terça-feira, 15 de novembro de 2011

Bone Marrow Transplant - Mayo Clinic

Transplante de Medula Óssea

Transplante de Células Hemopoéticas

http://www.sbhh.com.br/pdf/transp-celulas-hemopoeticas.pdf

Leukaemia vaccine being developed

05 Jan 2010, PR 03/10

White Blood CellScientists at King’s have developed a vaccine treatment for Leukaemia that can be used to stop the disease returning after chemotherapy or bone marrow transplant. The vaccine is due to be tested on patients for the first time. Eventually it is hoped the drug, which activates the body's own immune system against the leukaemia, could be used to treat other types of cancers.

Leukaemia is a cancer of the white blood cells and bone marrow affects around 7,200 patients a year. Around 4,300 die from the disease annually. Treatment comes in two stages - chemotherapy to rid the body of the disease, then to prevent it returning either further chemotherapy or a bone marrow transplant. Latest survival rates show that more than half the people with leukaemia die within five years of diagnosis.

The first patients to be treated as part of the clinical trial at King’s College Hospital, have the form of the disease known as Acute myeloid leukaemia (AML), the most common form in adults. Even with aggressive treatment half would usually find the disease returns. In the initial stages of the trial patients will be enrolled in the trial if they have had chemotherapy and a bone marrow transplant. If early trials are successful the vaccine may be tested in patients who cannot have a bone marrow transplant because they are unsuitable or a match cannot be found.

The study, led by Professors Ghulam Mufti and Farzin Farzaneh and Dr Nicola Hardwick, has involved intricate work to develop a man-made virus, which carries the two genes into the immune system.

Farzin Farzaneh, Professor of Molecular Medicine, in the Department of Haemato-oncology at the College, said if the trials are successful then the vaccine could be "rolled out" to treat other leukaemias and cancers. ‘It is the same concept as normal vaccines. The immune system is made to see something as foreign and can then destroy it itself. This has the chance to be curative.’

Cancer ‘vaccines’

The idea behind cancer 'vaccines’ is not necessarily to prevent the disease. Instead, once a patient has been diagnosed, the 'vaccine' programmes the immune system to hunt down cancer cells and destroy them. The vaccine then prompts the immune system to recognise leukaemia cells if they return which prevents a relapse of the disease. The vaccine is created by removing cells from the patient's blood and manipulating them in the laboratory.

The cells are given two genes which act as flags to help identify the leukaemia. It effectively focuses and boosts the immune system's ability to seek out and destroy cancer cells. The research is due to be published in the Journal of Cancer Immunology, Immunotherapy shortly.

The study follows successful experiments on experimental tumour models showing that injection with the gene modified tumour cells results in the induction of immune mediated tumour rejection.

The work, which has taken 20 years to develop, has more recently been funded by the Department of Health and various charities including: Cancer Research UK, the Leukaemia Research Fund (LRF) and the Elimination of Leukaemia Fund (ELF).

The research was carried out at King's College London's Experimental Cancer Medicine Centre (ECMC), which is one of 17 new centres across the country launched to develop basic science into treatments for patients as quickly as possible.

King’s Health Partners members King’s College London and King’s College Hospital are jointly sponsoring this groundbreaking research.

http://www.kcl.ac.uk/news/news_details.php?news_id=1257&year=2010

Patient Trials of New Leukemia Cancer Vaccine Begun

ScienceDaily (Jan. 31, 2011) — A new cancer treatment which strengthens a patient's immune system and enables the body to fight the disease more effectively is being trialled on patients for the first time in the UK.

The treatment will use a new DNA vaccine, developed by scientists from the University of Southampton, which will treat a selected group of volunteers who have either chronic or acute myeloid leukemia -- two forms of bone marrow and blood cancer.

Scientists believe they can control the disease by vaccinating patients against a cancer-associated gene (Wilm's Tumour gene 1), found 'expressed' in almost all chronic and acute leukemias.

A team of researchers and health practitioners, led by Professor Christian Ottensmeier of the University of Southampton Experimental Cancer Medicine Centre and Dr Katy Rezvani of Imperial College London and Imperial College Healthcare NHS Trust, hope to recruit up to 180 patients to the trial which will take place at hospitals in Southampton, London and Exeter over the next two years.

The research is funded by the charity leukemia & Lymphoma Research and the Efficacy and Mechanism Evaluation (EME) programme, which is financed by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR).

"In chronic myeloid leukemia, current treatment can reduce the cancer but the drug needs to be taken indefinitely and has unpleasant side effects. Prognosis of acute myeloid leukemia is currently poor and better treatments are urgently needed," comments Christian Ottensmeier, professor of experimental cancer medicine at the University of Southampton and consultant oncologist at Southampton University Hospitals NHS Trust.

