Blood Cancer &
 Leukemia

Leukemia Cancer News October 2004

The Marrow of Life

By Angilee Shah, AlterNet
Posted October 12, 2004

Among minority communities, the need for bone marrow donors has become a critical issue that can mean life or death for leukemia patients.

Sagarika Savur was set to graduate from the University of California, Irvine last spring. She was planning to move to New York and try to make it as a journalist.

But a sudden attack of headaches and breathing problems altered the 22-year-old's plans. In a matter of hours, she discovered that she had acute myelogenous leukemia, or AML, a cancer that affects the blood and bone marrow.

Today, instead of rushing to the New York subway every morning to get to a newsroom, she stays within the walls of the City of Hope National Medical Center in Southern California to be monitored and medicated. She was admitted to the hospital on Aug. 15 for a second round of chemotherapy, but she has still not gone into remission. A bone marrow transplant is the only treatment option left for Sagarika. So she waits in the hospital, where she will most likely remain until a donor with her tissue type can be found.

"Now chemotherapy is not an option," says Sagarika's father, Anand Savur. "Her only hope is a bone marrow transplant," he says, adding, "Time is critical now."

AML produces leukemia cells quite rapidly. Without any treatment, the disease can be fatal in a few months. Sagarika's battle is an especially difficult one; not just because of the pain caused by leukemia or of the side effects of chemotherapy but because Sagarika is South Asian.

A patient must find a bone marrow donor whose tissue type matches his or her own. The highest chance of a match comes first from within the patient's immediate family, and second from someone within the same ethnic group the common genes allow for similar tissue types.

AML is a type of cancer in which the patient cannot produce enough healthy blood cells because of unhealthy bone marrow, the tissue inside the bone that creates different types of blood cells. People with leukemia do not have enough healthy marrow cells, more commonly known as blood stem cells (not to be confused with embryonic stem cells, which come from human embryos). Blood stem cells are blank, not-yet-mature cells that have the capability of becoming platelets, red or white blood cells. In individuals with leukemia, the unhealthy blood stem cells create too many immature white blood cells, which in turn become leukemia cells. These leukemia cells make a patient susceptible to infection, and can cause bone pain, fever, and a host of other symptoms.

Because there are thousands of tissue types out there and fewer than 65,000 South Asians registered as potential donors, a South Asian patient's chances of finding a match is much less than a Caucasian patient. South Asians are not the only minorities in America in this predicament; out of more than five million potential donors registered, only about one million identify themselves as being in a racial minority.

For Sagarika, this means that she can only seek a match from the less than 1 percent of registered donors in America who are South Asian. Because the United States has the only national, centralized registry that includes a significant number of South Asians (South Asian countries, like India and Pakistan, do not have centralized registries), Sagarika and 35 other South Asian Americans like her are hoping that more South Asians will join the national registry to increase their chances of finding a match. In 2003, the national registry was only able to match about 2,000 minorities, out of over 15,000 matches in total.

The National Marrow Donor Program (NMDP) organizes and maintains the registry; of the 5.4 million people in its database, only 64,000 are of South Asian descent. Groups like the South Asian Marrow Association of Recruiters, or SAMAR and Asians for Miracle Marrow Matches or A3M, are stepping in to fill the minority void. Both organizations hold drives and programs to raise awareness around the issue. But it is not easy to convince people to register.

"It requires a lot of pre-education," says Enisha Narang, South Asian Outreach and Recruitment Coordinator for A3M. The NMDP says that, on average, a person needs to hear about bone marrow donation seven times before even considering registration. The relative success of drives, therefore, is not just about how many people register, says Narang. "Even if we don't recruit a lot of donors, we've gotten information out."

And getting the word out seems to be helping. Narang says A3M targets South Asians where they live. "We organize drives, she says, "at all different sorts of events wherever South Asian people gather," including temples, mosques, gudwaras, and even in private homes.

SAMAR uses the same strategy of community and volunteer-based organizing. Dr. Asif Amirali, a SAMAR volunteer in New York City, says that they have been successful, since their inception in 1992, in directly recruiting from start to finish 35,000 South Asians to register and helped to register 20,000 others. The rate of registration continues to rise.

SAMAR is also focusing some of its efforts in creating a national registry in India, which would be available for South Asians both on the subcontinent and in America. They face significant hurdles though.

"It's not easy to get the [Indian] government to commit resources to something like bone marrow registry," says Amirali. So SAMAR is looking for money from private and public sources to build the special labs and pay for testing. Because of the time it will take to begin the registry, plus the time is will take to build a list of donors, Amirali says, "It's going to take years to have a fully functioning registry [in India]."

Mrinmayee Kulkarni, 25, is one of the SAMAR volunteers who make drives and recruitment possible in America. Her work is driven by immediate necessity; Sagarika is one of Kulkarni's best friends. Their families were neighbors in India, so they have known each other since they were small children and have kept in touch ever since. When Kulkarni learned of her friend's illness, she immediately took action.

"I had initially contacted SAMAR to get tested," says Kulkarni, but she realized that the cure is much more complicated than a single person deciding to register. "They [patients] don't have any other cure. Sagarika is undergoing chemotherapy but that's just buying time," says Kulkarni.

Potential Donors on the National Registry
African Americans: More than 430,000
American Indian/Alaskan Natives: More than 65,000
Asian: More than 350,000
Hawaiian/Pacific Islanders: More than 7,000
Hispanic: More than 400,000
White: More than 2.8 million
Did not identify race: about 1 million
Total: More than 5 million

SOURCE: Patrick Thompson, Senior Public Relations and Media Outreach Coordinator, National Marrow Donor Program
Knowing that her registration alone was not going to find Savur a match, Kulkarni began organizing drives in the Washington D.C. area, where she lives, and encourages other South Asians to register. This summer, Kulkarni began volunteering and, in the first drive she organized, recruited 51 people. It has not been easy though. Like Narang, Kulkarni says that people in general, "are not educated enough." "Everybody has wrong notions about bone marrow transplantation and donations," she adds.

NMDP explains in its literature the process of bone marrow registration and donation. In the initial testing, a small amount of blood is drawn from the finger of the potential donor. If the donor is found to match a patient, a few more tests are run and then if the donor decides to continue the donor chooses if he or she wants to draw marrow cells from the hipbone or the blood. According to the NMDP web site, the marrow procedure takes about one hour and is done under general or local anesthesia, which is again, the donor's choice.

Dr. Amirali says a common misperception is that the marrow cells are taken from the back or spine, when in actuality, the needle goes into the hipbone on the side of the body a much less painful experience. "A six-month-old child has donated through the hipbone so any one of us can do it," says Amirali.

To donate from the blood stream, the donor must receive special injections for a few days. In the actual procedure, the blood is drawn through the arm and then run through a machine. In that machine, marrow cells are separated out and stored away in a process called aphaeresis. The blood, without marrow cells, is then returned to the donor's body through the other arm.

Donors recover in one or two days and experience manageable aches. "Most people are able to go back to work the next day or the day after," says Amirali, "and any pain is manageable with Tylenol or Advil."

