Outcome and toxicity assessment of feline small cell lymphoma: 56 cases (2000–2010)

Feline small cell lymphoma is associated with greater response to treatment and survival when compared to large cell lymphoma. Treatment-associated toxicity, response to rescue chemotherapy and prognostic factors are largely unknown. This retrospective study was performed to identify treatment-associated toxicity, response to rescue chemotherapy and treatment outcome for cats diagnosed with small cell lymphoma of various anatomic locations. Medical records from 56 cats were evaluated. All cats were treated with glucocorticoid and chlorambucil with discontinuation of treatment recommended at 1 year if complete clinical response was documented. Chemotherapy toxicity was uncommon (33.9%) and generally mild. Grade III or IV hepatotoxicity was documented in 10.7% of patients. Overall response rate was 85.7% with glucocorticoid and chlorambucil. Median progression-free survival was 1078 days. Overall response rate for rescue chemotherapy was 59%. Reintroduction of prednisone and chlorambucil was associated with significantly longer survival than prednisone and lomustine (>1500 vs. 492 days, P = 0.01). Median overall survival times for cats with lymphoma of the gastrointestinal tract was not significantly different from those with extra-intestinal disease locations (1148 vs. 1375 days, P = 0.23). Median overall survival was 1317 days. Toxicity, other than hepatotoxicity was mild. Rescue chemotherapy with re-introduction of glucocorticoids and chlorambucil was most successful. Discontinuation of glucocorticoid and chlorambucil with subsequent reintroduction as rescue chemotherapy appears to be just as effective as continued administration in cats

RNA loaded CD40-B cells stimulate antigen-specific IFN-γ responses in PBMCs.

<p>PBMCs were obtained from dogs at the time of diagnosis (pre) and 3 weeks post vaccination (post) and antigen-specific immune responses directed against (A) CDV-HA and (B) lymph node tumor antigens were determined by IFN-γ ELISPOT. *p<0.1, **p<0.05.</p

Kaplan Meier estimates comparing intent-to-treat Group 1 to unvaccinated control Group 3 for (A) time-to-progression (TTP) (p = 0.16) and (B) lymphoma-specific survival (LSS) (p = 0.37).

<p>Kaplan Meier estimates comparing intent-to-treat Group 1 to unvaccinated control Group 3 for (A) time-to-progression (TTP) (p = 0.16) and (B) lymphoma-specific survival (LSS) (p = 0.37).</p

Kaplan Meier estimates for lymphoma-specific survival (LSS) of relapsed dogs who received salvage therapy, demonstrating statistically significant differences between vaccinated Group 2 to unvaccinated control Group 3 (p = 0.038).

<p>Kaplan Meier estimates for lymphoma-specific survival (LSS) of relapsed dogs who received salvage therapy, demonstrating statistically significant differences between vaccinated Group 2 to unvaccinated control Group 3 (p = 0.038).</p

Kaplan Meier estimates comparing vaccinated Group 2 to unvaccinated control Group 3 for (A) TTP (p = 0.34) and (B) LSS (p = 0.18).

<p>Kaplan Meier estimates comparing vaccinated Group 2 to unvaccinated control Group 3 for (A) TTP (p = 0.34) and (B) LSS (p = 0.18).</p

Canine patient characteristics.

<p>Canine patient characteristics.</p

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma [version 3; referees: 2 approved]

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma [version 2; referees: 2 approved]

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting

NBD inhibits the expression of canonical NF-κB target genes in a subset of dogs with ABC-like DLBCL.

<p>NF-κB target gene expression within malignant lymph node tissues before and 24 hours after NBD peptide administration was determined by qRT-PCR. The relative quantification of gene expression in post treatment samples was normalized to pre-treatment values for each dog. β-actin was used as an endogenous control and all assays were performed in triplicate. p values are calculated on dCt data, ^★p<0.05, ^★★p<0.005.</p

NBD peptide promotes apoptosis and reduces tumor burden in a subset of dogs with ABC-like DLBCL.

<p><b>A</b>. Malignant lymph node tissue sections taken before (pre-) and 24 hours after (post-) NBD peptide treatment were stained using TUNEL and counterstained with DAPI. <b>B</b>. Apototic cells were counted in 10 high power fields and the average number of positive cells was determined for both pre- and post-treatment sections. <b>C</b>. Calculated percent decrease in tumor mass 24 hours after NBD peptide treatment. Measureable tumor burden was determined pre and 24 hours post NBD peptide treatment and the percentage change in tumor burden was calculated. ND (Not Determined).</p