Chronic Lymphocytic Leukemia (CLL) Treatment Shows Benefit in Phase III Clinical Trial


First Antisense Drug Provides Benefit to Subset of Chronic Lymphocytic Leukemia Patients


The first "antisense" drug to be tested in chronic lymphocytic leukemia (CLL) shows benefit in a phase III clinical trial for a specific subset of patients - those who are still sensitive to a chemotherapy drug often used to treat this cancer.

Researchers at The University of Texas M. D. Anderson Cancer Center, reporting in the early on-line edition of the March 20 Journal of Clinical Oncology, found that the agent, oblimersen (trade name: Genasense) produced a four-fold increase in "CP/nPR," a clinical response defined by no definitive evidence of disease, in patients who were sensitive to the chemotherapy drug fludarabine, compared to patients who no longer responded to fludarabine.

"The results make sense because oblimersen is designed to work alongside chemotherapy," says the study's lead author, Susan O'Brien, M.D., professor in the Department of Leukemia. "We found in this study that oblimersen enhances sensitivity to chemotherapy, and so we think it deserves further study in a population of CLL patients who are sensitive to chemotherapy agents," she says.

CLL, a cancer of the blood and bone marrow, is the second most common type of leukemia in adults. More than 15,000 new cases of the disease will be diagnosed this year, according to the American Cancer Society, and about 4,500 people will die from the cancer.

Fludarabine is a newer chemotherapy drug that is now being used as first treatment for many patients, according to O'Brien. Oblimersen is an experimental agent that inhibits the production of a protein known as Bcl-2 in cancer cells. This protein can stop a cell from destroying itself, and is often over-expressed in cancer. As an antisense drug, oblimersen provides a complementary genetic strand to the messenger RNA that produces Bcl-2, inactivating it and preventing the protein from being produced. "It gets rid of Bcl-2, and cells that have less Bcl-2 are more sensitive to chemotherapy," O'Brien says.

This study focused on patients who had relapsed after a prior fludarabine - containing regimen or were refractory to fludarabine; refractory patients had failed to respond to a prior fludarabine-based regimen or had progressed within six months of treatment. It enrolled 241 patients at cancer centers worldwide who were randomized to receive fludarabine combined with cyclophosphamide chemotherapy or the same regimen combined with oblimersen.

Researchers found that the primary endpoint of the study (CR/nPR) was achieved in 20 of the 120 patients (17%) in the oblimersen-treated group compared to 8 of 121 patients (7%) in the group treated with chemotherapy alone. This difference was statistically significant, says O'Brien.

Patients achieving nPR met all the criteria associated with a complete remission, except that on a bone marrow biopsy a nodule could be detected, which might or might not, be cancerous, she says. They did not experience the fever, night sweats, fatigue, abdominal discomfort or other symptoms associated with the disease for at least 180 days.

Although overall response rate was not significantly different between the two groups, maximum benefit was observed in fludarabine-sensitive patients, O'Brien says. This group included 51 patients in the oblimersen group and 50 patients in the group treated with chemotherapy alone, according to researchers.

For example, among all patients, median survival at 36 months was about the same - an estimated 33.8 months in the oblimersen-treated group and 32.9 months in patients treated with chemotherapy. But in patients who achieved CR/nPR, survival was three or more years in 70 percent of the patients in the oblimersen group compared with 38% in the chemotherapy-alone group, the researchers found. "Patients who were previously refractory to fludarabine did not benefit substantially from the addition of oblimersen, and because there were so many refractory patients in both arms of the trial, the survival curves were not significantly different between the groups," O'Brien says.

"We aimed to increase the CR/nPR rate to chemotherapy, and that aim was met," O'Brien says. "For CLL patients whose disease has progressed, but who are still sensitive to chemotherapy, oblimersen may represent a new treatment option."

Led by M. D. Anderson, collaborators in the study included investigators in the United States, Canada, Poland, Argentina and Australia.

Stem Cells from Blood Increase Survival for Advanced Leukemia Patients


Using Blood Stem Cells for Transplants Increases Survival for Advanced Leukemia Patients
Compared with stem cells from a bone marrow transplant, stem cells taken directly from the bloodstream and transplanted into patients with advanced leukemia may help increase their rate of disease-free survival, according to a study in the Jan. 18 issue of The New England Journal of Medicine.


Researchers led by William I. Bensinger, MD, of the Fred Hutchinson Cancer Research Center in Seattle, studied 172 patients, most of whom had leukemia or lymphoma. The patients had either a bone marrow transplant or a transplant using blood stem cells called peripheral blood cells.

The researchers found 57% of those with more advanced cancer who had peripheralblood cell transplants were still alive two years later, compared with only 33% of those who had a bone marrow transplant. "We were surprised by the results we saw. We didn?t think the differences in survival would be as great as they were," Bensinger says.

Regardless of what type of transplant they had, about the same number of patients with less advanced cancer were still alive two years later.

Stem cell transplants are given to leukemia patients to help them overcome the harsh effects of high-dose chemotherapy needed to kill leukemia cells. The cells can either be taken directly from a donor?s bone marrow ? by a relatively painful procedure that involves the insertion of a large needle into the center of the bone ? or removed from a donor?s bloodstream by a painless procedure.

There are several reasons for the effectiveness of peripheral blood cells, according to Bensinger. "Patients who receive peripheral blood not only recover their counts [of different types of blood cells] faster, they recover their immune function faster. There?s data suggesting fewer infections in these patients," he says.

He also points out that transplanted peripheralblood cells might have an increased ability to fight residual leukemia cells that have evaded chemotherapy.

One negative finding of the study centers on a debilitating condition known as graft-versus-host disease (GVHD) that often accompanies a transplant. The researchers found GVHD appears to be slightly worse with peripheral-blood cell transplants. Because of this Bensinger suggests patients with advanced cancers are the most appropriate candidates for the procedure. "Graft-versus-host disease is a complication of transplants that can lead to problems with organ function, skin problems, GI [gastrointestinal] problems such as diarrhea, and an inability to absorb nutrients properly ? so it can be a very debilitating illness," he says. "It is of concern, and that means we have to have more follow-up on this study."

Ralph Vogler, MD, scientific program director for the American Cancer Society (ACS), advises patients to ask their doctors about the risks of receiving peripheral blood cells compared to bone marrow transplants. "The advantages of a peripheral blood cell transplant are quicker blood count recovery and suggestively better survival," he says. But Vogler adds that some patients feel chronic GVHD is a disadvantage. "Grade III or IV graft-versus-host disease is extremely serious and still occurs too often," he says.

"GVHD is a two-edged sword," adds Herman Kattlove, MD, an oncologist and medical editor for the ACS. "Because it is an immune reaction against the transplant recipient?s body, it can lead to toxic side effects. But this immune reaction also reacts against the patient?s cancer cells and might account for the good results seen in this study. It didn?t seem to make any difference in the patients with less advanced cancer, probably because most of them had good results with either kind of transplant."