Kulkarni says, "The donation is not painful or life-threatening as people believe. It's not like the surgery it used to be 10 years ago." Furthermore, for minorities, registrations can be done free of charge through groups like SAMAR. The patients receiving the transplants cover any subsequent donations.

The cost of the procedures, however, is much less than the cost of not being able to find a match. Bone marrow and stem cell transplants are the only real cure for more than 60 diseases, including many types of leukemia and lymphoma, and anemia. While patients first try to match within their own family, nearly 70 percent of the 30,000 patients diagnosed with these diseases each year have to turn to the registry. NMDP has facilitated over 16,000 transplants; only about 400 of the matches have been for Asian patients.

That leaves Sagarika and countless other minority patients waiting anxiously for matches. For Sagarika, a transplant does not just mean a chance to finish college and pursue her journalism dream it means a chance at life.

Angilee Shah is a freelance writer in Southern California and the editor of ABCDLady Magazine.

Night Light Found To Increase The Risk Of Leukemia

10 Oct 2004
According to a new study the healthiest environment for your child at bedtime would be a pitch-black room as researchers say increased light at night may put children at risk for leukemia.

In the 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 have determined that light at night is found to disrupt the circadian rhythm and suppress the production of melatonin. Researchers also says, "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."

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

http://www.medindia.net

[Therapy-related MDS/leukemia carrying dup(11) (q21q23) with MLL gene tandem duplication]

[Article in Japanese]

Takimoto Y, Eguchi M, Eguchi-Ishimae M, Imanaka F, Kamada N.

Department of Internal Medicine, Hiroshima City Asa Hospital.

A 42-year-old woman had been given a diagnosis of malignant lymphoma, follicular, small cleaved cell. She had undergone chemotherapy including etoposide (1,500 mg/total) and was in her second complete remission. Four years and 4 months later, refractory anemia with excess of blasts (RAEB) with dup(11) (q21q23) x 2 developed in the patient and progressed to acute myeloid leukemia (AML-M5b).

Despite regression of the AML to RAEB, a clone with the additional abnormality of del(20) (q11q13.1) appeared and transformed the RAEB into AML-M6. Rearrangement of the MLL gene was observed, and FISH analysis demonstrated that the signal sequences from the gene's 5' and 3'-terminal regions had detached. RT-PCR techniques detected a tandem duplication of MLL gene exons 2 through 8. This was considered to be one of the mechanisms behind the formation of the 11q23 abnormality observed in this patient.

Ilex Clolar (Clofarabine) For Leukemia Will Go To Oncologic Drugs Advisory Committee In December

Ilex pediatric leukemia agent Clolar (clofarabine) will go before the Oncologic Drugs Advisory Committee Dec. 1, the firm says.

October 08, 2004
FDA recently extended clofarabines original Sept. 29, 2004 user fee date by three months. Ilex amended the clofarabine NDA with data on 14 additional patients from two Phase II trials in acute lymphoblastic leukemia and acute myeloid leukemia.

The additional clinical data yielded an increase in overall response rate for ALL patients in the studies (31% vs. 25%), while overall response in AML apparently decreased (26% vs. 34%).

Clofarabines updated PDUFA date is Dec. 30, 2004. The product is receiving a priority review and would be the first drug to be labeled initially for pediatric leukemia in more than a decade, Ilex said Sept. 28.

Clofarabine is one of two drugs slated for review by ODAC on Dec. 1: Inex/Enzon announced Sept. 27 that their non-Hodgkins lymphoma agent Marqibo will be reviewed Dec. 1.

Berlex' bisphosphonate Bonefos (clodronate) will be reviewed as an adjuvant therapy for breast cancer bone metastases on Dec. 2.

To watch a webcast of this meeting, click the button below. To arrange for live videoconferencing, or to order videotapes & DVDs, email [email protected] or call 800-627-8171.

Appeals court ruling upheld in leukemia case
BY TRISH HOLLENBECK Northwest Arkansas Times

October 8, 2004

The Arkansas Court of Appeals this week affirmed a ruling in a Washington County trial court to refuse to instruct the jury on negligence in a wrongful death case involving exposure to chemicals in paints.

The ruling was affirmed Wednesday.

The appeal involves Lincoln resident Betty Roach, administratrix of the estate of Randall Roach, deceased.

On April 20, 2001, Betty Roach sued three paint companies in Washington County Circuit Court, alleging that her husband got leukemia from benzene derived from automotive paint made by those companies. The jury returned a verdict in December 2002 finding that the companies were not at fault in causing damages to Roach. Fourth Circuit Judge Mike Mashburn presided over the trial.

According to the lawsuit, Randall Roach worked briefly as an auto body painter in Ohio with his brother, Stephen Roach, in 1978, then worked as an auto body technician in Fayetteville until 2000. In the course of his work, Roach was exposed to products containing benzene manufactured by PPG Industries, Sherwin Williams and E. I. DuPont de Nemours.

In December 2000, Roach was diagnosed with acute myelogenous leukemia. He died on January 18, 2001.

Jim Miller, attorney for two of the paint companies being sued Sherwin-Williams Company and PPG Industries Inc. said that the paints did not contain benzene but did contain two compounds from which trace amounts of benzene could form. He said that Roach was not exposed to enough benzene to cause any type of leukemia and that the specific leukemia that killed Roach was of a different type than that caused by benzene.

In the appeal, Roach argued that the trial court did not allow her to amend the complaint to conform to the proof to include a negligence count, ruling that it would be unduly prejudicial to defendants to allow the amendment after all the proof was presented. "It was the duty of the court to submit to a cause to the jury only upon issues raised by the written pleadings, or within the pleadings treated as amended to conform to the proof," according to the court of appeals decision, citing case law.

Scientists discover cell mutation that leads to leukemia - and could lead to treatment

Posted Oct 8, 2004 by Sarah Gilbert

When researchers at Brigham and Womens Hospital and Dana-Farber Cancer Institute discovered a cell mutation that leads to the most common type of leukemia, it was a huge breakthrough. Even more important than the scientific knowledge is the reality that drugs have already been developed that address these mutations, which are carried out by enzymes.

Fortuitously, for entirely different reasons, there have been a number of drugs developed to inhibit this enzyme activity, said Dr. Jon Aster, the lead researcher.

With drugs fairly far down the pipeline, he added, we think we can very quickly try some of these drugs in patients with T-cell acute lymphocytic leukemia.

As it stands, patients with this kind of leukemia must undergo toxic levels of chemotherapy, and roughly a quarter eventually are killed by the cancer. Drugs used to treat Alzheimers, among others, could be used on leukemia patients as early as next year.

From BloggingBaby.com

UVa leukemia research wins grant

By Claudia Pinto / Daily Progress staff writer
October 7, 2004

University of Virginia researchers will receive $5 million to develop drugs to shut down the errant proteins that cause leukemia, a cancer of the blood.

The grant, which will be distributed over five years, is from the Leukemia and Lymphoma Society.

