Researchers Taking Aim at Childhood Leukemia by Gina Shaw Leukemia is the most common of all childhood cancers. At the same time, it is also one of the most curable and one of the most deadly forms of cancer. Thatís because in children, the disease occurs in two basic formsóone of them almost always curable and one of them fatal in half of all patients. If thereís a ìbetterî leukemia diagnosis for a child to get, itís acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia. About 4,000 new cases are diagnosed each year in the United States, most of them in children under 10. Over the past 40 years, ALL has progressed from being almost always fatal to almost always curable. ìWeíve had amazing success in treating ALL,î said Dr. Soheil Meshinchi, a pediatric oncologist and clinical researcher at the Fred Hutchinson Cancer Research Center in Seattle. ìIt was a uniformly fatal disease 40 years ago, and now weíre curing 80 to 90 percent of patients.î But if youíre curing 80 percent to 90 percent of patients, that means between 10 percent and 20 percent still die. Thus, the latest research into this type of leukemia aims to identify the children who are likely to do worse early o n. ìOne prognostic factor is how quickly the child responds to treatment,î said Dr. Sima Jeha, associate professor of pediatrics at the University of Texas M.D. Anderson Cancer Center in Houston. ìIn ALL, 98 percent of children achieve remission, which means we donít see leukemia cells in their bone marrow after one month. If at the end of the first month, youíre not in remission, youíre in trouble.î So researchers looked at childrenís bone marrow even earlieróa week to two weeks after beginning treatment. ìWe found that the speed with which you clear the cancer cells from your bone marrow is an important indicator as to whether youíll relapse,î said Jeha. ìCombined with a more sophisticated way of following the remissionóusing molecular markers in the bone marrowó[this] is helping us to identify the rapid responders and decrease the intensity of their treatment, while intensifying the treatment of the slow responders to try and improve their survival rate.î Another predictor of a bad outcome in ALL is a gene translocation that scientists call the Philadelphia chromosome. ìItís a translocation between chromosome 9 and chromosome 21. Basically, part of chromosome 9 is chopped off and stuck on chromosome 21,î explained Meshinchi. ìThese patients are at such a high risk of relapse that we get them into remission and then immediately do a bone marrow transplant.î Without bone marrow transplantation, a child who has ALL and the Philadelphia chromosome has only a 30 percent chance of survival, although with a match-related transplant, the survival rate goes up to 60 percent to 70 percent. Scientists at the Childrenís National Medical Center in Washington, D.C., are also trying to identify new genetic markers in bone marrow cells that will predict which ALL patients will relapse and which will not. Dr. Michael Henry, a third-year fellow in pediatric hematology and oncology at Childrenís, is using microarray technology to try to isolate some of those genetic differences. ìOnce we get a list of genes that differ between those two groups, we can create a custom array and a diagnostic tool to identify patients at high risk of relapse, and augment their therapies from the beginning, where before we wouldnít have known to do so,î he said. Itís a long and exhaustive process. ìWe need as many samples as we can. So far, I have about 50 bone marrow samples, and weíre still analyzing them,î said Henry. From just the first set of samples, Henry was able to identify a couple of genes that might have a role in different relapse patterns, but more are needed. ìA really good gene candidate list would be about 50 to 70 genes,î he said. ìThe next step would be to take about 100 blinded samples, half of which are patients whoíve relapsed and half who have not, and see if we can use our gene list to predict which group each sample falls into based on its match on the gene list.î Improving the Odds Bone marrow transplantation is a major area of research at the Fred Hutchinson Cancer Research Center, said Meshinchi. For many children with leukemia, it may offer their only hope of a cure, but finding a matched bone marrow donor remains difficult, especially for children from various minority groups. ìA significant proportion of our patients in the marrow bank are Caucasian, so if youíre from another ethnic background, you have less of a chance of finding a matched donor in the marrow bank,î said Meshinchi. Scientists hope to up the odds for bone marrow transplantation by using cord bloodóblood from an infantís umbilical cord, which has in the past been simply discardedóas a source of marrow cells. ìCord blood is a rich source of stem cells, which have not yet developed antigenic properties. One of the major problems with bone marrow transplantation is whatís called graft-versus-host diseaseóthe new immune system from the donor cells attacks the patientís body,î Meshinchi explained. However, the stem cells found in cord blood do not have those same properties, so they can be less of a match to the childís own cells and still be transplanted without risking rejection. ìThe early data is quite promising, and a national cord blood bank is being developed,î Meshinchi said. Thereís just one problem: The amount of stem cells found in cord blood is very small, and the ìcell doseî in transplantation is important. Scientists at Fred Hutchinson and other cancer centers are now trying to find a way to coax the cord blood cells to grow in vitro, while retaining their ìpluri-potencyîóin other words, preventing them from developing into specific types of cells, such as liver, kidney or heart cells. ìThatís the main challenge,î said Meshinchi. ìOnce youíre able to do that, youíd have pretty much a donor for everyone.