Experimental combo targets genetic weakness in aggressive blood cancers

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Eligibility Criteria Participants with following: i) Adult participants (≥ 18 years) with newly diagnosed MDS/AML ≥ 10% blasts with TP53 aberration * TP53 aberration defined by: * Single TP53 mutation\> 10% VAF * ≥ 1 mutation of any VAF, irrespective of cytogenetics or TP53 allele loss * Single TP53 mutation 5-10% with complex karyotype and/or TP53 allele loss * (TP53 mutation will include any known pathogenic missense, truncating or splicing mutations (defined as Tier 1 or 2 in the UT MD Anderson CLIA lab myeloid NGS panel or validated by molecular pathologist; TP53 allele loss on FISH should be at least \> 5%) ii) Ineligible for intensive chemotherapy * Adult participants ≥ 60 years of age, OR * Adult participants 18 to 60 years of age with at least one of the following relevant clinical situations/status: * Eastern cooperative oncology group (ECOG) performance status ≥2 * Clinically significant organ comorbidities, as reflected by at least 1 of: * Left ventricular ejection fraction (LVEF) \</= 50% * Chronic stable angina or congestive heart failure controlled with medication * Creatinine clearance \< 45 ml/min calculated by the Cockcroft-Gault formula or measured by 24 hours' urine collection * Impaired pulmonary function: Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected * Forced expiratory volume in 1 second (FEV1) ≤65% of expected * Other contraindication(s) to anthracycline therapy (must be documented). * Other comorbidity the investigator judges incompatible with intensive remission induction chemotherapy, which must be documented and approved by the PI. * Adequate hepatic function defined by * Serum AST/ALT ≤ 3 x ULN, unless considered due to leukemic organ involvement. * Serum total bilirubin \< 2x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, leukemia organ involvement or Gilbert's syndrome. * The teratogenic effect of AZA is not well studied. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy UT MD Anderson Institutional Policy # CLN1114). This includes all female participants, between the onset of menses (as early as 8 years of age) and 55 years unless the participants presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * Men treated or enrolled on this protocol must also agree to use adequate contraception, for the duration of study participation, and 4 months after completion of AZA administration. * For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * Participants with a prior or concurrent malignancy may be eligible after discussion with the investigator/ PI * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria * Adult participants with MDS/AML without a known pathogenic TP53 mutation * Treated secondary AML (AML developing after prior exposure to hypomethylating agents, chemotherapy or allogeneic HSCT for previous myeloid disorders like MDS, CMML, other MDS/MON overlap syndromes) * Post MPN AML (advanced phase MPN) * Participants with immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation * Participants with active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment). * Participants with known and untreated major depressive disorder * Participants with known and active autoimmune disorder * Participants with known retinal disease except for known age related macular degeneration * Participants with another active cancer warranting therapy. A maintenance therapy for a stable/treated prior cancer is acceptable if it does not interfere with the trial therapy. This needs to be discussed with the PI. * Participants who are receiving any other leukemia treatment. * Participants who are receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to Ropeginterferon alfa-2b, AZA or other agents used in study. * Participants with psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because AZA and potentially rIFN\_A has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infant's secondary to treatment of the mother with the combination, breastfeeding should be discontinued if the mother is treated with combination. These potential risks may also apply to other agents used in this study.