Cold/Flu Breakthrough Remedy Undergoes NCI-Sponsored Trial In Leukemia Patients: Canada


Cancer patients - with their weakened immune systems - are particularly vulnerable when the cold and flu season hits. To help, the U.S. National Cancer Institute (NCI) is sponsoring a landmark trial to see whether a unique Canadian cold remedy - COLD-FX - can help.


The trial will examine whether using the #1 pharmacist recommended cold and flu fighting product in Canada - ginseng extract COLD-FX - reduces infections in chronic lymphocytic leukemia patients; enabling them to remain healthier to fight their disease. Cancer patients have weakened immune systems to begin with, usually as a result of chemotherapy or radiation.

The trial will be conducted by American cancer and infectious diseases experts at Wake Forest University School of Medicine in North Carolina. Wake Forest currently oversees approximately 150 cancer trials and is regarded as one of America's leading cancer research facilities.

The double-blind, placebo-controlled trial, involving 336 patients, was originally planned to include up to 19 U. S research sites. However, in approving the study, the NCI accelerated the process - targeting completion over a single cold and flu season. To assist in recruitment, it also opened up its cancer trials support unit network of more than 1,500 cancer research sites across the U.S.

The NCI says on its website that the trial is important because both the cancer and its treatment, "…can impair immune system functioning and markedly increase risk of infection, the most common complication…" of chronic lymphocytic leukemia. "Two randomized, controlled trials have shown that an extract of North American Ginseng, called CVT-E002 (COLD-FX), can significantly reduce the risk of ARI [acute respiratory infection] in older adults," the website says.

In the battle against respiratory infections, there are few effective and economical treatment options. Apart from COLD-FX, there is no known clinical proven therapy for both prevention and treatment that naturally enhances the immune system to fight viral respiratory infections.

A recently reported three-year, multi-center study of COLD-FX, involving 780 participants, demonstrated that it cut infections by one-third in seniors taking the flu shot. The trial also showed that using a combo of COLD-FX and a flu shot provided greater protection than using the flu shot alone. This research complemented earlier clinical trials that formed the basis of Canada's regulatory approval of 400 milligrams of COLD-FX daily to reduce the frequency, severity and duration of cold and flu symptoms by boosting the immune system.

A Patient's Story


Educator Fights Leukemia With Support of “Families”

After four hectic years as an elementary school principal in Roxana, Ill., Debra Ochs had learned to take surprises in stride. A substitute teacher fails to show up. A food fight erupts in the cafeteria. Two small brothers scuffle at the bus stop. “Each night, I made a list of things I wanted to accomplish the next day, and I was lucky if I crossed one thing off because the day never went as I planned,” says Ochs, 34, a Bethalto, Ill., resident.

Ochs family
Debra Ochs treasures time spent with her husband, Jeff; daughter, Annika; and one of the family's dogs.
The biggest surprise of all came early in 2003. A health crisis disrupted her work and family life — and nearly proved fatal. Up until that point, things had seemed peaceful and predictable. She and her husband, Jeff, a junior high school teacher, had a daughter, 4-year-old Annika, and had recently learned they were expecting a second child in the fall. For Ochs — an eager exercise buff who was “healthy as a horse” — that was welcome news but no reason to slow down. Yet she soon felt exhausted and nauseated, with aching bones and joints. Next came a serious sore throat that persisted despite two rounds of antibiotics. Ochs spent her entire spring vacation in bed. At her initial obstetrical checkup in April, she had a standard blood workup and was surprised when her doctor called that evening, asking her to return the next day for a repeat test.

“After that, he called a second time and said he would like to see me first thing the next morning,” Ochs says. “He wanted to be the one to tell me I had acute myelogenous leukemia (AML).”

That same day, she said a difficult farewell to her daughter, and Jeff drove her to the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine to begin an intensive, 30-day regimen of chemotherapy and blood transfusions under the direction of her new medical oncologist, John DiPersio, MD, PhD (the “Big D,” as Ochs jokingly calls him).

That month was rough for his patient, recalls DiPersio, Siteman deputy director and the Lewis T. and Rosalind B. Apple Professor of Oncology. “Her treatment was complicated by life-threatening infections, fevers and low blood counts, but she eventually went into remission,” he says.

During her hospital stay, Ochs participated in a pioneering research project — a collaborative effort between Siteman and Washington University’s Genome Sequencing Center that is supported by an $11 million grant from the National Cancer Institute (NCI). In an effort to trace genetic alterations associated with AML, Siteman scientists are collecting cell samples from leukemia patients at the time of diagnosis and at key intervals during the disease process.

“Her cells have been banked, a number of genes have been sequenced and new techniques are being developed to scan her entire AML genome for small mutations, deletions and genetic amplifications that might contribute to her disease,” DiPersio says. “We’re hoping to correlate those changes with prognosis and treatment.”

Beyond the physical effects of chemotherapy — fatigue, nausea, total hair loss — Ochs minded the psychological stress still more. “From the time you wake up in the morning to the time you go to bed at night, it is always there,” she says. “Even when you are sleeping, you dream about what’s going on. You constantly wonder: Is that the same feeling I had in my back before? Is that the same twinge? You worry about what will happen if you don’t make it, especially what will happen to your family.”

In Ochs’ case, she had an extra cause for anxiety: her unborn child. With the powerful chemotherapy agents she was taking, should she consider abortion? In the end, she and her husband, members of the Bethalto Church of God, decided to continue with the pregnancy. That July, a tiny daughter was born to them much too early, and she did not survive. They named her Zoe, which means “life” — an appropriate name, says Ochs, because if it hadn’t been for the blood work her physician had ordered during that first prenatal exam, she might not have survived.

Meanwhile, Ochs soon returned to her active life, including her part-time studies for a doctorate in education at Illinois State University. DiPersio — “a straight shooter,” she says gratefully — had given her the statistical chances for survival. If the disease did not recur during the first year, he said, she had a 30 percent chance of making it. After the second year, her odds rose to 70 percent, and after the third, to 90 percent.

A year to the day after her first hospitalization, Ochs discovered not only that she had relapsed but also that she had contracted bacterial pneumonia because of her low-functioning immune system. Soon she was back at Siteman, fighting for her life. This time, she took a more potent chemotherapy drug that caused severe side effects, but her doctors were in an even more desperate battle than she knew.

“The chance of getting patients into remission once they have relapsed within a year of diagnosis is actually quite low, only about 15 percent or 20 percent,” DiPersio says. “But we were fortunate to do that and prepare her for a stem-cell transplant.”

Unfortunately, Ochs’ two younger sisters were not a match, so Siteman — the fifth-largest unrelated donor transplant center in the world — had to search internationally for an unrelated donor. They found one in time, an unnamed European whom Ochs regards as her hero. “I think he is a wonderful person even though I don’t know him,” she says.

