Lymphoma Diagnostics, Standard of Care Treatment Options and Rescue Options

Transcription

1 Lymphoma Diagnostics, Standard of Care Treatment Options and Rescue Options Kelvin Kow, DVM, DACVIM (Medical Oncology) University of Florida College of Veterinary Medicine Lymphoma is the most common malignancy in small animal medicine where chemotherapy is considered to be standard of care. The symptoms associated with lymphoma are broad and generic including signs such as lethargy, anorexia, weight loss, polyuria/polydipsia, vomiting and diarrhea. The vast majority of lymphoma patients are asymptomatic at diagnosis and present due to palpation of an enlarged lymph node. At it s most basic, a definitive diagnosis can be made by fine needle aspiration and cytology. The standard staging scheme is based upon the WHO system ranging from Stage 1-5 as well as substages (a) or (b). The rationale and reason for performing a staging test is that it provides important prognostic information in that high stage patients tend to do worse than lower stage ones. That said, the vast majority of canine lymphoma patients are stages 3-5 with little difference in prognosis between a stage 3 vs. 4 patient. Stage 1- One lymph node affected only Stage 2- Greater than 1 lymph node on one side of the diaphragm Stage 3- Lymphadenopathy on both sides of the diaphragm Stage 4- +/- Liver, splenic involvement Stage 5- Bone marrow involvement, or extra-nodal lymphomas (CNS, Ocular, Cutaneous) Further diagnostics and staging are performed depending on the willingness of the client to attain further information that can provide prognostic information. At the University of Florida, clients who chose to treat their pets who have lymphoma are minimally required to also perform a complete blood count, chemistry profile and urinalysis. Additional diagnostic options offered include abdominal ultrasound, chest radiographs, bone marrow aspirate, the PARR assay as well as flow cytometry. Lymph node biopsies and immuno-histochemisty stains (CD3 & CD79) are still recognized as the gold standards in attaining immuno-phenotype. However, it has recently been surpassed by less invasive methods such as flow cytometry and immuno-cytochemistry. Immunophenotyping by flow cytometry are available through Dr. Anne Avery s lab at Colorado State University ( or North Carolina State University ( Flow cytometry utilizes a cell sorter that is able to differentiate cells based upon cell surface markers similar to immuno-histochemistry or immuno-cytochemistry. The PARR assay utilizes PCR technology to look for clonality in a population of cells. Lymphoma and leukemia cells are all derived from a single neoplastic clone while inflammatory diseases that cause lymphadenopathy are not.

2 Option Median Survival Time Approximate cost of treatment (UF) Misc details No Treatment 4-6 weeks - Rapid worsening of quality of life Prednisone 2 months - CHOP 1 year $ 4,000-4, treatments over 19 or 25 weeks Single Agent 7 months $ 2,000 5 treatments total, each treatment 2- Doxorubicin or 3 weeks apart COP 7 months $ 2,500 The overall prognosis is good with median survival times of 1 year with CHOP/Madison-Wisconsin based chemotherapy protocols. Even the vast majority of dogs respond very well to treatment, most of them will come out of remission at some point and require rescue chemotherapy. 1 Fig 1: Bracketed area represents time of treatment. Most dogs will come out of remission between 7-9 months post induction, however still achieve median survival times of 1 year. A rule of thumb frequently quoted is that the with each rescue protocol, the response rate and durability of subsequent remission is ½ that of the initial response to treatment. The decision to choose one rescue protocol over another depends on several factors: Client s wishes to continue chemotherapy vs. palliative care Quality of response of previous protocol Length of remission attained to date Time to progression of disease from the start of therapy Overall health condition & presence of underlying medical problems Cost and time commitment from client Degree of risk aversion of client Palliative Care If a client decides to choose palliative therapy only, the most straightforward approach is to start the patient back on a corticosteroid. Typically, the choice for canine patients is a 2mg/kg/day dose of Prednisone that is tapered down by 0.5mg/kg weekly until a maintenance dose of 0.5-1mg/kg/day is reached at the 3 rd or 4 th week. The survival time of beyond the re-induction of Prednisone is variable with most dogs with the average patient living for 1-2 additional months. First Round of Rescue Chemotherapy