Dr. John Bushweller, a UVa associate professor with the department of molecular physiology and biologic physics, said he was pleasantly surprised and dumbstruck when he learned about the grant.

I couldnt speak for a few minutes, Bushweller said. We couldnt do it without the money theyre providing. It would be impossible.

Bushweller said leukemia is caused when certain proteins important to blood cells become altered. He hopes the new medications created at UVa will essentially shut down these altered proteins.

The reason this is important is because the approach is targeted. We focus on the proteins, Bushweller said. Traditional chemotherapy is non-specific and toxic. This is targeted to a specific outcome.

The new drugs will focus on three altered proteins associated with leukemia. Bushweller and Dr. Milton Brown, a UVa associate professor of chemistry, have already created a therapy that targets one of the altered proteins.

In human cells the drug has shown to be effective, Brown said. The next step will be testing in animals. We hope to start that early next year.

The grant will be used to continue research thats already under way at UVa and to begin work on new therapies. In addition, the money will pay for eight new positions, including technicians and research associates.

Its estimated that 33,440 Americans will be diagnosed as having leukemia this year, according to the Leukemia and Lymphoma Society. More than half of all cases occur in people older than 67. But about 30 percent of cancers in children are leukemia.

Survival rates have more than tripled in the last 40 years with improvements in diagnosis and treatment. In 1960, the five-year-survival rate was 14 percent compared with 46 percent today. Still, its estimated that 23,300 Americans will die of leukemia this year.

Therapies for leukemia have gotten better. However, existing treatments are non-specific, Bushweller said. They attack many different kinds of cells. There is a lot of damage and many side effects.

If we are only hitting one or two, maybe three, proteins that are causing the leukemia, there should be less side effects and better outcomes.

Contact Claudia Pinto at (434) 978-7266 or [email protected].

Letter: Writer says marijuana helped his brother:
Thursday, October 7, 2004

To the editor:

Do we really get to vote on a medical marijuana question in November?

I think it should be legalized but I know that will not happen for a long time. I would fight very hard to legalize it for people with medial problems. Here's why: My brother passed away this last June from leukemia. He had it for 18 months and he smoked pot. After his first round of chemo, he lost a lot of weight and he had about six weeks at home before he went back in for more chemo.

At the hospital, the nurse checked his weight because the mixture of chemo administered to a patient goes by his or her weight, and my brother had gained 30 pounds while being home thanks to smoking pot.

You need to gain weight because you lose so much during chemo. If he hadn't smoked pot, he would not have gained as much and he would have been very fragile before the next round. Chemo takes such a toll on the body that he would have gotten much sicker without the weight gain.

Family and friends illegally bought pot for him -- myself included. We know it's illegal to buy but we were helping my brother, but even if I got caught, I would have done it again and again for my brother.

I respect the laws but not this one! I would buy for anyone who needed it to get them through chemo. I've seen first hand how much it helped my brother.

His doctors knew he smoked pot. They told him that if it was legal they would tell their patients to smoke it.

Power to the people who are trying to get this law to pass! If I can help in any way I will.

Michele R. Peloquin

The Leukemia & Lymphoma Society Awards Two $5 Million Grants to Advance the Development of Targeted Anti-Cancer Therapies

Society's Specialized Center of Research Grants Surpass $77 Million

WHITE PLAINS, N.Y., Oct. 6 /PRNewswire/ -- The Leukemia & Lymphoma Society today awarded two Specialized Center of Research (SCOR) grants, bringing funding for the program -- the Society's most synergistic research initiative -- past $77 million in the five years since its inception. The two new awards will advance the development of targeted anti-cancer therapies.

"The two Specialized Center of Research grants awarded this year have the essential ingredients we are looking for," said Marshall Lichtman, M.D., the Society's executive vice president, Research & Medical Programs. "They have outstanding and accomplished scientists, synergy among the projects and investigators, and a high probability of innovative therapies for the diseases under study." Each recipient receives $5 million, distributed over a five-year period.

John Bushweller, Ph.D., associate professor of physiology and chemistry, Department of Molecular Physiology and Biological Physics, University of Virginia, is one of this year's recipients. Dr. Bushweller is developing novel, highly-specific inhibitors of proteins that play a critical role in the development of acute and chronic myelogenous leukemia.

"We are on the brink of a very exciting time for the treatment of leukemia," said Dr. Bushweller. "We are now able to target drugs very specifically to certain proteins, resulting in more effective treatments with vastly reduced side effects and better long-term outcomes for patients." Dr. Bushweller cites the success of Gleevec® in the treatment of chronic myelogenous leukemia as a powerful example of the potential of this approach. "Our SCOR project is based on this concept," he added. "We hope that our research will make it to clinical trials in patients and prove to be highly effective weapons in the treatment of leukemia."

Tak Mak, Ph.D., professor, Department of Immunology and Medical Biophysics, and director, Advanced Medical Discovery Institute, University of Toronto, is the second SCOR recipient. He is studying signaling pathways in leukemia- and lymphoma-genesis.

"Our research efforts are focused on identifying the genetic changes in leukemias and lymphomas that have an impact on programmed cell death," Dr. Mak explained. "Defects in cell death contribute to the development of these cancers as well as to resistance to treatment."

By identifying and comparing leukemic stem cells (LSC) and normal hemopoietic stem cells from patients with myeloid and lymphoid malignancies, Dr. Mak will gain a better understanding of the mechanisms that underlie the resistance to cell death exhibited by LSC and their progeny. The goals of Dr. Mak's SCOR are to gain knowledge that will provide novel risk markers and therapeutic targets that will ultimately improve the design of human clinical trials.

"We are greatly encouraged by the recent discovery within our group that new mechanisms of resistance to cell death exist," Dr. Mak added. "These findings will pave the way for the development of novel targeted anti-cancer therapies."

"The cornerstone of the SCOR program is its collaborative structure: every recipient works with a cross-disciplinary team of leading researchers from their own and other universities and medical institutions," said Alan Kinniburgh, Ph.D. the Society's senior vice president of research. "The concept behind the program is that leukemia, lymphoma and myeloma treatments and cures will be discovered most quickly in an environment of collaboration and teamwork."

Dr. Bushweller's team is working in collaboration with Milton Brown, M.D., Ph.D., University of Virginia; D. Gary Gilliland, M.D., Ph.D., Harvard Medical School; P. Paul Liu, M.D., Ph.D., National Human Genome Institute of The National Institutes of Health; and Nancy Speck, Ph.D., Dartmouth Medical School.

Dr. Mak's team is working in collaboration with John E. Dick, Ph.D., Cynthia Guidos, Ph.D., Jayne Danska, Ph.D., University of Toronto; Doug Green, Ph.D., La Jolla Institute for Allergy Immunology; and Mark Minden, M.D., Ph.D., Ontario Cancer Institute.

