Although doctors rely on needle biopsies of bone marrow to diagnose and oversee treatment of leukemia, the procedures have limited value because they sample only the area where the needle is inserted. The core sample that is removed may not provide a true indication of the body's overall health.
Now, a combination of advanced imaging techniques may offer patients and doctors alike a noninvasive alternative to traditional biopsies and a method for monitoring patient response to therapeutic treatments. The modified magnetic resonance imaging (MRI) technique can assess a patient in less than 20 minutes and does not require injecting the patient with specialized dyes known as contrast agents. The new technique was developed by researchers at Cornell University's Weill Medical College and Memorial Sloan-Kettering Cancer Center in New York.
“In April 1998, we did an MRI scan of a single patient, a very sick man with acute myelogenous leukemia, expecting to measure small differences in image contrast between normal and leukemic marrow,” says Douglas Ballon, a physicist and Director of Weill Medical College's Citigroup Biomedical Imaging Center. But surprisingly, the image the team saw on the monitor was stark even without the use of contrast agents. The diseased marrow stood out, bright against the darker surrounding bone. “We were expecting to measure a very subtle effect, and instead found a method for imaging leukemic marrow over large areas of the body where very little signal was present from other structures,” he says. “Once we realized that we could do this, we began to think about true whole-body images.”
Essentially, the strong bright areas in Ballon's scans of leukemic marrow show water inside cells. On most MRI scans the image intensity reflects a combination of intracellular and extracellular water. With the Cornell imaging technique, MRI scans reveal the presence of leukemia by distinguishing between intracellular water (water inside cells) and extracellular water. Inside the body, extracellular water is present in the plasma part of blood and other fluids. By tweaking the software that processes the signals from the scans, the Cornell/Sloan-Kettering team has created a tool that highlights dense concentrations of cells and suppresses signals from fat, muscles, bladder contents, and other tissues.
The new MRI technique may help doctors monitor treatment of leukemia and several other diseases as well. “We believe it will also help in lymphoma, metastatic breast cancer, and prostate cancer,” Ballon says. For these cancers, the ability to assess the whole-body burden of disease in a patient may help doctors and patients to decide how aggressive future therapy should be.
Toward Better Biopsies
Leukemia is a disease in which the bone marrow makes too many white blood cells.
Normally, the body produces bone marrow stem cells that develop into mature blood cells. The three types of mature blood cells are red blood cells, which carry oxygen, white blood cells, which fight infection, and platelets, which help to prevent excessive bleeding by forming blood clots. In chronic myelogenous leukemia, the body directs too many bone marrow stem cells to become granulocytes, a type of white blood cell. Some of these bone marrow stem cells never mature into white blood cells. Gradually, the granulocytes and immature cells, known as blast cells, crowd out the red blood cells and platelets in the bone marrow.
Ballon's research is a collaborative venture. His expertise is in the physics of MRI – how protons in human bodies react under the scanner's strong magnetic field, and how to interpret the signals they produce. He works with Dr. Ann Jakubowski, a hematologist who treats leukemia patients, and a team of other specialists in medical physics and prostate cancer.
The team has studied some 70 patients and about a dozen healthy volunteers so far. About half of the patients had leukemia or lymphoma, and half had metastatic prostate cancer. Metastatic cancers – those spreading throughout the body – are of special interest because they are hard to track. Doing needle biopsies everywhere to look for tumors is impractical, and tumors often do not show up well on X-rays, CT scans, or other images.
“Because of certain properties of the water within the tumor cells they show up well on these scans, even when they are inside bones,” Ballon says. Being able to see tumors or leukemic marrow in whole-body scans is not a screening tool, he says. “MRI scans are too expensive for screening for most types of cancer. What we do think it will be used for is monitoring treatment,” he says.
The team has taken scans before and after treatment for both leukemia and prostate cancer patients. “Scans taken a day or two after chemotherapy have shown striking differences,” Ballon says. In leukemia patients, marrow in the pelvic bones that appeared bright on the images because of the high concentration of blast cells became a normal pale gray. Similarly, the appearance of prostate tumors “faded” after chemotherapy. “This is the promise of the technique,” Ballon says. “When patients are given chemotherapy, we hope to be able to check within a few days to see how effective it is, with no discomfort to the patients.”
The Cornell/Sloan-Kettering team uses a typical MRI scanner found in many hospitals, so the new technique could easily be adopted elsewhere. Meanwhile, Ballon and his colleagues are refining the new approach. “We will achieve better resolution (the ability to spot smaller tumors) soon, and be able to image difficult areas such as the chest by using better hardware now available with the scanner.”
Research on the new technique has been supported by the National Institute of Biomedical Imaging and Bioengineering and the National Heart, Lung, and Blood Institute.
Ballon D, Watts R, Dyke JP, Lis E, Morris MJ, Scher HI, Ulug AM, Jakubowski AA. Imaging therapeutic response in human bone marrow using rapid whole-body MRI. Magnetic Resonance in Medicine 52:1234-1238, 2004.