By August 2004, Ochs was well enough to go home, where her “families” were ready to support her: Annika and Jeff , her parents and sisters; the church and school families who had sent hundreds of cards and weeks’ worth of meals; and her husband’s colleagues, who had been teaching his classes during their free periods so he could be at her side.

Today, she continues to be healthy and in remission. At the January 2005 announcement of Siteman’s designation as an NCI Comprehensive Cancer Center, she was asked to speak, and she thanked those who had helped her, including DiPersio (“He is truly amazing,” she says); nurse coordinator Maggie Shamroe (“She has even taken the time to call me in the evening”); and cheerful housekeeper Margaret Norwood (“Every morning she opened the blinds to let the sunlight in and said, ‘Isn’t it a beautiful morning?’”).

Although she remains optimistic, Ochs knows that she cannot yet declare victory over her disease. While she waits and hopes for a cure, doctors like DiPersio are developing new treatments. With the help of cellular products provided by Siteman’s Good Manufacturing Practice laboratory, one of the largest university-run facilities of its type in the nation, he is working on a groundbreaking gene therapy trial. This study, aimed at patients who have relapsed after a failed unrelated stem-cell transplant, focuses on the genetic manipulation of T cells that cause graft-versus-host disease (GVHD), an often-fatal transplant complication.

Last fall, Ochs began a new job as director of curriculum and instruction for her district, a role that gives her more time with her family. Her priorities have shifted since her illness. “All those things we take for granted? Now I don’t,” she says. “I’m so thankful to be here, and I make the most out of every day.”

Molecules Might Identify High-Risk Acute-Leukemia Patients



New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.New research suggests that certain small molecules used by cells to control the proteins they make might also help doctors identify adult acute-leukemia patients who are likely to respond poorly to therapy.

Researchers say the findings should improve the understanding of acute myeloid leukemia (AML) and could lead to new therapies for patients with few treatment options.

The study examined the levels of molecules called microRNAs in leukemia cells from 122 patients with high- and intermediate-risk AML and in normal blood stem cells from 10 healthy donors.

The findings showed that both the leukemia cells and their normal counterparts had similar kinds of microRNA, but that the two groups differed in the levels of miRNAs present.

The research also identified two microRNAs present at abnormally high levels that were clearly associated with patient survival.

The investigators verified their findings in an additional group of 60 patients using a different technology.

The study, published online Jan.10, 2008 in the journal Blood, was led by researchers with The Ohio State University Comprehensive Cancer Center and the M.D. Anderson Cancer Center.

“If our results are validated by other groups, these two elevated microRNAs can be used to determine which patients require more aggressive treatment,” says first author Dr. Ramiro Garzon, assistant professor of internal medicine and a researcher with The Ohio State University Comprehensive Cancer Center.

“In addition, they may provide new targets for future therapies – knocking out these two microRNAs might benefit patients who have a poor prognosis.”

This possibility is particularly intriguing, he says, because the two microRNAs – called miR-191 and miR-199a – are also associated with cancers of the lung, prostate, colon, stomach and breast. This suggests that they may be part of a common cancer pathway.

Garzon noted that the study also found an association between high levels of a microRNA called miR-155 in AML patients and a gene mutation called FLT3-ITD. High levels of this microRNA have been reported in other cancers and to cause leukemia in mice.

“Clearly, our findings suggest that the quantity of microRNAs present is important in cancer, suggesting that modulating their levels might offer an effective way to treat the disease in these patients,” he says.

For this study, Garzon and his colleagues used blood samples from newly diagnosed AML patients who had either normal-looking chromosomes, a feature that indicates intermediate risk of recurrence, or other chromosome alterations. These included isolated trisomy 8, the t(11q23) translocation and multiple chromosomal abnormalities that signal a high risk of recurrence.

Together, these groups make up the majority of the 13,400 people expected to be diagnosed with AML in 2007. About 9,000 people that year were expected to die of the disease.

“Our efforts now should concentrate on characterizing how these altered microRNAs might promote leukemia and on developing drugs designed to inhibit their action,” Garzon says.

Funding from the National Cancer Institute, The Paul and Mary Haas Chair in Genetics, a Lauri Strauss Discovery Grant, the Kimmel Cancer Research Foundation, the CLL Global Research Foundation, the AIRC and PRRIITT Regione Emilia Romagna GebbaLab, and the Leukemia Clinical Research Foundation supported this research.

Other Ohio State researchers involved in this study were Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Hansjuerg Alder, Tatsuya Nakamura, Guido Marcucci, Clara D. Bloomfield and Carlo M. Croce.

Why Gene Therapy Caused Leukemia In Some 'Boy In The Bubble Syndrome' Patients



Severe combined immunodeficiency (SCID), sometimes called 'Boy in the bubble syndrome', is a genetic disorder in which the patient lacks most types of immune cell. Almost 10 years ago, two independent groups (one in London, United Kingdom, and one in Paris, France) used gene therapy to treat a few infants with the most common form of SCID, SCID-X1, which is caused by mutations in the IL2RG gene.

Although most infants showed dramatic improvement following gene therapy, 4 of the 9 infants that were successfully treated in Paris developed leukemia between 3 and 6 years after the treatment. The groups in London and Paris had used very similar gene therapy approaches and until now it was not clear why leukemia was detected only in some of the infants treated in Paris. However, Adrian Thrasher and colleagues, at the Institute for Child Health, London, now report that 1 of the infants successfully treated in London also developed a form of leukemia known as T cell acute lymphoblastic leukemia (T-ALL).

In the study, Thrasher and colleagues go on to show why that infant developed leukemia. During gene therapy, the correct form of the IL2RG gene and the vector that carried this into the cells integrated into part of the genome that contained a gene known as LMO2 and activated this gene. In combination with other genetic mutations that were not caused by the gene therapy (including activation of the NOTCH1 gene, deletion of the CDKN2A gene locus, and translocation of the TCRb gene into the SIL-TAL1 locus), this caused the development of leukemia.

In a related paper by Salima Hacein-Bey-Abina and colleagues, the researchers in Paris who performed the other gene therapy trial have now identified similar reasons to explain why 2 of the 4 infants that developed leukemia became sick. In one patient, the gene and vector integrated into the part of the genome that contained LMO2 and activated the gene, and in the other patient, the gene and vector integrated into part of the genome that contained a gene known as CCND2 and activated this gene.

In both infants, other genetic mutations not caused by the gene therapy contributed to the development of leukemia and these mutations were very similar to those observed in the patient treated in London (activation of the NOTCH1 gene, deletion of the CDKN2A gene locus, and rearrangement of the SIL-TAL1 locus).

The authors of both studies hope that these data provide insight that will help in the design of future gene therapy protocols to ensure similar efficacy but decreased toxicity.

Stem Cells May Benefit Leukemia Patients


University of Iowa researchers say leukemia patients may soon have another way to boost their immune systems - embryonic stem cells.

