Comparison of a Standard Regimen (CHOP) with Three Intensive Chemotherapy Regimens for Advanced Non-Hodgkin's Lymphoma:
Lymphoma is one of the most common cancers in both dogs and cats and one of the most commonly treated cancers in veterinary medicine. As a veterinary oncologist, I cannot remember a more exciting time in this field, as there are now some wonderful new therapeutic options available, including monoclonal antibody therapy for both T and B cell lymphoma in dogs.
Antibodies are proteins produced by plasma cells (mature B cells) used by the immune system to identify and neutralize foreign antigens like bacteria, viruses, parasites, and cancer cells. Each antibody recognizes a specific antigen and monoclonal antibodies are identical antibodies that each recognize a single, specific antigen. The scientist who discovered monoclonal antibodies shared the Nobel Prize in Medicine in 1984, signifying how important this discovery was to the world.
The immune system attacks foreign proteins (parasites, viruses, bacteria) in your body, but it doesn't always recognize cancer cells as foreign. Therapeutic monoclonal antibodies can be directed to attach to certain parts of a cancer cell, and therefore allow the immune system to more easily detect and eliminate the cell. Monoclonal antibodies do this through a variety of mechanisms: activating Antibody Dependent Cellular Cytotoxicity (ADCC); blocking growth factor signaling; stopping new blood vessels from forming; delivering radiation to cancer cells; and delivering chemotherapy to cancer cells
As canine lymphoma is incredibly similar to non-Hodgkin’s lymphoma (NHL) in people, it is helpful to look at the “human” experience with monoclonal antibodies. In the late 1990’s a large group of oncologists tested the various chemotherapy regimens for NHL and found that the standard CHOP regimen was just as good as the other more intense chemotherapy regimens. (see chart #1)
Fisher RI et al. N Engl J Med 1993;328:1002-1006 (chart #1)
It wasn’t until the development of Rituximab that there was any significant advancement in the treatment of NHL in people (see chart #2). The monoclonal antibody drug rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.
“The most substantial advancement in the treatment of B-cell malignancies, since the advent of combination chemotherapy, has been the addition of the monoclonal anti-CD20 antibody rituximab (Rituxan).” -Pharmacy and Therapeutics 2010 Mar; 35(3): 148–157.
Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin’s Lymphoma
Efrat Dotan, MD, Charu Aggarwal, MD, MPH, and Mitchell R. Smith, MD, PhD
JCO, Feugier, et al, 2005 (chart #2)
The veterinary oncology community has also been testing an anti-CD20 monoclonal antibody, also from Aratana. In the first trial, dogs were treated with either 1 cycle of CHOP along with the anti-CD20 MAb or 1 cycle of CHOP alone. The results are quite impressive (see chart #3) in that the median progression free survival times and the median overall survival times of the dogs treated with MAbs were 167 and 325 days, respectively, compared to 93.5 and 177 days for the placebo arm. In the second trial dogs were treated with either single agent doxorubicin and the anti-CD20 MAb or single agent doxorubicin alone. The number of dogs achieving a complete remission was greater in the group receiving the MAb than in the group receiving doxorubicin alone.
Monoclonal antibody therapy for T cell lymphomas in dogs is also available. T cell lymphomas are typically more aggressive than the B cell lymphomas in both dogs and people. There are however, indolent forms of T cell lymphoma that dogs can survive with for years. Not all T cell lymphoma are “terrible”. For those T cell lymphomas that are not indolent, the response to chemotherapy alone is not robust. In people, the addition of monoclonal antibodies to chemotherapy for T cell lymphomas has increased survival times and response rates. Clinical responses to the anti-CD52 antibody, alemtuzamab, were observed in over 33% of people with chemotherapy-refractory or relapsed peripheral T cell lymphoma. The canine (“caninized”) monoclonal anti-CD52 antibody developed by Aratana was granted a conditional license in Jan 2014. Since that time there have been 3 clinical programs involving the antibody—T-CHOMP, T-LAB and T-CEP.
T-CHOMP was a clinical study evaluating the anti-CD52 antibody in conjunction with a multi-agent chemotherapy protocol. T-LAB is the clinical trial in which the monoclonal therapy is used in addition to a short protocol involving single agent CCNU. Final results regarding the efficacy of the drug has not been published, but in our experience, the drug was well tolerated and safe. The T-CEP or Clinical Experience Program is the third piece in this program. This program is designed to determine in what scenario or scenarios this therapy is most effective—at the start of chemotherapy, after chemotherapy, when the pet has achieved minimal residual disease status, as maintenance therapy or as induction therapy.
The fact that monoclonal antibody therapy for canine lymphoma is now available is hugely important to veterinarians and pet owners alike.
Gerald Post, DVM, MEM, DACVIM (Oncology)
The Veterinary Cancer Center (www.vcchope.com)