About The Leukemia & Lymphoma Society

The Leukemia & Lymphoma Society®, headquartered in White Plains, NY, is the world's largest voluntary health organization dedicated to funding blood cancer research and providing education and patient services. The Society's mission: Cure leukemia, lymphoma, Hodgkin's disease and myeloma, and improve the quality of life of patients and their families. Since its founding in 1949, the Society has invested more than $360 million in research specifically targeting leukemia, lymphoma and myeloma. Last year alone, the Society made more than 812,000 contacts with patients, caregivers and healthcare professionals through services provided at its Home Office and by its 63 chapters nationwide.

For more information about blood cancer, visit http://www.LLS.org or call the Society's Information Resource Center (IRC), a call center staffed by master's level social workers, nurses and health educators who provide information, support and resources to patients and their families and caregivers. IRC information specialists are available at (800) 955-4572, Monday through Friday, 9 a.m. to 6 p.m. ET.

Contact: Jon Garbo
914-821-8969
------------------------------------------------------
Source: The Leukemia & Lymphoma Society

How Is Adult Acute Leukemia Diagnosed?

Signs and Symptoms of Acute Leukemia

Acute leukemia can cause many different signs and symptoms. Most of these occur in all kinds of acute leukemia, but some are particularly common with certain subtypes.

Patients with acute leukemia often have several generalized symptoms. These can include weight loss, fever, and loss of appetite. Of course, these are not specific to acute leukemia and are more often caused by something other than cancer.

Most signs and symptoms of acute leukemia result from a shortage of normal blood cells due to crowding out of normal blood cell-producing bone marrow by the leukemia cells. As a result, people do not have enough properly functioning red blood cells, white blood cells, and blood platelets.

Anemia, a shortage of red blood cells, causes shortness of breath, excessive tiredness, and a "pale" color to the skin.

Not having enough normal white blood cells (called leukopenia), and, in particular, too few mature granuloctyes (called neutropenia or granulocytopenia), increases the risk of infections. Although leukemia is a cancer of white blood cells and patients with leukemia may have very high white blood cell counts, acute leukemia cells do not protect against infection. Thrombocytopenia, (not having enough of the blood platelets needed for plugging holes in damaged blood vessels), can lead to excessive bruising, bleeding, frequent or severe nosebleeds, and bleeding from the gums.

Spread of leukemia cells outside the bone marrow, called extramedullary spread, may involve the central nervous system (brain and spinal cord); CNS, the testicles, ovaries, kidneys, and other organs. Symptoms of CNS leukemia include headache, weakness, seizures, vomiting, difficulty in maintaining balance, and blurred vision. Some patients have bone pain or joint pain caused by the spread of leukemic cells to the surface of the bone or into the joint from the marrow cavity.

Leukemia often causes enlargement of the liver and spleen, two organs located on the right and left side respectively, of the abdomen. Enlargement of these organs would be noticed as a fullness, or even swelling, of the belly. These organs are usually covered by the lower ribs but when enlarged, they can be felt by the doctor examining the patient.

Leukemia may spread to lymph nodes. If the affected nodes are close to the surface of the body (lymph nodes on the sides of the neck, in the groin, underarm areas, above the collarbone, etc.), the patient, or health care provider may notice the swelling. Swelling of lymph nodes inside the chest or abdomen may also occur, but can be detected only by imaging tests such as Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans.

Acute myelogenous leukemia (AML), particularly the M5 or monocytic form, may spread to the gums, causing them to swell, be painful, and bleed. Spread to the skin can cause small pigmented (colored) spots that can look like common rashes. A tumerous collection of AML cells under the skin or other parts of the body is called a chloroma or granulocytic sarcoma.

The T-cell type of acute lymphocytic leukemia (ALL) often involves the thymus. An enlarged thymus can press on the nearby trachea (windpipe) causing coughing, shortness of breath, or even suffocation. The superior vena cava (SVC), a large vein that carries blood from the head and arms back to the heart, passes next to the thymus. Growth of the leukemia cells may compress the SVC and cause swelling of the head and arms known as SVC syndrome. This can also affect the brain and can be life-threatening. Patients with SVC syndrome need immediate treatment.

Types of Specimens used in Diagnosis and Evaluation of Leukemia

If signs and symptoms suggest that a patient has leukemia, the doctor will need to sample cells from the patient's blood and bone marrow to make an accurate diagnosis. Other tissue and cell samples may also be taken in order to guide treatment.

Blood cell counts and blood cell examination: Changes in the numbers of different blood cell types and the appearance of these cells under the microscope help in the diagnosis of leukemia. Most patients with acute leukemia (ALL or AML) have too many white cells in their blood, not enough red blood cells, and not enough platelets. In addition, many of these white blood cells will be blasts, a type of cell normally found in the bone marrow but not in circulating blood. These immature cells do not function normally. Even though these findings suggest leukemia, usually the disease cannot be diagnosed for sure without obtaining a sample of bone marrow cells.

Bone marrow tests: In bone marrow aspiration a thin needle and a syringe are used to remove a small amount of liquid bone marrow (about 1 teaspoon). During a bone marrow biopsy procedure, a small cylindrical piece of bone and marrow (about 1/16 inch in diameter and 1/2 inch long) is removed with a slightly larger needle. Both samples usually are taken at the same time from the back of the hipbone. These tests are used to diagnosis leukemia and later, to tell if the leukemia is responding to therapy.

Blood chemistry tests: These tests measure the amount of certain chemicals in their blood but are not used to diagnose leukemia. In patients already known to have leukemia, these tests help detect liver or kidney problems due to damage caused by the spread of leukemic cells or to the side effects of certain chemotherapy drugs. These tests also help determine whether treatment is needed to correct abnormally low or high blood levels of certain minerals.

Excisional lymph node biopsy: A surgeon removes the entire lymph node (excisional biopsy). If the node is near the skin surface, this is a simple operation that can be done using a local anesthetic (numbing medication), but if the node is inside the chest or abdomen, general anesthesia (the patient is asleep) is used. This procedure is important in diagnosing lymphomas, but is only rarely needed with leukemias.

Lumbar puncture: A small needle is placed into the spinal cavity in the lower back (below the level of the spinal cord) to withdraw cerebrospinal fluid (CSF) to be examined for leukemia cells.

Laboratory Tests used to Diagnose and Classify Leukemia

All of the biopsy samples (bone marrow, lymph node tissue, blood, and cerebrospinal fluid) are examined under a microscope by a doctor with special training in blood and lymphoid tissue disease. The samples are usually examined by a pathologist (doctor specializing in diagnosis of disease by laboratory tests) and are often also reviewed by the patient's hematologist/oncologist (doctor specializing in medical treatment of cancer and blood diseases). The doctors will look at the size and shape of the cells and whether their cytoplasm contains granules, (microscopic collections of enzymes and other chemicals that help white blood cells fight infections).

Based on a cell's size, shape, and granules, doctors can classify bone marrow cells into specific types. An important element of this cell classification is whether the cell appears mature (resembles normal cells of circulating blood, that can fight infections and are no longer able to reproduce) or immature (lacks features of normal circulating blood cells, not effective in fighting infections, and are able to reproduce). The most immature cells are called blasts.