3 If a client decides to go with gold standard rescue therapy, the most effective protocol is to reinduce them with the same chemotherapeutic protocol they started with. This is assuming that there was a good initial response to therapy and a reasonable remission time was achieved. For example, if a patient has a complete remission (CR) with CHOP, and comes out of remission several months after completing treatment, the treatment of choice is to reinduce with CHOP as well. The caveat with a 2 nd round of the CHOP protocol is that a patient can receive a lifetime cumulative dose of Doxorubicin of mg/m 2. Going beyond this limit places a patient at significant risk of irreversible cardiomyopathy. Typically, another anthracycline, Mitoxantrone is used as a substitute for Doxorubicin when this cumulative dose is reached. Mitoxantrone is an anthracycline that does not have the cardiac side effects associated with Doxorubicin. It is not ideal as a first line therapy compared to Doxorubicin as it is a less efficacious chemotherapy agent. 1 Single agent Doxorubicin/Mitoxantrone or the COP protocol can be used as rescue drugs as an alternative to CHOP as it reduces the overall cost of treatment and the number of treatments compared to CHOP. Similar to a 2 nd round of the CHOP protocol, Mitoxantrone is used to replace Doxorubicin once the cumulative lifetime dose has been administered. With single agent Doxorubicin/Mitoxantrone protocols, a total of 5 doses are given at either 2-3 week intervals depending on the patients tolerance of the drug. Some clients choose alternatives to CHOP re-induction for financial and/or personal reasons. Part of the challenge in choosing rescue protocols are the plethora of options available. A brief listing of these include LAP, LOPP, MOPP/BOPP, ABVD, DMAC and DTIC-Doxorubicin. There are also various unpublished protocols that are often just alphabet soup rearrangements of different chemotherapy acronyms. Deciding on a rescue protocol is all the more challenging as few of the studies are prospective in nature and often compare different patient populations with varying degrees of pretreatment. Moreover, these studies often utilize different end points for the evaluation of treatment response. Rescue protocols are also utilized if a patient fails to achieve a good response to initial CHOP therapy or progressive disease occurs in a matter of days to 1 week after the completion of therapy. The major reason for poor response to treatment is the development of drug resistance. The best-known drug resistance mechanism is caused by a mutation in the multidrug resistance gene (MDR-1) that expresses the P-glycoprotein drug efflux pump. MDR-1 mutations result in a non-functional P- glycoprotein that inefficiently clears xenobiotic chemotherapeutic drugs from the body. Xenobiotic based agents include the Vinca alkaloids and the anthracyclines such as Doxorubicin. The alkylating drugs are not xenobiotics and are thus a mainstay of rescue protocols. 2