"We have already demonstrated that this new type of DNA vaccine is safe and can successfully activate the immune systems in patients with cancer of the prostate, bowel and lung. We believe it will prove to be beneficial to patients with acute and chronic myeloid leukemia."

Dr Katy Rezvani, clinical senior lecturer at Imperial College London and consultant haematologist at Imperial College Healthcare, says: "At Hammersmith Hospital we have been using targeted leukemia drug therapies, like tyrosine kinase inhibitors, for over 10 years. While these drugs are the first line therapy for chronic myeloid leukemia patients, they can rarely 'cure' the condition. This new vaccine has the potential to improve the outcome of leukemia treatments and could serve as a method of managing solid tumours."

Professor Freda Stevenson, an immunologist at the University of Southampton who is also working on the study, adds: "I'm very pleased with the results from the laboratory research, and am optimistic the vaccine will be successful in making a real difference to patients with myeloid leukemia."

In the study, each participant will receive six doses of DNA vaccine over a six month period, with further booster vaccinations if successful. The vaccine will be administered in a groundbreaking new way, using electroporation, in which controlled, rapid electrical pulses create permeability in cell membranes and enable increased uptake of biological material after its injection into muscle or skin tissue. The electroporation system was developed by the US pharmaceutical company Inovio.

Inovio's CEO Dr J Joseph Kim, says: "This study expands Inovio's long-standing relationship with the University of Southampton into an important disease area. We are proud that Inovio will make a significant contribution to this Phase II trial for these cancers with clear unmet medical needs."

The DNA vaccine was developed at the University with funding from leukemia & Lymphoma Research and Cancer Research UK.

Dr David Grant, Scientific Director of leukemia & Lymphoma Research, adds: "We are delighted to see this trial in leukemia go ahead. It is an important step for us to see the laboratory work on DNA vaccines that the charity has supported take the next logical step into clinical testing. The trial has undergone extensive international peer review and we are very excited to see the first patients being treated. We believe that this vaccine has real promise to improve outcomes in patients with leukemia."

The success of the vaccines will be measured over a two year survival period for acute myeloid leukemia and by assessing the immune system's response to the drug using a disease marker (BCR-ABL) for chronic myeloid leukemia.

http://www.sciencedaily.com/releases/2011/01/110131073139.htm

Study Reveals Need for Personalized Approach in Treatment of Acute Myeloid Leukemia

ScienceDaily (May 16, 2011) — A new discovery in mice by researchers at Wake Forest Baptist Medical Center may one day allow doctors to spare some patients with acute myeloid leukemia (AML) from toxic treatments, while also opening the door for new therapeutic research.

AML, the most common form of acute leukemia seen in adults, is an aggressive form of cancer that primarily affects the elderly. Despite years of research, outcomes for most patients remain poor, particularly for one subset of patients with a specific mutation of the FLT3 receptor.

At a microscopic level, each cell's surface is covered in proteins that allow for signals on the outside of a cell to "turn on" various activities inside that cell. FLT3 is one of those receptor proteins. Mutations of the FLT3 receptor are among the most common mutations seen in the disease -- affecting about 20 to 30 percent of AML patients -- and have been associated with worse prognosis.

A new study, published recently in the journal Experimental Hematology, reveals that one particular mutation of the FLT3 receptor, called internal tandem duplication (ITD), alters the patient's responsiveness to standard therapy.

"This research uses a mouse model to define the changes in chemotherapy response that the presence of the FLT3-ITD causes," said Timothy S. Pardee, M.D., Ph.D., an assistant professor of hematology and oncology and lead author of the study. "While its affect on prognosis has been well documented, its affect on therapy response has been poorly understood."

Pardee and colleagues used mice that had leukemia, either with or without the FLT3-ITD, to examine the effects of the mutation on responsiveness to two drugs used in combination as standard chemotherapy treatment for AML patients: cytarabine and doxorubicin. Both drugs work by altering the DNA of cells in different ways, causing them to essentially commit suicide.

The researchers found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin, but makes them extra sensitive to cytarabine, when the drugs are administered separately. More importantly, the mutation causes the cells to be resistant overall to the combination of the two drugs, the most common clinical application.

When the mutation occurs, it is a cancer-initiating event. The receptor is no longer able to turn itself off, so it continuously signals the cells to grow and repair damage, such as the damage intentionally caused by doxorubicin.

"The mice who had this mutation seemed to be able to repair certain kinds of DNA damage, specifically, the double strand DNA breaks that the doxorubicin creates," Pardee said. "The FLT3-ITD mutation is telling the cell to repair itself at a pace that keeps up with the amount of damage the drug is designed to cause. If you have a cancer cell that you're trying to kill by doing a certain type of damage and that cell is better at repairing that kind of damage, you have to do more damage to get the cell to die. The mice that were treated with just doxorubicin died at the same rate as those that received no treatment at all."