The percentage of cells that are blasts is a particularly important factor. Having at least 30% blasts in the marrow is generally required for a diagnosis of acute leukemia. In order for a patient to be considered to be in remission, the blast percentage must be no higher than 5%. Sometimes this examination does not provide a definite answer, and other laboratory tests are needed.

Cytochemistry: After cells from the sample are placed on glass microscope slides, they are exposed to chemical stains (dyes) that are attracted or react with to only some types of leukemia cells. These stains cause a color change that can be seen only under a microscope. For example, one stain causes the granules of most AML cells to appear as black spots under the microscope, but it does not cause ALL cells to change colors.

Flow cytometry: This technique is sometimes used to examine the cells from bone marrow, lymph nodes, and blood samples. It is very accurate in determining the exact type of leukemia. A sample of cells is treated with special antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of leukemia cells. If the sample contains those cells, the laser will cause them to give off light which is measured and analyzed by a computer. Groups of cells can be separated and counted by these methods.

Immunocytochemistry: As in flow cytometry, cells from the bone marrow aspiration or biopsy sample are treated with special antibodies. But instead of using a laser and computer for analysis, the sample is treated so that certain types of cells change color. The color change can be seen only under a microscope. Like flow cytometry, it is helpful in distinguishing different types of leukemia from one another and from other diseases.

Cytogenetics: Normal human cells contain 46 chromosomes, pieces of DNA and protein that control cell growth and metabolism. In certain types of leukemia, part of one chromosome may be attached to part of a different chromosome. This change, called a translocation, can usually be seen under a microscope. Recognizing these translocations helps in identifying certain types of ALL and AML and is important in determining the outlook for the patient. Some types of leukemia have an abnormal number of chromosomes. For example, ALL cells with over 50 chromosomes are more sensitive to chemotherapy. Those with less than 46 are more resistant to chemotherapy. The testing usually takes about 3 weeks, because the leukemic cells must grow in laboratory dishes for a couple of weeks before their chromosomes are ready to be viewed under the microscope. The results of cytogenetic testing are written in a shorthand form that describes which chromosome changes are present.

A translocation, written as t(1:2), for example, means a part of chromosome 1 is now located on chromosome 2.
An inversion, written as inv 16 means that part of the chromosome 16 is upside down and is now in reverse order but is still attached to the chromosome it originated from.
A deletion, written as -7, for example indicates part of chromosome 7 has been lost.
An addition, +8 for example, happens when all or part of a chromosome material has been duplicated, and too many copies of it are found within the cell.
Molecular genetic studies: Certain substances, called antigen receptors, occur on the surface of lymphocytes. These receptors are important in initiating a response from the immune system. Normal lymphoid cells have many different antigen receptors, which help the body respond to many types of infection.

Lymphocytic leukemias, such as ALL, however, start from a single abnormal lymphocyte, so all cells in each patient's leukemia have the same antigen receptor. Laboratory tests of the DNA, which contain information on each cell's antigen receptors, are a very sensitive way to diagnose ALL. Because different subtypes of ALL cells have different antigen receptor features, this test is sometimes helpful in ALL classification.

Tests of leukemia cell DNA can also find most translocations that are visible under a microscope in cytogenetic tests. DNA tests can also find some translocations involving parts of chromosomes too small to be seen with usual cytogenetic testing under a microscope.

This sophisticated testing is helpful in leukemia classification because many subtypes of ALL and AML have distinctive translocations. Information about these translocations may be useful in predicting response to treatment. These tests may be used after treatment to find small numbers of leukemia cells that can be missed under a microscope. See What's New In Leukemia Research for information on recent advances in genetics.

Imaging Studies

Imaging studies are ways of producing pictures of the inside of the body. There are several imaging studies that might be done in people with leukemia.

X-rays: During the course of diagnosis and evaluation of a person with leukemia, a chest x-ray and a bone scan are often obtained. These may show a mass in the chest, or evidence of leukemia in the bones or rarely in the joints.

Computed tomography (CT scan): This is a special kind of x-ray, in which the beam moves around the body, taking pictures from different angles. These images are then combined by a computer to produce a detailed cross-sectional picture of the inside of the body. CT scans are not often used in leukemia, but they can show enlargement of lymph nodes around the heart and trachea (windpipe) or in the back of the abdomen due to spread of leukemia cells. Involvement of these areas is more common in ALL than in AML.

Magnetic resonance imaging (MRI): This procedure uses powerful magnets and radio waves to produce computer-generated pictures of internal organs. The pictures look very similar to a CT scan, but are more detailed. This scan may be used when there is concern about leukemia involving the brain.

Gallium scan and bone scan: For this procedure, the radiologist injects a radioactive chemical that collects in areas of cancer or infection. This accumulation of radioactivity can then be viewed by a special camera. These tests are useful when a patient has bone pain that might be due to bone infection or cancer involving bones. This test is not used when the patient has already been diagnosed with leukemia.

Ultrasound: This test uses sound waves to produce images of internal organs. The test can distinguish solid from fluid-filled masses. It can help to show whether the kidneys, liver, or spleen have been affected by leukemia.

How Is Adult Acute Leukemia Classified?

Most types of cancers are assigned numbered stages, based on the size of the tumor and how far from the original site in the body the cancer has spread.

There is no need to stage leukemia, as one would other cancers, because leukemia already involves all the bone marrow in the body, and, in many cases, has also spread to other organs such as the liver, spleen, lymph nodes, testes, and central nervous system. Laboratory tests focus on accurately determining the type and subtype of leukemia. This in turn determines the prognosis of the specific disease, and helps predict which treatments will work the best.

As leukemia treatment has improved over the past 20 years, research has focused on why some patients have a better chance of cure than others. Certain consistently observed differences among patients with good and poor responses to treatment are called prognostic features and help doctors decide if a certain type of leukemia should receive more or less treatment.

The French-American-British (FAB) Classification of Acute Leukemias

Several years ago, an international conference of prominent hematologists/oncologists specializing in leukemia treatment and pathologists specializing in laboratory tests for blood disease diagnosis was held to decide upon the best system of classification of acute leukemias. This group of French, American, and British doctors decided that acute leukemias should be divided into eight subtypes of AML and three subtypes of ALL.

Some subtypes of AML or ALL defined in the FAB classification are associated with certain symptoms. For example, bleeding or blood clotting problems are often a problem for patients with the M3 subtype of AML, also known as acute promyelocytic leukemia. Identifying M3 leukemia is very important for two reasons. The first is that these serious complications can often be prevented by appropriate treatment. The second reason is that M3 leukemias usually respond to retinoids (drugs chemically related to vitamin A). Addition of retinoids to the treatment program allows doctors to lower the doses of chemotherapy drugs and reduce the severity of certain side effects.

Some types of acute leukemia, such as the L3 subtype of ALL and M5 subtype of AML tend to have a worse prognosis and many doctors recommend more intensive chemotherapy for these patients.

