://www.nature.com/nature/journal/vaop/ncurrent/index.html.

“In trying to understand why certain cancers respond to drugs while certain other cancers fail to respond, we found that a single gene can be the culprit for drug resistance,” said Kevin Shannon, MD, senior author of the paper and a pediatric cancer specialist at UCSF Children’s Hospital. “The subtlety of what makes a cancer cell become resistant to a drug is truly remarkable.”

“When treating patients for cancer, clinical specialists usually only have one or two chances to choose the right drug before it is too late. This makes it incredibly important to understand drug resistance so that we can prioritize therapeutic options,” said Jennifer Lauchle, MD, the study’s lead author and a pediatric blood and cancer specialist at UCSF Children’s Hospital.

In the initial stages of the study, the researchers used a strain of mice that developed acute myelogenous leukemia, or AML, to assess the effectiveness of an experimental cancer drug called a MEK inhibitor. AML is an aggressive cancer that affects both children and adults and causes abnormal white blood cells to grow rapidly and accumulate in the bone marrow, thereby interfering with the production of normal blood cells.

The researchers created the mouse model of AML through two key steps. First they utilized a strain of mice that had a single gene mutation closely resembling the mutation found in leukemia and some other cancers. Then they introduced an infectious particle called a retrovirus, which produces additional mutations that work together and result in AML. The retrovirus also “tags” these new genetic mutations, which allows researchers to identify them later on. These steps resulted in a model of AML that, like human AML and other advanced cancers, has several genetic mutations that interact with one another.

To assess the effectiveness of the MEK inhibitor, the researchers compared a group of mice with AML that was treated with the drug to a group that was left untreated and found that the drug increased survival time threefold. However, all of the leukemia cells that initially responded to the drug later relapsed, which is similar to what happens in many human patients.

“This shows that even if you make what seems to be a really good drug, resistance is a major problem that must be overcome,” said Shannon, who is also a leader of the hematopoietic malignancies research program at UCSF’s Helen Diller Family Comprehensive Cancer Center.

In the next phase of the study, the research team set out to uncover the genes that triggered drug resistance by comparing cells from the original drug responsive AML to those of the relapsed AML. Because AML in the mouse model had been created with a retrovirus, the new mutations that caused the leukemia to relapse could be pinpointed through forward genetic analyses. These analyses identified two new single gene mutations that rendered the MEK inhibitor ineffective and brought about the relapsed AML.

According to the researchers, this same method can be used to study other types of cancer in order to identify additional genes responsible for drug resistance. “The hope is that this new strategy will enable us to identify more effective therapies and to find ways to anticipate and overcome drug resistance,” Shannon added.

Additional co-authors from UCSF include Doris Kim, Doan Le, MD, Michael Crone, Kimberly Krisman, Kegan Warner, Jeannette Bonifas, Qing Li, MD, Kristen Coakley, Ernesto Diaz-Flores, PhD, Matthew Gorman, MD, Mary Tran, Scott Kogan, MD, and Jeroen Roose, PhD. Co-authors from other institutions are Keiko Akagi, PhD, and Linda Wolff, PhD, of the National Cancer Institute; Sally Przybranowski, MS, and Judith Sebolt-Leopold, PhD, of Pfizer Global Research and Development; Neal Copeland, PhD, and Nancy Jenkins, PhD, of the Institute of Molecular and Cell Biology; and Luis Parada, PhD, of the University of Texas Southwestern.

The research was supported by grants from the National Institutes of Health, the Leukemia and Lymphoma Society, the US Army Neurofibromatosis Research Program, the Ronald McDonald House Charities of Southern California/Couples Against Leukemia, the Jeffrey and Karen Peterson Family Foundation, and the Frank A. Campini Foundation.

One of the nation’s top children’s hospitals, UCSF Children’s Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 2,000 babies born in the hospital.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Source : news.ucsf.edu

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FDA criticizes Genzyme study of leukemia drug

Just days before a key meeting to consider Genzyme Corp.’s application for a new leukemia drug to treat older patients, the Food and Drug Administration released a briefing document criticizing the Cambridge biotechnology company’s clinical study of the drug, called Clolar.

Genzyme said the drug deserves to be approved to treat adult acute myeloid leukemia in people who aren’t healthy enough to undergo chemotherapy, citing results of its study involving patients over 60 years old.

The company said it found older patients with the disease had a 45.5 percent overall remission rate when they took the treatment.

Clolar, the brand name for the drug clofarabine, won FDA approval in 2004 to treat a different form of leukemia - cancer of the blood or bone marrow - in patients under 21 who have had relapses after undergoing chemotherapy. Genzyme filed a new drug application Nov. 21 for older patients with acute myeloid leukemia.