And, while the FLT3-ITD mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

"It's almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell," Pardee said. "When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it."

Doxorubicin falls into a class of extremely toxic drugs known as anthracyclines. As with other chemotherapy agents, they are known to cause hair loss. However, they are also known to suppress normal cells in the bone marrow and to cause cardiac toxicity. Treatment with drugs of this class can directly injure the heart muscle and sometimes even cause heart failure, Pardee explained.

"Virtually every AML patient in America and Europe who can handle this combination of drugs will receive this standard treatment under current practice guidelines," Pardee said. "More studies are needed to determine the applicability of these findings in humans, but this study shows, in an animal model, that those with the FLT3-ITD mutation are deriving no benefit from the addition of doxorubicin.

"We're hopeful that in the future, these findings will lead to more personalized patient care," he said. "The 'one-size-fits-all' approach to treating AML needs to be re-examined."

In addition to investigating ways to personalize approaches in treatment, Pardee said that future research may focus on developing drugs that can be combined with cytarabine in patients with this mutation and be effective, perhaps by inhibiting the FLT3 receptor or working in ways other than creating double strand DNA breaks.

This research was funded by several sources including the Leukemia and Lymphoma Society, National Cancer Institute, and Wake Forest University Comprehensive Cancer Center. Johannes Zuber, M.D., and Scott W. Lowe, Ph.D., of the Cold Spring Harbor Laboratory, in New York, appear as co-authors on the paper. Lowe is also affiliated with Howard Hughes Medical Institute, in New York.

http://www.sciencedaily.com/releases/2011/05/110516075931.htm

Sorafenib Shows Potential For Treating Some Forms Of Leukemia

ScienceDaily (Jan. 29, 2008) — The drug sorafenib, which is used to treat kidney and liver cancer, may be effective acute myeloid leukemia patients with specific gene mutations.

Previous studies have shown that sorafenib is especially effective against acute myeloid leukemia cells that have certain mutations known as internal tandem duplication (ITD) mutations of the Fms-like tyrosine kinase 3 (FLT3) gene.

Michael Andreeff, M.D., Ph.D., of the University of Texas M. D. Anderson Cancer Center in Houston and colleagues examined sorafenib's ability to kill leukemia cells that express either the common form or mutant copies of FLT3. They also gave sorafenib to mice bearing leukemia cells with known FLT3 gene mutations and to leukemia patients with and without the mutations.

The researchers found that sorafenib slowed growth and induced cell death in the FLT3 mutant leukemia cells and increased survival of the mice with FLT3 mutant leukemia. Sorafenib reduced the percentage of leukemia cells in blood and marrow in patients with this mutation, but not in patients without the mutation.

"Our findings imply that sorafenib is a potent antileukemic agent in patients with FLT3-ITD mutant [acute myeloid leukemia], a form of [the disease] that responds poorly to traditional chemotherapy," the authors write.

This research was recently published in the Journal of the National Cancer Institute.

http://www.sciencedaily.com/releases/2008/01/080129160827.htm

Kidney Cancer Drug Attacks A Major Type Of Acute Myeloid Leukemia

ScienceDaily (Jan. 29, 2008) — A drug used to treat kidney cancer also targets a genetic mutation active in about one third of patients with acute myeloid leukemia (AML), the most common and lethal form of adult leukemia, researchers at The University of Texas M. D. Anderson Cancer Center report in the Jan. 29 edition of the Journal of the National Cancer Institute.

In a Phase I clinical trial, the drug sorafenib reduced the median percentage of leukemia cells circulating in the blood from 81 percent to 7.5 percent and in the bone marrow from 75.5 percent to 34 percent among AML patients whose leukemia includes the FLT3-ITD mutation. Two patients had circulating leukemia cells, or blasts, drop to zero.

"AML patients with this mutation have a particularly poor prognosis, so this highly targeted drug appears to be a significant step forward in leukemia therapy," says senior author Michael Andreeff, M.D., Ph.D., professor in M. D. Anderson's Department of Stem Cell Transplantation and Cellular Therapy and Department of Leukemia.

The JNCI paper reports the drug's effect in lab experiments, a mouse model of the disease, and in a Phase I study of 16 patients with relapsed or resistant AML known to have the FLT3-ITD mutation.

There have been no major side effects in the clinical trial to date, so no maximum tolerated dose has been reached, Andreeff notes. The drug has little effect on cells with normal versions of the gene and does not interfere with normal blood cell formation.

