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

Daisuke Ito, Michael Childress, Nicola Mason, Amber Winter, Timothy O'Brien, Michael Henson, Antonella Borgatti, Mitzi Lewellen, Erika Krick, Jane Stewart, Sarah Lahrman, Bartek Rajwa, Milcah C. Scott, Davis Seelig, Joseph Koopmeiners, Stephan Ruetz, Jaime Modiano

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Abstract

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.

Original languageEnglish (US)
Article number42
JournalF1000Research
Volume4
DOIs
StatePublished - Jan 1 2017

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Lymphoid Progenitor Cells
B-Cell Lymphoma
Lymphoma
Stem Cells
Placebos
Cells
Dogs
Doxorubicin
Blood
Lymph Nodes
Canidae
Blood Cells
Chemotherapy
P-Glycoprotein
Heterologous Transplantation
ATP-Binding Cassette Transporters
Glycoproteins
Adenosine Triphosphate
Disease-Free Survival
Therapeutics

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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. / Ito, Daisuke; Childress, Michael; Mason, Nicola; Winter, Amber; O'Brien, Timothy; Henson, Michael; Borgatti, Antonella; Lewellen, Mitzi; Krick, Erika; Stewart, Jane; Lahrman, Sarah; Rajwa, Bartek; Scott, Milcah C.; Seelig, Davis; Koopmeiners, Joseph; Ruetz, Stephan; Modiano, Jaime.

In: F1000Research, Vol. 4, 42, 01.01.2017.

Research output: Contribution to journalArticle

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abstract = "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 na{\"i}ve 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.",
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AU - Childress, Michael

AU - Mason, Nicola

AU - Winter, Amber

AU - O'Brien, Timothy

AU - Henson, Michael

AU - Borgatti, Antonella

AU - Lewellen, Mitzi

AU - Krick, Erika

AU - Stewart, Jane

AU - Lahrman, Sarah

AU - Rajwa, Bartek

AU - Scott, Milcah C.

AU - Seelig, Davis

AU - Koopmeiners, Joseph

AU - Ruetz, Stephan

AU - Modiano, Jaime

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