For the first time, scientists used embryonic stem cells in mice to develop functioning white blood cells that fight infection. The breakthrough may help doctors eventually use the cells as an alternative source for bone marrow transplants.

The procedure has not been tested on humans, but researchers say they're getting closer to that goal.

"Embryonic stem cell therapies are no longer distant," said Dr. Nicholas Zavazava, the director of transplant research at UI's medical school.


Zavazava led the stem cell study, which was published in the online edition of Blood, the official journal of the American Society of Hematology.

Patients with severe blood and immune disorders use marrow, umbilical cord blood or peripheral blood for treatment in traditional transplants. Zavazava said embryonic stem cells have an advantage over those methods since they have greater compatibility.

He said the study also opens up the possibility of using embryonic stem cells to condition a patient for kidney and other organ transplants. Currently, certain drugs are used so the body does not reject the transplant.

In the study, scientists induced the protein HOXB4 into embryonic stem cells from mice. The protein is known for helping cells spread and reproduce. The researchers then coaxed the stem cells into a hematopoietic mode, making red and white blood cells and platelets for transplantation.

Zavazava said the study, which lasted about three years, did not violate Iowa's former law that prohibited forms of stem cell research, because only mice were used. Gov. Chet Culver last year signed a bill that lifted the restriction against cloning for therapeutic purposes.

Zavazava said the new law is "a positive thing. We don't sit in our labs and think the FBI or police will come in and lead us to prison."

Nilotinib Appears To Help Chronic Myelogenous Leukemia Patients When Standard Care Fails


The targeted agent nilotinib (AMN107) appears to offer striking benefits in patients with chronic myelogenous leukemia (CML) who are resistant to Gleevec, the standard therapy for this cancer, say researchers at The University of Texas M. D. Anderson Cancer Center.



Results of a 119-patient, phase I dose-escalation study, published June 15 in The New England Journal of Medicine, show that nilotinib offers a relatively favorable safety profile and obvious activity, researchers say, even though the study was not designed to measure the agent's effectiveness.

"We are very excited about this drug," says the study's lead investigator, Hagop Kantarjian, M.D., professor and chair of the Department of Leukemia. "With it, I believe we are going to make another quantum leap in the treatment of CML, allowing us to treat our patients according to their cancer's distinct molecular signature."

Nilotinib is the younger sibling of Gleevec, both of which were developed by Novartis Pharmaceuticals Corporation, which also funded the study. Preclinical studies have shown that nilotinib, which is administered in pill form, is up to 50 times more potent than Gleevec because it was designed to more efficiently bind to, and shut down, the protein enzyme responsible for the disease.
v The June 15 NEJM also includes a report on a phase 1 clinical trial for dasatinib, a medication developed by Bristol-Myers Squibb for CML and acute lymphoblastic leukemia, and an editorial noting the importance of both papers' findings for CML patients and for swift, targeted drug development based on an understanding of cancer at the molecular level.

While Kantarjian notes that nilotinib seems to have fewer side effects than Gleevec, which is considered a safe drug, some patients in this trial were found to have abnormal electrical activity in their hearts, and one patient experienced two cardiac events. "We believe this issue is manageable with the right dose of nilotinib and with careful monitoring, but of course we want to test the agent further to make sure it is 100 percent safe," he says.

"At this point, Gleevec should remain the standard of care," Kantarjian says. "For CML patients who respond to Gleevec, and most of them do, 93 percent are doing well five years after treatment."

The study, which included researchers and patients from M. D. Anderson, the University of Frankfurt and Heidelberg University in Germany, and the H. Lee Moffitt Cancer Center, tested nilotinib in Gleevec-resistant patients who had little or no other treatment options available to them.

The participants had either CML or "Philadelphia-positive" acute lymphocytic leukemia (ALL). These diseases are caused by the swapping of genetic material in bone marrow stem cells, which results in an abnormality called the Philadelphia chromosome, and creation of a new gene. This gene produces the fusion protein, BCR-ABL, which leads to development of leukemia. Gleevec and nilotinib both bind to, and inactivate, BCR-ABL.

In the trial, researchers continually increased the dose of nilotinib from a low of 50 mg. to as much as 1,200 mg. daily in some patients.

Nilotinib improved outcomes in all three forms of CML, and was most effective in treating chronic phase CML, Kantarjian says. Of the 12 patients in this category, 11 had a complete hematological remission of their cancer, meaning a disappearance of all findings consistent with advanced stage CML, and return of blood counts to normal.

A total of 13 of 33 patients in the blastic phase of the disease disease - the most advanced stage - had a hematological response (defined as control of white blood cell counts), and 9 had a cytogenetic response (elimination of cells with the cancer-causing defect). Of 46 patients in the accelerated phase, 33 had a hematological response and 22 had a cytogenetic response.
The agent had less activity than expected in patients with ALL. Only 2 of 13 patients responded, and that may be because the cancer was too advanced to be affected by a single drug, Kantarjian said.

The researchers also found that nilotinib's side effects were quite tolerable, and different than those seen with Gleevec. They included myelosuppression (a reduction in the ability of the bone marrow to produce blood cells), transient increases in bilirubin due to breakdown of red blood cells, and skin rashes.

Kantarjian adds that occasional patients experienced an abnormally long "QTcF" interval, a measurement of the time between the onset and the end of electrical activity in the heart's ventricular chamber. Prolongation of this interval is considered a marker of a cardiac arrhythmia. One patient had two adverse cardiac events that were associated with use of nilotinib, and one sudden death was reported in a patient beyond the follow-up time analysis, he says, but the cause of that death is unknown.

"This finding indicates the need for careful monitoring for cardiac events and arrhythmias in all patients who are receiving nilotinib, and a strict avoidance of medications that may prolong the QTcF interval," the researchers write in their paper.

"We would like to see, in the long run, if there are any unusual side effects to nilotinib, and then directly compare it with Gleevec in newly diagnosed CML patients," Kantarjian says. "In the future, nilotinib could possibly emerge as the standard of care."

Co-authors of the study include, from M. D. Anderson: Francis Giles, M.D., Susan O'Brien, M.D., and Jorge Cortes, M.D.; from J. W. Goethe Universitat, Frankfurt: Oliver G. Ottmann, M.D., Lydia Wunderle, M.D., Barbara Wassmann, M.D., and Dieter Hoelzer, M.D.; from Novartis Pharmaceuticals: Chiaki Tanaka, M.D., Paul Manley, M.D., Patricia Rae, William Mietlowski, Ph.D., Kathy Bochinski, Margaret Dugan, M.D., and Leila Alland, M.D.; Andreas Hochhaus, M.D., from the Univeristate Heidelberg; Kapil Bhalla, M.D., from Moffitt Cancer Center; Maher Albitar, M.D., Ph.D., from Quest Diagnostics; and James D. Griffin, from the Dana Farber Cancer Center.

