Bone Marrow Transplantation Offers Novel Treatment for Canine Lymphoma
A new therapy for canine lymphoma that was first used in human medicine offers promise in treating the one in four Boxers affected by the cancer. The therapy, bone marrow transplantation, uses a dog’s own stem cells to stimulate bone marrow function and immune system recovery following radiation to kill cancer cells.
The first bone marrow transplantation (BMT) performed in an academic setting in a dog took place in late 2008 at North Carolina State University Veterinary Teaching Hospital. Though it is too soon to assess the survival rate, 45 dogs have received BMTs at the hospital, the first veterinary academic institution in the world to offer the procedure.
“It will take another few years to really know the cure rate,” says Steven Suter, V.M.D., Ph.D., DACVIM, assistant professor of oncology at North Carolina State University College of Veterinary Medicine. “A dog most likely will have to be cancer-free two years following treatment to be considered cured. We currently are seeing a survival rate of 45 to 50 percent, but we need more time to determine definitely.”
Performed for many years in humans diagnosed with lymphoma, leukemia and other life-threatening blood diseases, bone marrow transplantation has boosted survival rates to 85 percent for some cancers. The procedure used in humans is based on protocol developed in dogs.
“In dogs, we first filter stem cells out of the blood,” Suter explains. “Then, the dog receives radiation to kill the rapidly dividing cancer cells in the body. The harvested stem cells are later transfused back into the dog, where they begin growing and developing. The first sign that the procedure is successful is a rising white blood count.”
Chemotherapy, with or without radiation, is the mainstay treatment for lymphoma. Chemotherapy induces remission in about 75 percent of dogs, giving them an average of eight to 16 months to live. When signs reappear, another round of chemotherapy achieves a second, shorter remission in about 40 percent of dogs. Fewer than 20 percent of dogs achieve a third remission. Ultimately, chemotherapy is credited with the long-term survival of about 2 percent of dogs.
“Many of our patients come to us after being on chemotherapy,” Suter says. “People are in a bit of a ‘desperation’ mode since their dog has already relapsed when they find us and learn about bone marrow transplantation.”
A painless procedure, BMT takes about six hours. Afterward, dogs are hospitalized for two weeks while their blood counts are monitored and while waiting for the stem cells to start growing and developing. Not all dogs are candidates for BMTs. Dogs with significant disease, those that relapsed after chemotherapy, and those with other serious illnesses are considered poor candidates.
Dogs may relapse from four to 18 months following therapy. Suter is optimistic that survival rates may emulate those for humans and average 65 percent or higher. “Dogs with T-cell lymphoma, the type common in Boxers, don’t seem to relapse as commonly as dogs with B-cell lymphoma,” he says.
Though BMT is a costly procedure for owners to consider, averaging from $13,000 to $16,000, it may not be more than chemotherapy considering that dogs often receive multiple rounds of chemotherapy, which could run from $3,000 to $6,000 based on the number of treatments, Suter says. “BMT certainly carries a great likelihood of survival,” he adds.
A Common Tumor in Dogs
Lymphoma is one of the five most common tumors in dogs, accounting for up to 24 percent of all canine tumors. The lifetime risk for Boxers is one in four compared to one in 15 for all dogs. Other breeds at risk are Airedale Terriers, Bulldogs, Bullmastiffs, Golden Retrievers, Saint Bernards and Scottish Terriers. Though the cancer most commonly occurs in middle-aged and older dogs, even puppies can be affected.
A tumor that grows in lymph nodes and arises from lymphocytes, or white blood cells that fight disease, lymphoma may interfere with the production of normal blood cells if the tumor infiltrates bone marrow. Though it may be restricted to certain organs, it is more commonly found in most of the body’s lymph nodes. Affected lymph nodes are felt as enlarged masses under the neck, in front of the shoulders or behind the knees.
A definitive diagnosis usually involves getting a sample from an affected node. Veterinarians conduct a physical examination and take a tissue biopsy. If lymphoma is diagnosed, it is important to learn how widespread the cancer is through radiographs and/or ultrasounds. Other testing includes blood samples for complete blood count and blood biochemical profile information, urinalysis and a bone marrow sample.
T-cell and B-cell lymphocytes are two subtypes of white blood cells that are part of the normal immune system. Either cell type may undergo changes that lead to lymphoma. The different types are associated with different chromosomal changes that occur in dogs with lymphoma.
When a 7-year-old Boxer named “Patton” began excessively drinking water, owner Cindy Hearn of White Lake, Mich., thought it was due to chewing on rawhide bones. “The thirst continued, and then I noticed a slightly enlarged lymph node under his jaw,” she says.
The veterinarian performed blood work, which showed an elevated level of calcium. A fluid sample from the enlarged lymph node indicated lymphoma. Hearn opted to have Patton treated with chemotherapy. The treatment went well, and she credits chemotherapy with giving her nine months longer with her beloved Boxer
“Patton was my companion, my friend and buddy,” Hearn says. “I realized that I was only gaining time with chemotherapy, but it was valuable time to me. Lymphoma isn’t a painful cancer to dogs, thankfully. It’s just painful to the ones who love them.”
A couple in Toledo, Ohio, hoped to buy more time with their 6-year-old Boxer, “Eva,” when they had her treated for a rare lymphoma that occurs in the skin. Douglas and Sydney Leavitt first noticed an orange-sized tumor in Eva’s leg, followed a few months later with nodules and sores on her feet, muzzle and eyelids. Since the nodules came and went, the veterinarian thought they were from allergies the dog had suffered most of her life.