A Phase I/Phase II clinical trial for AML is open at M. D. Anderson that combines sorafenib with the standard of care chemotherapy combination for AML, idarubicin and cytosine arabinoside. Presently, the trial is open for relapsed patients and those newly diagnosed with high-risk disease, says study co-author Jorge Cortes, M.D., professor in M. D. Anderson's Department of Leukemia. As safety and dose escalation research progress, sorafenib will be made available to other patients and assume a role in frontline therapy.

About 14,000 new cases of AML are diagnosed annually in the United States and the disease kills about 9,000 people each year. AML is characterized by swift proliferation of immature white blood cells in the blood and bone marrow that crowds out normal cells, leaving patients exposed to infection, severe anemia, and bleeding.

While major progress has been made treating some forms of leukemia and lymphoma, acute myeloid leukemia has seen less improvement in recent years. Andreeff says that's because AML exploits multiple molecular pathways and that these pathways differ from one type of AML to the next.

Andreeff and colleagues have shown that molecular pathways subverted and used by AML collude with each other, so when one pathway is blocked, the others redouble their efforts to fuel the disease.

"Here we have a great response against an important mutation, but sorafenib alone will not cure patients," Andreeff notes. Combination therapy will be required. Andreeff and colleagues are planning to examine other sorafenib combinations against FLT3-mutant disease.

After in vitro tests showed that sorafenib inhibited the growth of FLT3 mutant leukemia cell colonies, the research team tested the medication in a mouse model of the disease. Sorafenib-treated mice had a median survival of 36.5 days compared with 20.5 days in untreated mice. Bioluminescence imaging showed widespread cancer growth in untreated mice and barely detectable disease in those that had received the drug.

Sorafenib, known commercially as Nexavar® and co-developed by Bayer AG and Onyx Pharmaceuticals, already is approved for advanced renal cell carcinoma and inoperable liver cancer by the U.S. Food and Drug Administration. It is being tested against other solid tumors.

The drug targets both tumor cell growth and angiogenesis - new blood vessels woven by cancer to sustain itself - by targeting two classes of kinases, which are enzymes that affect proteins by attaching phosphate groups to them.

Sorafenib's antileukemia effects appear to be superior to early results of new therapies under development that more narrowly target the FLT3 gene. Andreeff says the drug's ability to hit multiple kinases probably accounts for this, but the exact molecular mechanisms involved require further study.

Co-authors with Andreeff and Cortes are lead author Weiguo Zhang, M.D., Ph.D., who conducted most of the project's laboratory research, Marina Konopleva, M.D., Ph.D., Yue-xi Shi, Teresa McQueen, Xiaoyang Ling, Ph.D., all of the department of Stem Cell Transplantation and Cellular Therapy; David Harris, Zeev Estrov, M.D., and Alfonso Quintas-Cardama, M.D. all of the Department of Leukemia; and David Small, M.D. of Johns Hopkins University School of Medicine.

Research was funded by grants from the National Cancer Institute, a Leukemia SPORE Career Development Award, and the Cancer Therapy Evaluation Program.

http://www.sciencedaily.com/releases/2008/01/080129160739.htm

Compound Found in Common Wart Treatment Shows Promise as Leukemia Therapy

ScienceDaily (Oct. 26, 2011) — A new potential leukemia therapy targets only cancer cells, while leaving healthy cells alone. Many current chemotherapy treatments affect cancer cells and healthy cells, causing significant side effects, such as fatigue, hair loss, nausea, anxiety and depression.
This research is being presented at the 2011 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition in Washington, D.C., Oct. 23-27.

Leukemia is a cancer of the blood and bone marrow, the spongy center of bones where blood cells are formed. According to the Leukemia and Lymphoma Society, an estimated 43,050 people were diagnosed with leukemia in the U.S. in 2010.

Lead researcher and AAPS fellow, Peter A. Crooks, Ph.D., and his colleagues from the University of Arkansas for Medical Sciences have developed a potent compound that only impacts cancer cells, and starts killing them as early as four hours after treatment begins.

"This is one of the most potent and selective compounds I have ever seen during my more than 30-year career," said Crooks.

The molecules used to create this anti-leukemic agent are structurally similar to the compound found in many gout treatments and over-the-counter products used to treat warts, which also prevent cell growth. This agent is able to reach cancer cells before they mature, so catching the disease in its early stages will eradicate it quickly. This is especially vital for treating acute myeloid leukemia, which progresses rapidly without treatment.

"It's good to get excited in the early stages of research when you discover a treatment that could potentially be as outstanding as this," said Crooks. "However, the next phase is to test the treatment in animal models and pinpoint the most effective delivery method."

http://www.sciencedaily.com/releases/2011/10/111026091233.htm