Green Tea Extract May Help Some Chronic Leukemia Patients


Herbology

A new case study by Mayo Clinic researchers provides preliminary evidence to suggest a component of green tea may lead to clinical improvement in patients with chronic lymphocytic leukemia (CLL). Findings are published online in Leukemia Research. In the small case study, the researchers report on four patients who appeared to have an improvement in the clinical state of their disease after starting over-the-counter products containing epigallocatechin gallate (EGCG), an extract of green tea. Three of the four patients met the standard criteria used to define a response treatment for clinical trials. These same investigators had previously shown that EGCG kills leukemia cells from patients with CLL in the test tube by interrupting the communication signals they need to survive. That study was published in Blood in 2004.

"The experience of these individuals provides some suggestion that our previously published laboratory findings may actually translate into clinical effects for patients with this disease," says Tait Shanafelt, M.D., Mayo Clinic hematologist and lead author of the article. Despite these encouraging preliminary findings, he urges caution. "We do not know how many patients were taking similar products and failed to have any benefit. We also do not yet know the optimal dose that should be used, the frequency with which patients should take the medication, and what side effects will be observed with long-term administration."

Dr. Shanafelt and his colleagues say more studies are needed to determine these things before they would recommend widespread use by patients. Dr. Shanafelt is also the lead investigator in an ongoing clinical trial sponsored by the National Cancer Institute studying pharmacologic doses of EGCG in pill form for patients with CLL.

CLL is a blood and bone marrow cancer that affects 8,000 to 15,000 new patients each year in the United States. Its called chronic leukemia because it progresses more slowly than acute leukemia, and lymphocytic because it affects a group of white blood cells (lymphocytes), which typically fight infection.

CLL has no known cure and affects each individual differently. Some patients may live with it for decades and not require treatment, while others need immediate chemotherapy, and some die within months despite therapy. Because the course of the CLL is so variable, physicians have historically adopted an attitude of watchful waiting with early-stage CLL patients. However, new tests, new medications and a better understanding of the disease have stimulated interest in clinical trials to evaluate whether options beyond watchful waiting will better serve some patients.

"Green tea has long been thought to have cancer-prevention capabilities," says Dr. Shanafelt. "It is exciting that research is now demonstrating this agent may provide new hope for CLL patients."

Other Mayo Clinic researchers who collaborated on this paper included Neil Kay, M.D.; Yean Kit Lee; Timothy Call, M.D.; Grzegorz Nowakowski, M.D.; David Dingli, M.D., Ph.D.; and Clive Zent, M.D.

To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories.

Leukemia gene normally has mammary gland function


St. Jude discovers gene linked to highly lethal leukemia when mutated is normally critical for mammary gland function during nursing

A gene critical for normal mammary gland function during nursing helps trigger highly lethal leukemias when it undergoes a mutation that fuses it to another gene, according to investigators at St. Jude Children's Research Hospital.


The discovery of the gene’s normal function and that its only major role involves the mammary glands suggests that drugs that might be developed in the future to treat it could also be given to leukemia patients with few serious side effects.

A report on this finding appears in the July 19 online posting of the August 6 issue of Molecular and Cellular Biology.

The researchers made their discovery while trying to determine the normal functions of a gene called MKL1 (megakaryoblastic leukemia 1), which is part of a mutation that causes acute megakaryoblastic leukemia (AMKL) in children, according to Stephan Morris, MD, a member of Pathology and Oncology at St. Jude. AMKL is a leukemia in which megakaryocytes—the bone marrow cells that normally produce the blood platelets that control blood clotting—reproduce uncontrollably. The leukemia mutation, caused by the fusion of MKL1 to the gene RBM15, forms the RBM15-MKL1 fusion gene, according to Morris. AMKL resulting from this mutation usually has only a 20-25 percent survival rate.

The other authors include Yi Sun (lead author), Kelli Boyd, Wu Xu, Jing Ma, Carl Jackson, Amina Fu and Zhigui Ma (St. Jude); Jonathan Shillingford, Gertraud Robinson and Lothar Hennighausen (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.); and Johann Hitzler (The Hospital for Sick Children, Toronto, Canada).

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization

Desperate situation of the leukemia patients in Romania


“The situation of the people suffering from acute leukemia in Romania is dramatic. The medicines are not enough, hospital conditions are disastrous. The main issues are the lack of money and improper resource management. Therefore, leukemia patients in Romania have fewer chances to survive and to recover than the ones in Western Europe, for instance.
However there are Romanian doctors trying to change this tragic situation. One of them is MD Andreea Moicean, in the Fundeni University Institute, Center of Hematology and Bone Marrow Transplantation, the most important institute of this type in Romania.
[c:1:s]What is the current situation of the leukemia patients in Romania?
Andreea Moicean: Leukemia patients are divided in two categories: the ones suffering from chronic leukemia and the ones with acute leukemia. For the patients in the first category efficient and very expensive drugs, recently discovered, are also available in Romania. (e.g. Glivec for chronic granulocyte leukemia).
I must mention though that the access to these medicines is somehow restricted, for Romanian patients. Mainly this access depends on a commission of the National House for Health Insurance that monthly approves the start and also the continuation of the treatment. This commission gives the green light within the limits of the approved and inflexible funds. Those commissions exist in the Western countries, too.
Apart from that, in Romania, modern and efficient treatments for chronic leukemia are not at discretion but they are accessible.
The most important issue in Romania is the situation of acute leukemia patients.
In the field of acute leukemia, as it was emphasized at the latest Congress of European Group for Blood and Marrow Transplantation (EBMT), which took place between 24 and 28 March, 2007, at Lyon, France, no new medicines have been released in the last decades.
What has been brought as novelty in treating acute leukemia, recently, was the treatment strategy and particularly: the administration of new combinations of the well-known cytostatics and, most important, the use of large and very large doses of these drugs.
Sadly, in Romania, acute leukemia patients rarely benefit from proper treatment and looking after.