The original FAB system was based only on appearance of leukemic cells under the microscope after routine processing or cytochemical staining. More recently, doctors have found that cytogenetic studies, flow cytometry, and molecular genetic studies provide additional information that is sometimes useful in classification of acute leukemias and predicting the patient's prognosis. In the coming years we will learn more about the underlying genetic defects that cause leukemia. These defects, rather than the appearance of the cells under the microscope, will be used to classify leukemias and understand their prognoses. These genetic defects might also form the basis for treating the leukemias.

The next few pages will discuss the details of acute leukemia classification. Some patients will find this interesting and helpful in understanding their leukemia. Others may be less interested in the details of these tests and may wish to skip ahead to the section on Treatment of Adult Acute Leukemias.

French-American-British (FAB) Classification of AML

FAB Subtype Name Approximate % of adult AML patients Prognosis compared to average for AML
M0 Undifferentiated AML 5% Worse
M1 Myeloblastic leukemia with minimal maturation 15%
M2 Myeloblastic leukemia with maturation 25% Better
M3 Promyelocytic leukemia 10% Best
M4 Myelomonocytic leukemia 25%
M4 eos Myelomonocytic leukemia with eosinophilia Rare Better
M5 Monocytic leukemia 10% Worse
M6 Erythroid leukemia 5% Worse
M7 Megakaryoblastic leukemia 5% Worse

French-American-British (FAB) Classification of ALL

FAB Subtype Approximate % of adult ALL patients Immunologic Type Comments
L1 30% T cell or pre-B cell
L2 65% T cell or pre-B cell
L3 5% B cell Poor prognosis with standard therapy. Also called Burkitt's type leukemia.

Undifferentiated or Biphenotypic Acute Leukemias

More refined tests have shown that a number of acute leukemia cases have both lymphocytic and myeloid features. Sometimes leukemic cells have both myeloid and lymphocytic characteristics on the same cell. In other cases, a patient's leukemia may include some cells with myeloid features and other cells with lymphocytic features. Categorizing these acute leukemias is difficult and controversial. Sometimes these types of acute leukemias are called ALL with myeloid markers, AML with lymphoid markers, or biphenotypic (2 type) leukemias.

Status of Acute Leukemia After Treatment

Adult acute leukemia is either classified as being in remission (with no evidence of disease), or with active disease (with the patient either just newly diagnosed or in relapse). Minimal residual disease is a term which is used when there is chemical evidence (either molecular or cytogenetic ) that leukemic cells remain in the bone marrow, but there are not enough of these cells around to be found by routine examination under the microscope. For a patient to be in fulminant relapse they must have greater than 30% blast cells present in the bone marrow.

New Cancer Drug Possibility

(Ivanhoe Newswire) -October 4, 2004- A scientific discovery may put us one step closer to developing new cancer drugs. Temple University researchers in Philadelphia found the c-myb gene, which leukemia cells depend on for proliferation, is responsible for the formation of white blood cells. Researchers knew the c-myb gene affected the spread of leukemia but did not know its normal function. Discovering this allows scientists to try to stop cancer from developing by removing the gene, which they did in a mouse model.

New technology enabled researchers to delete the c-myb gene from T cells in one specific type of tissue rather than from the entire organism. In the process, they discovered c-myb is required for white blood cell formation.

Researchers now believe the c-myb gene plays a critical role in breast cancer's development as well as leukemia's. In other research not yet published, c-myb was deleted from breast tissue. Researchers are providing genetic explanations of how and why c-myb is essential for the proliferation of white blood cells and breast cells by demonstrating that when it's removed, cell proliferation is impaired and the risk of developing cancer is reduced.

Researchers say, "We hope to develop a drug that blocks the harmful activity of this gene in the near future. This finding was very serendipitous. We used to think c-myb was only associated with the development of leukemia but found it's also involved in the development of breast cancer."

This article was reported by Ivanhoe.com, who offers Medical Alerts by e-mail every day of the week. To subscribe, go to: http://www.ivanhoe.com/newsalert/.

SOURCE: Proceedings of the National Academy of Sciences, published online Sept. 27, 2004

Treatment of Newly Diagnosed Acute Promyelocytic Leukemia With Arsenic Trioxide May Remove Need for Anthracycline Chemotherapy

Long Lasting Complete Remissions Reported in 88% of Patients

SEATTLE, Oct. 4 /PRNewswire-FirstCall/ -- An Iranian investigational study of single-agent arsenic trioxide for the treatment of acute promyelocytic leukemia (APL) was presented on Sept. 29 at the 16th Annual meeting of the European Organization for Research and Treatment of Cancers, National Cancer Institute and American Association for Cancer Research (EORTC-NCI-AACR). In the study, 63 patients with newly diagnosed APL were treated with arsenic trioxide and over the course of two treatments, 90 percent of the patients achieved a complete remission. Of the 11 patients who suffered a relapse, eight went back into remission after a third treatment. Currently, 88.5 percent of the patients in this ongoing study are still alive, with a mean survival time of nearly 34 months since the start of treatment. Cell Therapeutics, Inc. (CTI) (Nasdaq: CTIC; Nuovo Mercato) markets arsenic trioxide (TRISENOX(R)) in the United States and Europe for relapsed and refractory APL.

 Data on a phase I study of CTI's polyglutamate camptothecin were also presented at the EORTC-NCI-AACR meeting. These data showed that CT-2106 was well tolerated with manageable toxicities and demonstrated evidence of anti-cancer activity in three tumor types. One pancreatic cancer patient with metastasis to the lungs has experienced a partial response, two patients with colorectal cancer experienced stable disease for more than 12 weeks and two patients with non-small cell lung cancer had disease stabilization for more than 35 weeks. The preliminary disease control rate was 33 percent (8 of 24 patients).

About TRISENOX(R)
TRISENOX(R) (arsenic trioxide) is marketed by CTI. TRISENOX was approved for marketing in 2000 by the U.S. Food and Drug Administration to treat patients with relapsed or refractory acute promyelocytic leukemia (APL), a rare, life-threatening form of cancer of the blood. TRISENOX was granted marketing authorization from the European Commission in March 2002. APL, one of eight subtypes of acute myeloid leukemia (AML), represents 10-15 percent of the more than 20,000 patients diagnosed with AML each year.

TRISENOX is currently being studied in more than 40 clinical and investigator-sponsored trials in a variety of cancers. U.S. marketing approval for TRISENOX was granted based on results from a U.S. multicenter study in which 40 relapsed APL patients were treated with TRISENOX 0.15 mg/kg until bone marrow remission or a maximum of 60 days. Thirty-four patients (85 percent) achieved complete remission. When the results for these 40 patients were combined with those for the 12 patients in a pilot trial, an overall response rate of 87 percent was observed.

WARNING: TRISENOX should be administered under the supervision of a physician who is experienced in the management of patients with acute leukemia. Some patients with APL treated with TRISENOX have experienced APL differentiation syndrome -- with symptoms similar to retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome. Arsenic trioxide can cause QT prolongation (which can lead to torsade de pointes) and complete atrioventricular block.

