mutant p53-based personalized trial using decitabine and arsenic trioxide on aml/mds

Conditions: P53 Mutation; Myeloid Malignancy; MDS; Aml

Summary: tp53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. here the investigators try to evaluate the side effect and treatment potential of dac+ato in p53 mutated high-risk aml/mds patients. about 200 aml/mds patients will be sequenced for tp53 sequence before recruitment. the investigators estimated about 5 patients, based on the reported p53 mutation frequency in aml/mds, will be p53-mutated. in the trial, the investigators will selectively recruit the mp53 aml/mds patients that are predicted to respond to dac+ato regimen with highest chance (based on the relevant basic studies). the investigators designate mutant p53-based clinical trials as 'panda (p53 and arsenic)-trials'.

tp53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. in two independent clinical trials reported recently, dna demethylating drug decitabine (dac) treatment yielded a surprisingly high rate of complete remission (cr) in mp53-expressing myelodysplastic syndromes (mds) patients and acute myeloid leukemia (aml) patients. notably, all of the mp53-expressing patients in the two clinical studies, despite of cr, relapsed quickly. this was attributed to a failure in thoroughly clearing all leukemia-specific mutations and the preexisting mp53 subclone outgrew in all of the relapse patients. indeed, the investigators also found p53 dysfunctional cells quickly develop a dac resistance mechanism in cultured tissue (unpublished data). meanwhile, the investigators found arsenic trioxide (ato) selectively inhibit p53-mutated cells involving mutant p53 reactivation and mutant p53 degradation (presumably mediated by upregulated mdm2 and rchy1/pirh2 through reactivated mutant p53). in addition, dac and ato show synergy in inhibiting p53-mutated cells. in current phase i trial, the investigators try to evaluate the side effect and treatment potential of dac+ato in p53 mutated high-risk mds patients. about 200 aml/mds patients will be recruited for tp53 sequencing before being trialed. the investigators estimated about 50 patients, based on p53 mutation frequency in aml/mds, will be sequenced to be mp53-positive. the mp53-positive aml/mds patients are known to have an extremely poor prognosis. the investigators will select high-risk mp53 mds patients that are predicted to respond to dac+ato with highest chance based on our relevant basic studies. the other participants (free of p53 mutation) will be excluded from the trial.

Eligibility criteria:
inclusion criteria: * occurrence of p53 mutants that are predicted to respond to ato+dac with highest chance * patients newly diagnosed with myelodysplastic syndromes. * ecog performance status ≤ 3. * aged from 18 to 75. * active bone marrow hyperplasia indicated by morphology * normal liver and renal function, bilirubin ≤35μmol/l, asl/alt lower than 2xuln, creatinine level ≤150μmol/l * normal cardiac function * written informed consent. exclusion criteria: * patients previously treated. * confirmed cns involvement. * abnormal liver function which does not meet the inclusion criteria. * severe cardiac diseases including myocardial infarction or heart insufficiency. * qt interval ≥450ms on ecg. * with other visceral malignancy. * active tuberculosis or hiv(+). * patients with pregnancy or lactation. * allergic or significantly contraindicated to any drugs involved in intervention. * significantly contraindicated to hma chemotherapy. * ecog performance status ≥3, cci \>1, adl \<100. * unable to understand or follow the study protocol. * previous intolerance or allergy history to similar drugs. * aged \ 75yrs * mds patients previously treated with decitabine. * participation at same time in another study in which investigational drugs are used. * any other conditions interfering the study.

Keywords: p53 mutation personalized treatment decitabine arsenic trioxide aml mds