The company and the FDA are scheduled to present their findings Tuesday to an outside panel of specialists, called the Oncological Drug Advisory Committee, which will make a recommendation. Such recommendations are typically followed by the agency.

But in the briefing document posted on the FDA’s website yesterday, regulators said Genzyme didn’t follow the agency’s guidance in designing its Phase II clinical study. While the FDA had advised the company to conduct a “randomized’’ study, comparing patients who took Clolar with those who underwent an alternative treatment or took a so-called sham drug, the company ran a “single-arm’’ study consisting only of patients who used Clolar.

The regulatory feedback suggests the FDA believes “this study was poorly conceived,’’ said Ira Loss, health care analyst for Washington Analysis, a research firm advising institutional investors on regulatory trends. “My strong sense is that the committee will recommend against approving the drug for this indication.’’

Shares of Genzyme, which has been working to get production problems at its Allston Landing plant under control, slid $1.37, or 2.4 percent, to $55.53 yesterday on the Nasdaq exchange.

Beth Trehu, product general manager for clofarabine at Genzyme, said the company wanted to run a randomized study, it was unable to get physicians to agree on a “comparative’’ treatment for the population of older patients with acute myeloid leukemia.

Nonetheless, said Trehu, “we think our study shows a very positive benefit/risk ratio, a very positive response rate, and very durable remissions. We’re hoping the [oncology] panel will recommend approving our drug based on its efficacy and safety.’’

Source : www.boston.com

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Leukemia can be cured without brain damage

Doctors have found a way to cure leukemia in children while sparing them from a toxic treatment that can cause brain damage, a study says.

In a study of 498 children with acute lymphoblastic leukemia — the most common pediatric cancer — doctors from St. Jude Children's Research Hospital treated them only with drugs and did not administer radiation to the brain, according to a study in today's New England Journal of Medicine. Although radiating the skull can help prevent cancer from spreading to the brain, it can also cause leave children with serious learning disabilities.

FORUM: Choose less aggressive cancer treatment to avoid side effects?

Most doctors today are scaling back their use of cranial radiation, using it for only for children who are at high risk of relapse, or up to 20% of patients, the study says.

About 3,300 children are diagnosed with acute lymphoblastic leukemia each year.

The study is the first to do away with cranial radiation for everyone, including high-risk children.

Even without the radiation, 94% of children survived at least five years after diagnosis. That's the highest survival rate seen in a major study, says senior author Mary Relling, St. Jude's chair of pharmaceutical sciences. And 86% survived that long without a relapse, the study says.

Because most relapses occur within a few years of diagnosis, these children are probably cured, says Stephen Sallan of Children's Hospital Boston, who was not involved in the study.

And even without radiation, high-risk children in the study had longer remissions than these children usually have, Relling says. These children may have done better because of many small adjustments to their chemotherapy regimens, which last about 2½ years. For example, doctors used a stronger steroid than usual.

But Sallan says it's too soon to know whether the St. Jude regimen will become the new standard of care. It's possible the new drug combinations used in the study could cause problems in the future, he says. For example, the steroid used in the study, dexamethasone, increases the risk of bone decay, which can lead children to have joint replacement surgery.

Dexamethasone and other types of chemo used in the study also can affect the brain, Sallan says.

And Sallan says doctors can't definitively say that the high-risk children in this study do better than others. That's because researchers didn't randomly assign half of the patients in the study to try each treatment.

But Sallan notes that he's eager for updates on the progress of children in the study. If they continue to thrive, other hospitals eventually may give up cranial radiation as well.

READERS: Have you or a loved one ever chosen less aggressive cancer treatment in order to avoid harmful side effects?

Source : www.usatoday.com

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New drug cocktail brings hope to leukemia cancer patients

Using an asthma medication already available on the market, scientists were able to treat chronic myeloid leukemia by targeting a gene involved with the inflammatory response.
Specifically, the gene Alox5 was found to play a vital role in the development and maintenance of cancer stem cells. Normally, “it processes essential fatty acids to leukotrienes, which are important agents in the inflammatory response.”

The researchers found that chronic myeloid leukemia (CML) did not develop in mice without Alox5 because of impaired function of leukemia stem cells. Also, Alox5 deficiency did not affect normal stem cell function, providing the first clear differentiation between normal and cancer stem cells.

Using this knowledge, the team treated CML mice with two already-available prescription medications: Zileuton and Gleevec (imatinib). Zileuton, an asthma medication, was chosen because it inhibits the Alox5 inflammation pathway. Imatinib is a leukemia medication. Combined, the two drugs “provided an even better therapeutic effect.”

The research is published in the journal Nature Genetics, and is authored by Shaoguang Li, M.D., Ph.D., et al. of the University of Massachusetts Medical School in Worcester.

Source : www.digitaljournal.com

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