The most common adverse events associated with TRISENOX have been generally manageable, reversible and usually did not require interruption of therapy. These have included hypokalemia, hypermagnesemia, hyperglycemia and thrombocytopenia as reported in 13 percent of the patients (n=40). Abdominal pain, dyspnea, hypoxia, bone pain and neutropenia were reported in 10 percent of these patients, while arthralgia, febrile neutropenia and disseminated intravascular coagulation were reported in eight percent of patients.

About Acute Promyelocytic Leukemia (APL)
APL, one of eight subtypes of acute myeloid leukemia (AML), is a malignant disorder of white blood cells. It can affect patients of any age. APL is characterized by a specific chromosomal abnormality -- a switch, or translocation, of genetic material from chromosome 17 to chromosome 15. This genetic alteration results in an abnormal protein that inhibits normal cell growth and prevents maturation of white blood cell precursors in the bone marrow, ultimately resulting in cancer. The standard treatment for newly diagnosed APL has been a combination of chemotherapy and all-trans-retinoic acid (ATRA), which results in a complete response in 70-90 percent of newly diagnosed patients. However, approximately 20-30 percent of patients who receive this treatment regimen relapse. This poor response to drug therapy has led to the use of allogenic stem cell transplantation (the transfer of healthy, young cells from the bone marrow or bloodstream of a donor) to prolong survival. TRISENOX provides another treatment option for this patient population.

About CT-2106
CT-2106 is the second agent in CTI's portfolio, after XYOTAX(TM) (paclitaxel poliglumex), to exploit the polyglutamate-conjugate technology, where an anti-cancer agent is conjugated to a naturally biodegradable poly-amino acid.

About Cell Therapeutics, Inc.
Headquartered in Seattle, CTI is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable. For additional information, please visit http://www.cticseattle.com.

SuperGen and MGI PHARMA Announce Filing of MAA for Approval of Dacogen(TM) in Europe

DUBLIN, Calif. and MINNEAPOLIS, Oct. 1 /PRNewswire-FirstCall/ -- SuperGen, Inc. (Nasdaq: SUPG - News) and MGI PHARMA, INC. (Nasdaq: MOGN - News), today announced that a Marketing Authorization Application (MAA) seeking approval of Dacogen(TM) (decitabine) for injection has been submitted to the European Agency for the Evaluation of Medicinal Products (EMEA) by SuperGen's European subsidiary, EuroGen Pharmaceuticals Ltd. Dacogen is the Company's investigational anti-cancer therapeutic for the treatment of patients with myelodysplastic syndromes or MDS. MGI PHARMA has exclusive worldwide rights to the development, manufacture, commercialization and distribution of Dacogen.

"We are very pleased to have completed this regulatory milestone for Dacogen," said Dr. James Manuso, President and Chief Executive Officer of SuperGen. "SuperGen remains committed to bringing Dacogen to patients as quickly as possible, with the support of our new partner, MGI PHARMA."

"The MAA submission for Dacogen marks a key regulatory milestone," said Lonnie Moulder, President and Chief Executive Officer of MGI PHARMA. "We believe that Dacogen will become an important treatment option for hematologic cancer patients, and we look forward to the upcoming U.S. NDA filing as the next regulatory milestone."

SuperGen completed Phase III clinical trials of Dacogen in patients with MDS in March 2004. SuperGen and MGI are collaborating on the regulatory development process for Dacogen in MDS, and expect to complete the NDA filing during the fourth quarter of 2004. MGI PHARMA plans to initiate a Phase III trial of Dacogen for the treatment of acute myelogenous leukemia (AML) in early 2005 and plans to evaluate Dacogen for further development in other hematologic malignancies. Alternative dosing schedules for Dacogen, including subcutaneous administration and more rapid intravenous infusions, are currently being evaluated in clinical studies.

About Dacogen

Dacogen is an investigational drug. It has not yet been approved for marketing in the U.S. or by other regulatory agencies in their respective countries; therefore, safety and efficacy have not yet been established in any patient population. In clinical trials, Dacogen has been shown to have a broad spectrum of activity in several hematological malignancies as well as solid tumors. Dacogen belongs to a class of drugs called hypomethylating agents, with a unique mechanism of action. Methylation is a process in which methyl (CH3) groups are added to DNA which may inactivate or "silence" tumor suppressor genes.

About MDS

MDS is a cancer of the bone marrow that is often fatal. Some cases of MDS progress to leukemia. According to the Aplastic Anemia and MDS International Foundation (http://aamds.org/), 20,000 to 30,000 new cases of MDS are diagnosed annually in the United States. The number of new cases diagnosed each year is increasing. The average life expectancy for patients diagnosed with MDS is 6 months to 5 years, depending on the severity of the disease.

About SuperGen

Based in Dublin, California, SuperGen is a pharmaceutical company dedicated to the acquisition, rapid development and commercialization of therapies for solid tumors, hematological malignancies and blood disorders. SuperGen's product portfolio includes Orathecin(TM) (rubitecan) capsules, an investigational drug intended for the treatment of pancreatic cancer; Nipent® (pentostatin for injection); Mitomycin (generic brand of Mitomycin®); and SurfaceSafe® cleaner. For more information about SuperGen, please visit http://www.supergen.com.

About MGI PHARMA

MGI PHARMA, INC. is an oncology-focused biopharmaceutical company that acquires, develops and commercializes proprietary products that address the unmet needs of cancer patients. MGI PHARMA has a portfolio of proprietary pharmaceuticals, and intends to become a leader in oncology. MGI PHARMA markets Aloxi® (palonosetron hydrochloride) injection, Salagen® Tablets (pilocarpine hydrochloride) and Hexalen® (altretamine) capsules in the United States. The Company directly markets its products in the U.S. and collaborates with partners in international markets. For more information about MGI PHARMA, please visit http://www.mgipharma.com.

This news release contains certain "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements are typically preceded by words such as "believes," "expects," "anticipates," "intends," "will," "may," "should," or similar expressions, and include statements regarding the timing of the submission of an NDA for Dacogen to the U.S. Food and Drug Administration. These forward-looking statements are not guarantees of MGI PHARMA's or SuperGen's future performance and involve a number of risks and uncertainties that may cause actual results to differ materially from the results discussed in these statements. Factors that might cause either company's results to differ materially from those expressed or implied by such forward-looking statements include, but are not limited to, whether a submission for regulatory approval for Dacogen will be made in the U.S. in a timely fashion, if at all; whether the drug will be timely approved, if at all in any country where a submission is made; whether the drug, if approved will be successfully commercialized; continued sales of MGI PHARMA's or SuperGen's other marketed products; development or acquisition of additional products; reliance on contract manufacturing and third party suppliers; changes in strategic alliances; and other risks and uncertainties detailed from time to time in either company's filings with the Securities and Exchange Commission, including their most recently filed Forms 10-Q or 10-K. MGI PHARMA and SuperGen undertake no duty to update any of these forward- looking statements to conform them to actual results.