When a biopsy revealed Eva had an advanced stage of cutaneous lymphoma, the Leavitts opted for treatment with high doses of prednisone to help keep Eva comfortable. The therapy offers a short-term reprieve at an economical cost. They realized that once they began the treatment, it would negate the effectiveness of chemotherapy if they later decided to try it. In essence, there would be no turning back.
The prednisone put the cancer into remission for about six weeks. “Eva started acting like a puppy and seemed to feel great,” recalls Sydney Leavitt. “Once the tumor returned, it was aggressive. It got to the point that just walking outside made her feet bleed. Still, she was happy. When a tumor on her toe became necrotic, we had to have her put down.”
Predicting Treatment Response
As many as 100,000 to 200,000 new cases of lymphoma are diagnosed each year in dogs, yet only about 9,000 dogs receive treatment. Owners say they would choose treatment if they knew their dogs would respond. Predicting the reliability of treatment for lymphoma has been elusive.
Determining how well a dog will respond to treatment traditionally has been based on the clinical staging of the cancer. The number and location of affected lymph nodes as well as whether the cancer involves the spleen, bone marrow or other organ systems are important. Whether a dog shows signs of illness, including lethargy, anorexia or weakness, is considered as well.
Dogs with significant bone marrow involvement and those that are sick tend to respond poorly. The challenges of determining the likelihood of dogs to experience cancer remission, which is often followed by tumor recurrences, may partly be due to the diversity of cells within tumors, says Daisuke Ito, D.V.M., Ph.D., research associate at the University of Minnesota Masonic Cancer Center at the College of Veterinary Medicine.
“Cancer stem cells, which are more accurately called tumor-initiating cells (TICs), tend to be resistant to commonly used cancer drugs,” Ito says. “These TICs are thought to be responsible not only for the formation of tumors but also for maintaining and spreading them, and thus for their recurrence after treatment. Even when we successfully eliminate the bulk of tumor cells, causing tumors to shrink and patients to achieve remission, a minority of TICs survives and might eventually fuel tumor regrowth or recurrence.”
Developing new therapies to target and eliminate TICs might lead to longer remissions and eventually cures for canine lymphoma. “We have identified a population of cells called lymphoid progenitor cells, or LPCs, that resemble TICs,” Ito says. “Our collective findings show that these LPCs atypically expand in the lymph nodes of dogs with lymphoma compared to those of healthy, unaffected dogs. These LPCs are genetically and possibly functionally related to the bulk of tumor cells. Potentially, these LPCs can be used as a novel target for the treatment of lymphoma.”
Similar to lymphoma in humans, canine lymphoma may be more than one disease. Thirty subtypes of lymphoma have been identified in people, and each responds differently to treatment protocols. Suter and his colleagues at North CarolinaStateUniversity are investigating techniques to discern lymphoma subtypes in dogs.
One way may be using microRNA (miRNA) signatures to target cancer genes. MiRNAs can regulate target genes by binding and inhibiting their RNA coding, and thus encouraging or discouraging the development of disease. “Different types of lymphoma appear to have distinct miRNA signatures, raising the possibility that miRNA could be used more precisely to diagnose the type of lymphoma,” Suter explains. “Our preliminary studies show that many of the same MiRNAs associated with lymphoma in humans also are associated with lymphoma in dogs.”
Canine lymphoma is a difficult cancer to face with a beloved dog. Treatments that offer quality of life and increased longevity are welcomed. For the Leavitts, when their Boxer, Eva, approached her last days, they chose to take the dog on leisurely walks and invited friends to take part in a party in her honor.
Hearn, whose Boxer, Patton, suffered from lymphoma, says, “It’s how you spend your life with your dog that matters. The everyday life you shared until he became sick. I am thankful to have had many good days with Patton.”
Online Boxer Health Survey Coming Soon
Aiming to better understand health issues affecting Boxers, the American Boxer Charitable Foundation plans to conduct an online breed health survey. The survey will collect data on diseases such as arrhythmogenic right ventricular cardiomyopathy (AVRC), degenerative myelopathy and hip dysplasia.
The survey also will query for information regarding breeding practices, health testing and disease incidence in Boxers. Judy Voran, a member of the American Boxer Charitable Foundation, hopes the survey will provide insights on Boxer health and shed light on new research opportunities. Owners may complete the survey anonymously.
“The results obtained from this health survey might provide a broader range of statistics than we currently have available,” Voran says. “Surveys like this help us better understand what diseases we should try to breed against.”
The link to the breed health survey initially will be distributed to a select group of American Boxer Club (ABC) members. Once the sample group easily completes the pilot test and the results are validated, the American Boxer Charitable Foundation plans to open the survey to all owners and breeders of Boxers registered with the American Kennel Club.
“The online format allows us to reach as many people as possible, which will help provide an accurate sample of current Boxer health concerns,” Voran says.
Meanwhile, the ABC Health and Research Committee is producing a health and research brochure that will include the latest information about breed health issues, such as AVRC, degenerative myelopathy, subaortic stenosis and other diseases. It will provide information about the new genetic test for ARVC that is available through Washington State University College of Veterinary Medicine.
“We published our last health and research brochure in 2001,” Voran says. “This update will help Boxer breeders and owners better understand health issues facing our dogs.”
For more information about the online breed health survey or the health and research brochure, please contact Dr. Joyce Campbell, chairwoman of the ABC Health and Research Committee and a trustee of the American Boxer Charitable Foundation, at [email protected].
Purina appreciates the support of the American Boxer Club and particularly Joyce Campbell, D.V.M., chairwoman of the ABC Health and Research Committee and a trustee of the American Boxer Charitable Foundation, in helping to identify topics for the Purina Pro Club Boxer Update newsletter.