An actual situation, from the statistical point of view, is difficult to be produced by any of competent officials (from the Ministry of public Health, from the Romanian Society of Hematology, from the National House for Health Insurance).
And the reason is the complete lack of accurate and complete statistics - at any level (either locally at the level of sanitary units, or centrally at the level of the above mentioned institutions) -, regarding the number of people suffering from hematological malign diseases, including acute leukemia.
To put it simple: we do not know the number of people suffering of acute leukemia in Romania, either general or by leukemia categories. This is an example of improper management and lack of communication.
In the Center for Hematology and Medullary Transplant of Fundeni Clinical Institute, which is the largest unit treating hematology patients in the country and the oldest (with a total of 157 beds, it is a mammoth unit compared to any of the ones existing in the Western countries!!!), we have registered, between 1979- 2005, only the adult patients with acute lymphoblast leukemia - 802
- and the one diagnosed with acute myeloblast leukemia - 1827. Talking strictly about years 2004 and 2005, we have come up with an average of 40 patients per year with acute lymphoblast leukemia and 50 patients per year with acute myeloblast leukemia.
What about the treatments? Are they the same as abroad? Do the Romanian leukemia patients have the same chances of recovering?
A. M.: Unfortunately, and I regret to say that, to the question whether acute leukemia is treated in the same way here like abroad, my answer is yes and no. To the second question I can definitely answer NO, the Romanian people suffering from acute leukemia DO NOT have the same chances of healing.
The reasons can be grouped in two main categories:
The first one refers to the medicines: cytostatics, antibiotics, antiviral, antifungal, growth factors, and cortisones, all essential and indispensable for the treatment of acute leukemia. The quantities are insufficient and frequently they are not provided in due time.
A doctor, treating averagely 12 hematological patients of all kinds, is given “a portion” of cytostatics, antibiotics, which will - at most -provide the proper treatment for only one acute leukemia patient.
But what if there are 2? What about the other patients? They may need the same medicine, except in smaller quantities! There are terrible situations when, for instance, a patient comes in on, let’s say, April 2nd and he cannot have a proper and complete treatment, not until after the 15th of the month, when the medicine provisions for this month arrive.
This may lead to loosing the remission, altering of the treatment protocol with a definite impact on the recovering chances. The money spent are the same only the efficiency is lower. Improper management.
The second category refers to the hospital conditions: hygiene, isolation, diet, quality of air and water. In Romania, all these are much below the ones imposed by efficient treatment of acute leukemia patients. There exist no written European standards in the sanitary field, but there are some requirements imposed by the level of care.
You cannot look after an acute leukemia patient in the same conditions as a chronic leukemia patient, because you might kill him. You cannot hospitalize in the same place an acute leukemia patient with a patient having lymphoma.
The first one may develop life risking complications, while the second may very well receive the correct treatment in ambulatory conditions, too (option often chosen in Western Europe).
We must understand one thing: the acute leukemia patient is not an ordinary hematological patient. He is one of the most complicated and demanding patients of known by medical science. The basis of acute leukemia treatment has radically changed during the last decade.
It consists now of administration, after inducing the remission, of high and very high doses of cytostatics within a short period of time.
Administering small and repeated doses, to acute leukemia patients, over a period of 2.5 - 3 years, treatment popular in the 70s - 80s, is now obsolete.
These large doses that represent the basis of the modern treatment for acute leukemia are meant to diminish, ideally to eradicate, the residual disease which represents the source of relapse and the cause for late death in acute leukemia.
During and after these very aggressive treatments, the acute leukemia patient is extremely vulnerable to infections of all kind: bacterial, viral, fungic - infections that represent the precocious cause of death in acute leukemia.
These infections have both internal origins, meaning that they originate within the natural cavities of the human body (bowel, alimentary canal, pharynx, and upper breathing apparatus), and contamination from the environment: air, water, food.
Therefore an acute leukemia patient must be hospitalized from the very beginning in an extremely clean environment, even “sterile”, similar to the one required by transplantation: filtered air, filtered water, sterile food, in a room with its own bathroom/ toilet for one, maximum two patients, not more.
There are also some other issues related to visitors and to overworked medical staff. We have the same situation in the whole country. Anywhere in Romania, there are no conditions for a proper looking after leukemia patients.
The hospitals are poorly equipped, the hygiene conditions are way below the international standards and all these are making patients’ life much more difficult. Is this mainly because of money shortage? What about the management?
A.M.: This situation is due to the lack of money. However, part of these issues could be solved by a better management.
There are lots of examples of possible improvements such as: instead of having 4 or 8 patients with all types of hematological diseases (acute leukemia mixed with chronic leukemia, lymphomas, anemia, and hemorrhagic syndromes) hospitalized in the same room, a good management would have rooms with only 1-2 beds with its own bathroom/ toilet exclusively for caring the acute leukemia patients,
while the others can be hospitalized in rooms with more beds with common bathroom/ toilet or in clinic because they don’t have such severe diseases.
This separation would be beneficial from all points of view: the treatment would develop without complications or with fewer complications, for the patient, less expenditures, better results in terms of surviving and quality of life, and even better healing chances.
Back in the ‘90s, when I visited for the first time a hematology unit in Western Europe, in France, they were saying that treating acute leukemia was much more expensive compared to curing lymphomas and chronic leukemia.
Today, by rationalizing the consume because of hospitalization conditions for the acute leukemia patient on one hand, and because of introducing expensive medicines in the practice of lymphomas and chronic leukemia treatments on the other hand, we cannot talk with the same certitude about expensive and cheap diseases.
This is just an issue of management and of understanding the treatment programs on medium and long term.
To draw a conclusion, in Romania we desperately need to build adequate hospital units dedicated strictly to the care of acute leukemia patients, with trained personnel for dealing with these very fragile patients and with permanent supplies of the necessary medicines.”

Exposure To Night Light may Increase The Risk Of Leukemia



A pitch-black room may be the healthiest environment for your child at bedtime. According to new research , increased light at night // may put children at risk for leukemia. Researchers have determined that light at night is found to disrupt the circadian rhythm and suppress the production of melatonin.

As an antioxidant, in many studies melatonin has been shown to protect DNA from oxidative damage. Once damaged, DNA may mutate and carcinogenesis may occur. Past research has found a correlation between night workers and an increased risk for breast cancer, further supporting the theory that light at night is a risk factor for leukemia.

Researchers conclude saying that if melatonin levels are altered by magnetic fields, a potential relationship between these fields and cancer, including leukemia, would be possible.

Leukemia pill shows promise against stomach cancer


Gleevec, which was just approved for treating leukemia, also shows promise against a type of stomach cancer . The Food and Drug Administration approved the use of a promising anti-leukemia drug for treatment of a relatively rare form of abdominal cancer. The drug, Gleevec, administered as a pill once a day, is effective in treating both forms of cancer because of its ability to target and kill cancer cells without attacking healthy cells and causing severe side effects. //


Approved last spring for a common type of adult leukemia, Gleevec can now be used to treat gastrointestinal stromal tumors, or GIST, which affect as many as 5,000 people in the US each year. Studies have shown it to be as effective in treating chronic cases of GIST as it has been in treating chronic myelogenous leukemia (CML).

Researchers reported 59 percent of patients with advanced-stage GIST went into remission and up to 75 percent showed some type of improvement with limited side effects. GIST accounts for about two percent of all abdominal cancers. If caught early, these tumors can usually be removed surgically, but growths often return. According to its manufacturer, Novartis Oncology, Gleevec also is being studied as a possible treatment for prostate cancer, small-cell lung cancer and a rare type of brain cancer.

Treating Leukemia With Natural Cells


Natural killer cells are part of the body’s immune system and help protect the body against infection and some cancers, particularly leukemia. A new study shows promising treatment for acute myelogenous leukemia // patients may lie in artificially stimulating natural killer cells from a patient’s family member. Researchers say this method could help treat patients with the highly fatal cancer of the bone marrow that has become resistant to standard treatment with chemotherapy.