CONTACT:
For further information about MGI PHARMA, please contact:

Jennifer Davis David Melin
MGI PHARMA - Investors MGI PHARMA - Media
Tel: (212) 697-1976 Tel: (952) 346-4749
E-mail: [email protected] E-mail: [email protected]

For further information about SuperGen, please contact:

Timothy L. Enns Sharon Weinstein
SuperGen, Inc. Euro RSCG Life NRP
Tel: (925) 560-0100 x111 Tel: (212) 845-4271
E-mail: [email protected] E-mail: [email protected]

-----------------------------------------------
Source: SuperGen, Inc.; MGI PHARMA, INC.

Contact: Sooike Stoops
[email protected]
32-9-244-6611
VIB, Flanders Interuniversity Institute of Biotechnology

New therapy for specific form of leukemia

1-Oct-2004
Leuven Leukemia, or cancer of the bone marrow, strikes some 700 Belgians each year. Medical science has been at a total loss regarding the origin or cause of some forms of this disease - including T-cell acute lymphatic leukemia, or T-ALL. But now, researchers from the Flanders Interuniversity Institute for Biotechnology (VIB), connected to the Catholic University of Leuven, have discovered the possible cause of the disease in 6% of the T-ALL patients. The scientists have found small circular DNA fragments in the cells of these patients that contain the ABL1 cancer gene. ABL1 also plays an important role in other forms of leukemia. The good news is that ABL1 is counteracted with the drug Glivec, and so this medication can now also provide help to a number of T-ALL patients.

T-ALL: T-cell acute lymphatic leukemia In normal circumstances, our white blood cells combat foreign intruders, like viruses and bacteria. However, in leukemia, there is a breakdown in the formation of white blood cells. The cells in the bone marrow that should develop into white blood cells multiply out of control without fully reaching maturity. These blood cells function inadequately, disrupting the production of normal blood cells. Among other effects, this makes patients more susceptible to infections. Leukemia appears in several forms - in the case of T-ALL, a large accumulation of immature white blood cells occurs within a very short time. This is the most common type of cancer in children under the age of 14 - striking children between two and three years of age, in particular. At present, an optimal treatment, with chemotherapy, cures over half of these children.

ABL1 plays a prominent role in several forms of leukemia

ABL1 is a kinase, a type of protein that catalyzes a number of processes in the cell - in the case of ABL1, this is the process of cell division. It is crucial that kinases function in a very controlled manner within our cells. Loss of control of their functioning disturbs the normal functioning and division of cells. Thus, such disorders in the functioning of ABL1 are a major cause of certain forms of leukemia.

Existing drug now used with T-ALL patients Research performed by Jan Cools and his colleagues, under the direction of Peter Marynen, shows for the first time that ABL1 also lies at the root of T-ALL - which has a direct effect on the treatment of T-ALL patients. Indeed, a drug exists - called Glivec - that suppresses the action of ABL1. Glivec has already been successfully administered to patients with other forms of leukemia in which ABL1 plays a role. The new research results show that Glivec can also provide a better treatment for a small group of T-ALL patients. Jan Cools has already successfully conducted the first laboratory tests with Glivec on the cancer cells of these patients.

Ingenious research

The team of Jan Cools and Peter Marynen, along with Carlos Graux and colleagues from the Centre for Human Heredity under the direction of Anne Hagemeijer, noticed that the ABL1 gene was present in greater quantities in the white blood cells of 6% of the T-ALL patients. The genetic code of ABL1 is at chromosome 9. Through a flaw at the ABL1 gene, a piece of DNA is split off and 'takes on a life of its own' as it were. This fragment contains the ABL1 gene, connected to another gene. Due to this fusion, ABL1 works non-stop - stimulating cell growth unremittingly. This process leads to an uncontrolled growth of immature white blood cells and thus to T-ALL. With these findings, the researchers have revealed a new mechanism for the formation of active cancer genes on circular DNA fragments.

The researchers are now concentrating their efforts on discovering the role of ABL1 and other kinases in all T-ALL patients. In the future, they hope to be able to administer Glivec, and other kinase inhibitors, to treat these patients as well.

Relevant scientific publications

The research of the VIB scientists from Peter Marynen's group appears on 1 October in the authoritative journal, Nature Genetics (Graux C, Cools J et al., Nature Genetics, 36(10):1084-1089 (2004)) and is online on the journal's website: http://www.nature.com/naturegenetics.

Meeting: 2001 ASCO Annual Meeting
Category: Bone Marrow Transplantation
SubCategory: Autologous Bone Marrow Transplantation

Myelodysplastic Syndrome (MDS) and Leukemia After Autotransplantation for Lymphoma: a Multicenter Case-Control Study.

Abstract No: 23
Author(s): Catherine Metayer, Rochelle E. Curtis, Kathy A. Sobocinski, Mary M. Horowitz, Julie M. Vose, Dan Weisdorf, Smita Bhatia, Joseph W. Fay, Cesar O. Freytes, Steven C. Goldstein, Roger Herzig, Armand Keating, Carole Miller, Thomas J. Nevill, Andrew L. Pecora, Doug J. Rizzo, Lois B. Travis, Stephanie F. Williams, National Cancer Institute, Bethesda, MD; Autologous Blood and Marrow Transplant Registry, Milwaukee, WI.

Abstract: Although several reports indicate that patients receiving autotransplants for lymphoma have an increased risk of MDS/leukemia, the separate contributions of pre-transplant and transplant-related therapy to this risk are not well-characterized, in part due to incomplete data regarding all pre-transplant therapies. We conducted a case-control study of 56 patients with MDS/leukemia from a cohort of 955 patients receiving autotransplants for Hodgkin disease and 1,784 for non-Hodgkin lymphoma between 1989 and 1995 at 12 institutions in the U.S. and Canada. Three age-, sex-, latency-matched controls were randomly selected for each case.

Detailed abstraction of medical records was undertaken to determine all pre- and post-transplant therapy, and transplant-related procedures. In multivariate analyses, the largest contributor to MDS/leukemia risk was pre-transplant chemotherapy with 4- and 10-fold risks in patients given mechlorethamine (e.g., MOPP-like regimens) and chlorambucil, respectively (p <0.05), compared to those receiving only cyclophosphamide-based treatment before transplant. MDS/leukemia risk increased with increasing dose of mechlorethamine and duration of chlorambucil therapy.

Overall, transplant conditioning regimens including total-body irradiation (TBI) at doses [less than or equal to] 12 Gy did not appear to elevate leukemia risk; however, statistically significant 4- to 5-fold excesses were found at TBI doses of 13 Gy. In univariate analyses, patients transplanted with peripheral blood versus bone marrow stem cells had a 2-fold increased risk of MDS/leukemia (p <0.05), but the association (1.7-fold increase) was not significant in multivariate analyses adjusting for other risk factors. There was no association between graft purging or use of mobilization chemotherapy/growth factors and MDS/leukemia. Based on preliminary analyses, our data suggest that the strongest factors influencing MDS/leukemia risk are the types and intensity of conventional pre-transplant chemotherapy. Although some transplant-related factors may also play a role, these findings require confirmation in other patient populations.

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