Browsing by Author "Dabas, Rosy"

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    Anti-leukemic Activity of Anti-thymocyte Globulin
    (2018-09-17) Dabas, Rosy; Storek, Jan; Khan, Faisal Masood; Morris, Don G.; Mahoney, Douglas J.
    Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies. The most frequent indication is acute myeloid leukemia (AML). Relapse and graft-versus-host disease (GVHD) are the major causes of HCT failure. Most immunosuppressive drugs used for GVHD prophylaxis increase relapse, presumably due to inhibiting not only GVHD but also graft-versus-leukemia effect (GVL). Polyclonal rabbit anti-thymocyte globulin (ATG), now widely used for GVHD prophylaxis, is the only immunosuppressive drug reducing GVHD without increasing relapse. The reason for ATG not increasing relapse is not known. We hypothesized that this could be due to an anti-leukemic activity of ATG. I investigated the anti-leukemic activity both in vitro and in vivo (in patients). I first evaluated whether ATG at clinical concentrations kills leukemic blasts in vitro. I showed that ATG does kill leukemic blasts, via complement-dependent cytotoxicity (CDC) and direct induction of apoptosis. Next, I investigated whether ATG kills in vitro not only leukemic blasts but also leukemic stem cells (LSCs). I showed that ATG does kill LSCs, primarily via CDC, however, only at a higher concentration than needed for killing leukemic blasts. In spite of the anti-leukemic activity of ATG in vitro, in vivo ATG has so far been considered not to have an anti-leukemic activity as in 3/3 randomized studies ATG did not reduce relapse. We hypothesized that this could be due to differential effects of ATG pre- versus post-HCT. Specifically, we hypothesized that the direct anti-leukemic effect of ATG is countered by the anti-GVL effect of ATG post- but not pre-HCT. I evaluated associations between pre- versus post-HCT ATG area-under-the-curve (AUC) and relapse. I found that high pre-HCT AUC was associated with a low incidence of relapse. Conversely, there was a trend toward an association between high post-HCT AUC and a high incidence of relapse. The association between pre-HCT AUC and relapse is an indirect evidence for anti-leukemic activity of ATG in vivo. These findings are expected to lead to clinical studies harnessing the anti-leukemic effect of ATG, e.g., by dosing ATG so as to achieve a higher than conventional pre-HCT AUC and a conventional post-HCT AUC. This could lead to decreasing relapse without increasing GVHD which may lead to improved survival.
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    Synergy of anti-leukemic effects between anti-thymocyte globulin, busulfan, and fludarabine
    (2017-11-30) Yang, Lucy; Dabas, Rosy; Storek, Jan
    Antithymocyte Globulin (ATG) is an anti-GvHD (Graft versus Host Disease) drug that has recently been shown to have anti-leukemic effects. In Alberta, Busulfan and Fludarabine are used to treat acute myeloid leukemia. However, both drugs also lead to the death of healthy cells within the body, especially with increased doses. It would be beneficial to study ways to maintain their effects while decreasing their toxicity, such as synergy with ATG. Different concentrations of ATG were combined with different concentrations of Busulfan and Fludarabine separately to test their effects on pre-conditioned leukemia cell samples from acute myeloid leukemia patients. Cell death was quantified using flow cytometry. The cells from five patients were used and combined into graphs that compared cells dyed by 7AAD (dead cells) between the drugs. In some of the combinations, there appeared to be increased cell death in test tubes with a combination of ATG with Busulfan or ATG with Fludarabine. However, with the use of the Wilcoxon Matched Pairs Test, the difference was deemed not significant. Even though there were no significant differences, it could be due to the low sample size. Furthermore, other concentrations not tested in this experiment could yield better results. If synergy exists between ATG and Busulfan or Fludarabine, the two drugs should be moved up in patients’ conditioning schedules to allow synergism to occur, leading to more cancer cell death with less risk for side effects.