Patients with AML do not have killer cells able to effectively fight the cancer cells. For the study researchers compared 19 patients with AML to a control group of eight patients with renal cancer. The groups received different types of chemotherapy drugs, and both groups received a protein substance that makes infection-fighting cells multiply and mature. This substance artificially stimulated the natural killer cells obtained from a patient’s family member and infused into the patient.

The infused natural killer cells expanded in the AML patients with the ability to fight tumors, but there were no notable responses in the patients with renal cancer. Researchers believe the chemotherapy combination of cyclophosphamide and fludarabine allowed for the expansion of infused natural killer cells. These donated cells thrived in some patients for more than 28 days, and five of the 19 patients achieved remission. However researchers say more research needs to be done in order to broaden the treatment capabilities of AML and give more hope for patients
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Hope for Chemo-Resistant Leukemia Patients


For patients with chemo-resistant leukemia, a new drug is showing promising results.For the past decade, researchers // have been experimenting with bacteria-based recombinant immunotoxins. An immunotoxin is bioengineered and consists of only the most essential and functional part of the antibodies that are commonly used to fight leukemia. One of those immunotoxins, BL-22, is showing encouraging results in a phase II study.


Researchers say in a phase I study, 19 of 31 patients with hairy cell leukemia had a complete remission of the disease after treatment. Another six people had partial responses. Researchers say, even if patients did not have remissions, they usually had improvements in their blood count to a level that was nearly normal. This is significant because most hairy cell leukemia patients die from low blood counts.

Researchers say the goal of the phase II study is to determine the best dosage levels and they hope that that response rate [in phase II] will be higher since they are treating with a good dose in all the patients. In the first cycle, trial participants were given 40 micrograms/kilograms every other day for three doses. If patients needed repeated cycles, they were given 30 micrograms/kilograms every other day for three doses.

Researchers say the study showed positive results and many of the patients had complete remissions for a long time.
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A Doctor, a Mutation and a Potential Cure for AIDS


The startling case of an AIDS patient who underwent a bone marrow transplant to treat leukemia is stirring new hope that gene-therapy strategies on the far edges of AIDS research might someday cure the disease.

The patient, a 42-year-old American living in Berlin, is still recovering from his leukemia therapy, but he appears to have won his battle with AIDS. Doctors have not been able to detect the virus in his blood for more than 600 days, despite his having ceased all conventional AIDS medication. Normally when a patient stops taking AIDS drugs, the virus stampedes through the body within weeks, or days.

[Dr. Gero Hutter] Sixten Koerper

Dr. Gero Hütter isn't an AIDS specialist, but he 'functionally cured' a patient, who shows no sign of the disease.

"I was very surprised," said the doctor, Gero Hütter.

The breakthrough appears to be that Dr. Hütter, a soft-spoken hematologist who isn't an AIDS specialist, deliberately replaced the patient's bone marrow cells with those from a donor who has a naturally occurring genetic mutation that renders his cells immune to almost all strains of HIV, the virus that causes AIDS.

The development suggests a potential new therapeutic avenue and comes as the search for a cure has adopted new urgency. Many fear that current AIDS drugs aren't sustainable. Known as antiretrovirals, the medications prevent the virus from replicating but must be taken every day for life and are expensive for poor countries where the disease runs rampant. Last year, AIDS killed two million people; 2.7 million more contracted the virus, so treatment costs will keep ballooning.

While cautioning that the Berlin case could be a fluke, David Baltimore, who won a Nobel prize for his research on tumor viruses, deemed it "a very good sign" and a virtual "proof of principle" for gene-therapy approaches. Dr. Baltimore and his colleague, University of California at Los Angeles researcher Irvin Chen, have developed a gene therapy strategy against HIV that works in a similar way to the Berlin case. Drs. Baltimore and Chen have formed a private company to develop the therapy.

Back in 1996, when "cocktails" of antiretroviral drugs were proved effective, some researchers proposed that all cells harboring HIV might eventually die off, leading to eradication of HIV from the body -- in short, a cure. Those hopes foundered on the discovery that HIV, which integrates itself into a patient's own DNA, hides in so-called "sanctuary cells," where it lies dormant yet remains capable of reigniting an infection.

But that same year, researchers discovered that some gay men astonishingly remained uninfected despite engaging in very risky sex with as many as hundreds of partners. These men had inherited a mutation from both their parents that made them virtually immune to HIV.

The mutation prevents a molecule called CCR5 from appearing on the surface of cells. CCR5 acts as a kind of door for the virus. Since most HIV strains must bind to CCR5 to enter cells, the mutation bars the virus from entering. A new AIDS drug, Selzentry, made by Pfizer Inc., doesn't attack HIV itself but works by blocking CCR5.

About 1% of Europeans, and even more in northern Europe, inherit the CCR5 mutation from both parents. People of African, Asian and South American descent almost never carry it.

Dr. Hütter, 39, remembered this research when his American leukemia patient failed first-line chemotherapy in 2006. He was treating the patient at Berlin's Charité Medical University, the same institution where German physician Robert Koch performed some of his groundbreaking research on infectious diseases in the 19th century. Dr. Hütter scoured research on CCR5 and consulted with his superiors.

Finally, he recommended standard second-line treatment: a bone marrow transplant -- but from a donor who had inherited the CCR5 mutation from both parents. Bone marrow is where immune-system cells are generated, so transplanting mutant bone-marrow cells would render the patient immune to HIV into perpetuity, at least in theory.

There were a total of 80 compatible blood donors living in Germany. Luckily, on the 61st sample he tested, Dr. Hütter's colleague Daniel Nowak found one with the mutation from both parents.

To prepare for the transplant, Dr. Hütter first administered a standard regimen of powerful drugs and radiation to kill the patient's own bone marrow cells and many immune-system cells. This procedure, lethal to many cells that harbor HIV, may have helped the treatment succeed.

The transplant specialists ordered the patient to stop taking his AIDS drugs when they transfused the donor cells, because they feared the powerful drugs might undermine the cells' ability to survive in their new host. They planned to resume the drugs once HIV re-emerged in the blood.

But it never did. Nearly two years later, standard tests haven't detected virus in his blood, or in the brain and rectal tissues where it often hides.

The case was presented to scientists earlier this year at the Conference on Retroviruses and Opportunistic Infections. In September, the nonprofit Foundation for AIDS Research, or amFAR, convened a small scientific meeting on the case. Most researchers there believed some HIV still lurks in the patient but that it can't ignite a raging infection, most likely because its target cells are invulnerable mutants. The scientists agreed that the patient is "functionally cured."

Caveats are legion. If enough time passes, the extraordinarily protean HIV might evolve to overcome the mutant cells' invulnerability. Blocking CCR5 might have side effects: A study suggests that people with the mutation are more likely to die from West Nile virus. Most worrisome: The transplant treatment itself, given only to late-stage cancer patients, kills up to 30% of patients. While scientists are drawing up research protocols to try this approach on other leukemia and lymphoma patients, they know it will never be widely used to treat AIDS because of the mortality risk.

