Abstract P3-12-04: P53 based strategy to reduce hematological toxicity of chemotherapy: A Pilot Phase II study
Authors: Jenkins Carol A , Argiris Athanassios , Swords Ronan , Karnad Anand , Goros Martin , Pollock Bradley , Yuan Zhi-Min , Ha Chul S , Elledge Richard , Kelly Kevin R , Ganapathy Suthakar , Su Hang 
Published: May 2015

Background: P53 activation is a major pathway by which normal tissues respond to DNA damaging agents such as chemo and radiotherapy. We have shown that the use of very low dose arsenic (LDA) for 3 days before chemotherapy in animal models temporarily and reversibly suppresses p53 activation for about 5 days. LDA-mediated protection requires functional p53 and thus is selective to normal tissues, as essentially every cancer cell has dysfunctional p53. Arsenic Trioxide (ATO) is currently used to treat acute promyelocytic leukemia (APL) at much higher dose (50-fold higher than the dose we used for suppression of p53). The primary objectives of this trial were to: 1) define the lowest safe dose of ATO that blocks p53 activity in vitro as measured in patients(pts)’ peripheral lymphocytes and 2) assess the potential of LDA to decrease hematological toxicity in pts receiving chemotherapy.

Methods: Pts with malignancies other than leukemia who were to receive at least 4 cycles of myelosuppressive chemotherapy given at least 2 weeks apart were eligible. Pts had to have no baseline p53 activation in peripheral lymphocytes but p53 had to be responsive as measured by an in vitro assay. For objective 1, dose escalation was performed at the starting dose of ATO 0.005mg/kg/day for 3 days. For objective 2, ATO 0.005mg/kg /day x 3 was given prior to chemotherapy cycles 2, 4 and 6 only. WBC, ANC, HgB and platelet counts were obtained on chemotherapy days 1 (prior to chemotherapy), 8, 15 and 22, normalized to the corresponding counts from day 1 and compared between cycles with a paired t-test. The presented analysis compares cycles 1 and 2.

Results: Thirty-three evaluable pts were accrued. Chemotherapy was: TC 8, AC 7, 8 other regimens 18 pts. ATO at a dose of 0.005mg/kg/day for 3 days blocked p53 activity in vitro as measured in pts’ peripheral lymphocytes and was not associated with any toxicity. For WBC and ANC, potential protective effect was most pronounced on day 8. The mean normalized WBC counts were 0.54 in cycle 1 and 0.72 in cycle 2 on day 8 (p=0.01). 64% of pts had higher normalized WBC in cycle 2 over cycle 1, 24% remained the same (±5%) and 12% lower value. The mean normalized ANC counts were 0.53 in cycle 1 and 0.85 in cycle 2 on day 8 (p=0.02). 59% of pts had higher normalized ANC in cycle 2 over 1, 31% same, and 9% lower. There was no significant change detectable for HgB as less than 10% of pts had &gt; grade 1 anemia. The mean normalized platelet counts were 0.91, 1.11 and 1.21 in cycle 1 and 0.77, 0.83 and 1.03 in cycle 2 on days 8,15 and 22 respectively (corresponding p values=0.001, &lt;0.001, and 0.04). It is worth noting that &gt;96% of pts had normal platelet counts or grade I thrombocytopenia. On an explorative subset analysis using the exact Wilcoxon signed rank test, the chemotherapy regimen that gained the most protective effect was AC (doxorubicin and cyclophosphamide) used for breast cancer, with mean normalized WBC counts of 0.39 and 0.46 (p=0.03) and ANC counts of 0.39 and 0.49 (p=0.02) on day 8 of cycle 1 and 2 respectively.

Conclusions: Our data suggest that LDA pretreatment confers significant protection against chemotherapy induced leukopenia and neutropenia. Further study is needed to confirm its beneficial effect on AC chemotherapy.

Citation Format: Carol A Jenkins, Athanassios Argiris, Ronan Swords, Anand Karnad, Martin Goros, Bradley Pollock, Zhi-Min Yuan, Chul S Ha, Richard Elledge, Kevin R Kelly, Suthakar Ganapathy, Hang Su. P53 based strategy to reduce hematological toxicity of chemotherapy: A Pilot Phase II study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-04.