4 The most common rescue protocols currently utilized by medical oncologist incorporate the alkylating agent, Lomustine/CCNU. While Lomustine can be used as a single agent rescue agent, the overall response rate is quite low. It is most effectively used as part of the L-Asparaginase/Lomustine/ Prednisone (LAP) protocol or the LOPP protocol. The LAP protocol only utilizes L-Asparaginase with the first 2 treatments. The overall response rate to this protocol is ~75% with the majority of these patients achieving a complete response. The median time to progression from induction is approximately 70 days. 3 The LOPP protocol combines Lomustine with Vincristine, Procarbazine and Prednisone. If a patient has done poorly on Vincristine, Vinblastine is often used as a substitute. The overall response rate of this protocol is approximately 60% with 35% of patients achieving a complete response with an overall response time of 98 days. 4 In addition to the typical side effects of chemotherapy such as myelosuppression, Lomustine can occasionally lead to hepatoxicity. A liver profile is recommended as a baseline prior to starting Lomustine. ALT levels should be monitored every other treatment. Preexisting elevations in liver values are not necessarily a contraindication for treatment as it often indicates underlying infiltration of the liver with lymphoma. 5 An improvement in liver values with treatment is often seen if this is the case. L-Asparaginase/Lomustine/Prednisone L-Asparaginase at 10,000U/m 2 SQ or IM on day 0 and 21 only Lomustine at mg/m 2 PO q 21 days Prednisone 2mg/kg/day tapering down to 0.5mg/kg/day PO *Treatment occurs on a 21 day cycle for 5 cycles or 2 beyond a complete response or progressive disease LOPP-UF Protocol Lomustine at mg/m 2 PO q 21 days Vincristine 0.6mg/m 2 IV on day 0, then on d Procarbazine 50mg/m 2 PO on day 0-13 Prednisone 40mg/m2 PO on day 0-13 *treatment occurs on a 28 day cycle 2 nd Rescue Protocol and Beyond Once a patient has failed a first rescue protocol, the choice of subsequent treatments varies tremendously and is often dependent on the institution where one is trained. Some options at this stage include single agent melphalan, chlorambucil, actinomycin, dacarbazine or cytosine arabinoside.

5 Other drugs thrown into this mix include Bleomycin, Vinblastine, Vinorebine and Mustargen. At the time of the publication of these notes, Actinomycin and Mustargen are used minimally due to limited availability. It is for this reason that protocols such as DMAC protocol (Dexamethasone, Melphalan, Actinomycin and Cytosine Arabinoside) 6 and MOPP (Mustargen, Vincristine, Procarbazine and Prednisone) are minimally utilized. 7 A consultation with an oncologist is often helpful at this stage. Information helpful to provide during a consultation includes the immunophenotype (B vs. T cell), stage/substage of disease, efficacy and response time with the initial induction or rescue protocols as well as history of side effects with certain drugs. Non-Cemotherapy Related Treatment Options Radiation therapy can also be used as a treatment option. In veterinary medicine, radiation for lymphoma patients typically occurs as ½ body radiation where either the cranial and caudal ½ of the body an additional drug within a multi-agent lymphoma treatment protocol. 8 Dr. Steven Suter at North Carolina State University utilizes TBI for lymphoma treatments as part of their bone marrow transplant (BMT) program for lymphoma. At this time, the majority of patients treated with TBI-BMT are previously untreated lymphomas that have had a complete response to CHOP based chemotherapy. TBI-BMT is not recommended at this point as a rescue option for relapsed lymphoma. Long term survival measured in terms of years appears to be possible for the majority of patient treated with this modality. References 1. Withrow, Stephen J., and David M. Vail. Withrow & MacEwen's Small Animal Clinical Oncology. St. Louis, Mo: Saunders Elsevier, pp Mealey KL. Adverse Drug Reactions in Herding Breeds. Compendium of Continuing Education for the Practicing Veterinarian 2006;28: Saba et al. Combination chemotherapy with L-asparaginase, lomustine, and prednisone for relapsed or refractory canine lymphoma. J Vet Intern Med (2007) vol. 21 (1) pp LeBlanc et al. Efficacy and toxicity of BOPP and LOPP chemotherapy for the treatment of relapsed canine lymphoma. Veterinary and Comparative Oncology (2006) vol. 4 (1) pp Kristal et al. Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs. J Vet Intern Med (2004) vol. 18 (1) pp Alvarez et al. Dexamethasone, melphalan, actinomycin D, cytosine arabinoside (DMAC) protocol for dogs with relapsed lymphoma. J Vet Intern Med (2006) vol. 20 (5) pp Northrup et al. Mechlorethamine, procarbazine and prednisone for the treatment of resistant lymphoma in dogs. Veterinary and Comparative Oncology (2009) vol. 7 (1) pp Mayer and Larue. Radiation therapy in the treatment of canine lymphoma. Can Vet J (2005) vol. 46 (9) pp Avery. Molecular diagnostics of hematologic malignancies. Topics in Companion Animal Medicine (2009) vol. 24 (3) pp