î Battling Most Deadly Form Acute lymphocytic leukemiaís much deadlier cousin is acute myelogenous leukemia, or AML. Some 600 to 800 children are diagnosed with AML every year, and it accounts for about 25 percent to 30 percent of all leukemia cases in childrenóand its cure rate, compared to ALL, is dismal. ìEven with bone marrow transplantation, right now weíre barely pushing a 50 percent cure rate in children with AML,î said Meshinchi. And with AML, sometimes the ìcureî can prove to be as bad as the disease. ìThe therapy for ALL is pretty mild to moderate as far as chemotherapy goes, and itís virtually all outpatient except for a couple of days of planned admissions,î Meshinchi said. ìBut for AML, the treatment is very toxic, with a much more intense and more virulent chemotherapy. And thereís between a 10 percent to 15 percent death rate as a result of the therapy itself.î Most scientists agree that conventional chemotherapy has reached its limits in treating AML. Now, they have turned their attention toward developing more targeted therapiesóagents aimed specifically at the abnormal proteins that are fundamental to a particular type of cancer. Instead of killing normal and cancerous cells alike, as conventional chemotherapy has done, these targeted treatments act like heat-seeking missiles, aiming directly at the disease while sparing healthy cells. One headline-making leukemia drug is Gleevec, a molecularly targeted agent that has proven to be one of the most promising treatments to date for people who have chronic myelogenous leukemia (CML), a form of the leukemia found mostly in adults. Now, using the success of this drug as a road map, researchers are trying to find ìa Gleevec for AML,î said Meshinchi. ìOne of the approaches that has been quite successful, at least in the context of AML, has been targeting therapies at a marker called CD33,î explained Meshinchi. ìA very potent chemotherapy agent is bound to an antibody that recognizes a target on the leukemic cell.î Mylotarg, the trade name for the new drug, was developed by the Fred Hutchinson Cancer Research Centerís Dr. Irwin Bernstein and has been successful in the adult trials that must precede all trials of new cancer therapies in children. ìInitially, we test new drugs with patients who have been refractory to other forms of treatment, meaning that theyíre extremely difficult to treat and are not expected to respond to anything,î Meshinchi said. ìMylotargís success rate with them has been over 30 percent, which is an amazing accomplishment. Now, this drug is moving to the forefront and being used in combination with chemotherapy in newly diagnosed adult AML patients, with amazing results in early trials.î A National Cancer Institute-supported consortium called the Childrenís Oncology Group, which oversees all child and adolescent cancer-related research, should be opening a pilot study o f Mylotarg involving 100 pediatric patients within the next six months, according to Meshinchi. ìBased on that data, if things go well, we will open a much larger national study, in which virtually all children nationwide with AML will be treated with this protocol.î As with the less deadly acute lymphocytic leukemia, researchers are also trying to identify, early on in treatment, which children with acute myelogenous leukemia are at greater risk of relapse. ìIf you can identify the group at a higher risk of relapsing, then you can alter their treatment,î said Meshinchi. ìYou can transplant them earlier, you can give them different drugs, and so on. Meanwhile, low-risk patients may be able to be spared bone marrow transplants.î About 15 percent of children with AML have a mutation in a gene-encoding enzyme called FMS-like tyrosine kinase 3 (FLT3). ìThe presence of this mutation has been associated with quite dismal outcomes,î said Meshinchi. ìPatients without the mutation have a 50 percent cure rate, while the ones with the mutation have a less than 20 percent cure rate.î In normal marrow cells, the gene-encoding FLT3 switches on and off. A mutated FLT3 gene remains active, and this activation allows the cells with this mutation to grow out of control. Several ìsmart drugsî targeting the FLT3 receptors have shown promise in early trials. ìThere are several labs that have been working on it for the last couple of years,î said Meshinchi. ìThe early data in adults are quite promising,î he added, noting that Fred Hutchinson along with five other cancer centers are set to start a pediatric trial of a new drug aimed at FLT3 within the next few months. ìWeíre hoping to move beyond what weíve been able to do with conventional therapies,î Meshinchi said. ìThatís the most exciting area weíre working on now: to identify high-risk patients and try to develop targeted therapies for the group with resistant leukemia.î Gina Shaw is the medical writer for The Washington Diplomat.