There is a potentially safer alternative: Re-engineering a patient's own cells through gene therapy. Due to some disastrous failures, gene therapy now "has a bad name," says Dr. Baltimore. In 1999, an 18-year-old patient died in a gene therapy trial. Even one of gene therapy's greatest successes -- curing children of the inherited "bubble boy" disease -- came at the high price of causing some patients to develop leukemia.

[Chart]

Gene therapy also faces daunting technical challenges. For example, the therapeutic genes are carried to cells by re-engineered viruses, and they must be made perfectly safe. Also, most gene therapy currently works by removing cells, genetically modifying them out of the body, then transfusing them back in -- a complicated procedure that would prove too expensive for the developing world. Dr. Baltimore and others are working on therapeutic viruses they could inject into a patient as easily as a flu vaccine. But, he says, "we're a long way from that."

Expecting that gene therapy will eventually play a major role in medicine, several research groups are testing different approaches for AIDS. At City of Hope cancer center in Duarte, Calif., John Rossi and colleagues actually use HIV itself, genetically engineered to be harmless, to deliver to patients' white blood cells three genes: one that inactivates CCR5 and two others that disable HIV. He has already completed the procedure on four patients and may perform it on another.

One big hurdle: doctors can't yet genetically modify all target cells. In theory, HIV would kill off the susceptible ones and, a victim of its own grim success, be left only with the genetically engineered cells that it can't infect. But so far that's just theory. All Dr. Rossi's patients remain on standard AIDS drugs, so it isn't yet known what would happen if they stopped taking them.

In 1989, Dr. Rossi had a case eerily similar to the one in Berlin. A 41-year-old patient with AIDS and lymphoma underwent radiation and drug therapy to ablate his bone marrow and received new cells from a donor. It is not known if those cells had the protective CCR5 mutation, because its relation to HIV hadn't been discovered yet. But after the transplant, HIV disappeared from the patient's blood. The patient died of his cancer 47 days after the procedure. Autopsy tests from eight organs and the tumor revealed no HIV.

Symptoms of hypercalcaemia


It is not always easy for a doctor to spot that you have hypercalcaemia. You may not have any specific symptoms. It may be that you just feel unwell or a bit “off colour”. And the severity of your symptoms doesn’t always match up to the calcium level in your blood. People with a mildly high calcium level can have very severe symptoms, and people with a very high calcium level may only have mild symptoms. Many of the symptoms are common in the advanced stages of cancer, even in people who do not have hypercalcaemia.
All this can make it difficult for your doctor to pick hypercalcaemia up. But generally speaking the first signs include

  • Extreme tiredness (fatigue) and lethargy
  • Feeling weak
  • Not wanting to eat much (anorexia)
  • Constipation
  • Loss of concentration and interest in doing things
  • Mild confusion

If the hypercalcaemia is not treated then the symptoms become much worse and can include

  • Feeling and being sick
  • Drowsiness
  • Passing large amounts of urine
  • Feeling very thirsty
  • Dehydration
  • Confusion
  • Agitation
  • Muscle spasms, tremors.
  • Bone pain and weakness
  • Irregular heart beat
  • Difficulty thinking and speaking clearly
  • Coma and finally death, if not treated

Because calcium plays a role in the normal working of the brain and spinal cord, patients with severe hypercalcaemia may also

  • Have fits
  • Be unable to coordinate muscle movement which can affect walking, talking and eating
  • Have changes in personality
  • Have hallucinations

If you have hypercalcaemia, you will need treatment from your specialist. It can be a life threatening condition if it is not treated. You may have to spend a day or two in hospital to get your calcium levels down.

Skin cancer patient 'cured' using his own blood cells



A 52-year-old man with advanced melanoma, the lethal form of skin cancer, has been successfully treated using just his own blood.

The development has been hailed by British experts as an "exciting advance" in the use of cancer immunotherapy, which harnesses the body's immune system to fight the disease.

Researchers in the US who were treating the patient extracted white blood cells, the key component of the immune system, and grew one type – the infection-fighting CD4+ T cells – in the laboratory. The cloned T cells, which had been vastly expanded, were then reinfused to the patient to fight the cancer.

The man was diagnosed with stage four melanoma, when death normally occurs within months. The cancer, triggered by sunburn, started in a mole on the skin and had spread to a lymph node in his groin and to his lungs. But, two months after the T-cell treatment, scans revealed no tumour. Two years later, when he was last checked, the man remained free of the disease. He had previously had surgery and drug treatment without any response.

Melanoma is the deadliest form of skin cancer, causing 1,800 deaths a year in the UK. It is the fastest rising cancer, with cases up 40 per cent in the past decade. The cancer is caused by intermittent, intense exposure to the sun. The typical victim is the office worker who spends two weeks broiling on a beach each summer. Adults with fair skin who suffered severe sunburn before the age of 15 are at highest risk.

Cassian Yee, who carried out the experimental treatment with colleagues at the Fred Hutchinson Cancer Research Centre in Seattle, said that one in four late-stage melanoma patients had the same type of immune system and tumour antigen as the patient, for whom the therapy could be effective. But he warned that they had only proved its success in one patient. "We were surprised by the anti-tumour effect of these CD4+ T cells and its duration of response. For this patient we were successful, but we would need to confirm the effectiveness of the therapy in a larger study."

The findings are published in The New England Journal of Medicine, which describes them in a commentary as a "novel strategy" which points to a "feasible new direction" for treatment.

Louis Weiner, the author of the commentary and director of the Lombardi Comprehensive Cancer Centre in Washington, said that although it was too early to be sure of the significance of this one case, the indications were that it will give a substantial boost to the technique of cancer immunotherapy. "I suspect that if the destination is not yet at hand, it is in sight. The endgame has begun," he said.

Cancer immunotherapy is a growing area of research which has proved successful in some other cancers, including kidney cancer. The aim is to developless toxic treatments which are at least as effective as chemotherapy and radiation.

Ed Yong, a health information manager at Cancer Research UK, said: "While it's always good news when anyone with cancer gets the all-clear, this treatment will need to be tested in large clinical trials to work out how widely it could be used."

Professor Peter Johnson, Cancer Research UK's chief clinician and a consultant in Southampton, said: "Although the technique is complex and difficult to use for all but a few patients, the principle that someone's own immune cells can be made to work in this way is very encouraging."

How immunotherapy works

* Cancer immunotherapy is the technique of harnessing the body's immune system to attack the cancer.

* The immune system normally responds to threats to the body by distinguishing between itself and foreign invaders.

* In the case of cancer, this is difficult because most tumours consist of the body's own cells growing out of control.

* However, many cancer cells display unusual antigens or receptors on their surface that allows them to be identified.

* Antibodies and cancer vaccines to stimulate the immune system are being developed to attack these tumour cells.

 

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