Page 731 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 33 Hematopoietic Tumors 709

TABLE 33.6 First-Line Rescue Protocol a (programmed cell death), tumor ablation, and immune-system
reconstitution, as well as novel immunomodulatory therapies for
lymphoma, are all active areas of investigation in both human and
Cycle 1
VetBooks.ir Week 1 Baseline ALT ________ Units/L veterinary medicine.
l-Asparaginase, 400 Units/kg SC
b
2
CCNU 70 mg/m PO Treatment Approaches Using Immunologic or
Prednisone, 2 mg/kg PO, once daily
Biologic Agents
Week 2 Prednisone, 1.5 mg/kg PO, once daily
Monoclonal Antibody Approaches
Week 3 Prednisone, 1.0 mg/kg PO, once daily Enhanced durability of first remissions in humans with B-cell
Cycle 2 NHL has been achieved primarily through the institution of
Week 1 Optional ALT ________ Units/L monoclonal antibody (mAb)-based therapies (so-called R-CHOP
l-Asparaginase, 400 U/kg SC protocols that are the current “standard-of-care” in people). The
2
CCNU 70 mg/m PO “R” refers to rituximab (Rituxan), a recombinant chimeric murine/
Prednisone, 1.0 mg/kg PO, EOD human antibody directed against the CD20 antigen, a hydropho-
bic transmembrane protein located on normal pre-B and mature
Week 2 Prednisone, 1.0 mg/kg PO, EOD
B lymphocytes. After binding, rituximab triggers a host cytotoxic
Week 3 Prednisone, 1.0 mg/kg PO, EOD immune response against CD20-positive cells. Unfortunately,
rituximab does not have therapeutic activity in dogs because of
Cycle 3–5 a lack of external recognition of a similar antigen on canine lym-
Week 1 Mandatory ALT ________ Units/L phoma cells and the inherent antigenicity of human-derived anti-
2
CCNU 70 mg/m PO bodies in dogs. 321,322 Recently, caninized mAb designed to target
Prednisone, 1.0 mg/kg PO, EOD
either B-cell (blontuvetmab; Blontress) or T-cell (tamtuvetmab;
Week 2 Prednisone, 1.0 mg/kg PO, EOD Tactress) lymphomas were conditionally approved by the USDA
for use in dogs with lymphoma; however, after being assessed in
Week 3 Prednisone, 1.0 mg/kg PO, EOD
prospective clinical trials involving a large number of dogs, their
a Treatment discontinuation criteria: (1) After completion of protocol, two treatments beyond target specificity was found to be inadequate to effect clinical effi-
complete response (CR); (2) progressive disease; (3) increase in ALT activity >2× upper limit cacy, and they are no longer available and are not currently rec-
of normal (or 2× baseline if higher than baseline at initiation)—institute drug discontinuation ommended for use. Several laboratories throughout the world are
and reinstitution/dose reduction dependent on normalization of ALT. working to characterize and develop more specific and effective
b Prophylactic liver protectants recommended (e.g., Denamarin). mAb therapies for use in canine lymphoma, 323–326 and practitio-
ALT, Alanine aminotransferase.
ners await their development.
Antitumor Vaccine Approaches
of a particular rescue protocol should depend on several factors, Several antitumor vaccine approaches have been investigated
including cost, time commitment required, efficacy, adverse event in dogs with lymphoma, including tumor vaccine extract using
profile, and experience of the clinician with the protocols in ques- killed lymphoma cells combined with Freund’s adjuvant 327,328 and
tion. As the complexity of rescue protocols does not yet appear to autologous killed and/or gene engineered lymphoma tumor cell
be associated with significant gains in rescue durability, the author vaccines 329,330 ; however, no significant gains in remission times or
(DMV) tends to choose simpler and less costly protocols (e.g., overall survival have been documented. Exploratory vaccines tar-
CCNU/l-asparaginase/prednisone) (Table 33.6); however, the use geting telomerase 331,332 (see Chapter 15, Section D), heat shock
of multiple varied rescue protocols, switching as needed based on proteins, 333,334 and RNA-loaded CD40-activated B cells 335,336
response, continues as long as clients are comfortable with their in dogs with lymphoma have also been conducted. These studies
dog’s quality of life. This sequential application of several different involved small numbers of nonrandomized patients and lacked
rescue protocols can result in several months of extended survival controlled populations for comparison. A xenogeneic DNA vac-
with acceptable quality of life. cine designed to target canine CD20 is currently undergoing
clinical trials in the United States. Although preliminary activity is
Strategies to Enhance Effectiveness of Therapy suggested in many of these reports and they are serving to enhance
in Lymphoma our basic understanding of immunotherapeutic methodologies,
their development is still early; complete safety and efficacy trials
Despite the plethora of published chemotherapeutic protocols have not been completed to date.
for dogs with lymphoma, it appears we have achieved as much as
we can from currently available cytotoxic chemotherapeutics in Adaptive Immunotherapy Approaches
standard settings. The 12-month median survival “wall” and the Much excitement has been generated in physician-based medi-
20% to 25% 2-year survival rates have not improved dramatically. cine about adaptive immunotherapy approaches, in particular
Further advances in remission and survival durations await the the application of chimeric antigen receptor T cells (CAR-T; see
development of new methods of delivering or targeting traditional Chapter 14). These approaches are currently the subject of several
chemotherapeutic drugs, new generations of chemotherapeutic proof-of-concept trials in dogs with NHL. 337,338
drugs, or novel nonchemotherapeutic treatment modalities; in
particular, the development of targeted immunotherapies, which Surgery
is the standard of care in physician-based oncology. Mechanisms Most dogs with lymphoma have multicentric disease and therefore
of avoiding or abrogating MDR, enhancing tumor apoptosis require systemic chemotherapy to effectively treat their disease.