Inclusion Criteria:

Patients in the Phase 1 dose-escalation portion must have a diagnosis of relapsed orrefractory AML, ALL or acute leukemia of ambiguous lineage according to World HealthOrganization (WHO) 2022 classification, or, in the US only, a diagnosis of MDS or MM asdetermined by pathology review at the treating institution, and whose disease hasprogressed after available standard therapies known to be active for their AML, ALL, oracute leukemia of ambiguous lineage or, in the US, for MM or MDS.For patients with MDS (US only): 1. Patients with MDS must have IPSS-R risk categorization of "high" or "very high" at initial diagnosis or at study entry and have bone marrow blasts ≥ 5% (which is the definition of high-risk MDS in this study) 2. Patients with MDS must have relapsed or refractory disease and have exhausted available standard therapies including at least 2 cycles of treatment with HMAFor patients with MM (US only): 1. Have a confirmed diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) 2016 classification (Kumar, 2016) and whose disease has progressed after treatment with a minimum of 3 prior anti-myeloma regimens including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb); patients must not be candidates for available therapies with established clinical benefit 2. Have measurable disease as defined in the protocol 3. Meet the laboratory parameters set in the protocolFor patients with relapsed/refractory AML in the venetoclax and azacitidine combinationcohort (in countries and sites where permitted): 1. Have MLLr or NPM1m. For patients with relapsed/refractory AML in the gilteritinib combination cohort (in countries and sites where permitted): 2. Have MLLr or NPM1m AND any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.Patients in the Phase 2 dose expansion portion of the study must have a confirmeddiagnosis of relapsed AML or ALL as determined by pathology review at the treatinginstitution, and who have ≥5% blasts by morphologic assessment in the bone marrow andfailed available standard therapies known to be active for their AML (Arm G and H) or ALL(Arm I). If the primary disease is a transformation from MDS or other hematologicmalignancies, patients need to receive available standard therapies for acute leukemiabefore enrolling this trial. Participants who are candidates for stem celltransplantation must have been offered this therapeutic option. Patients withextramedullary disease or peripheral blasts as the only manifestation of relapse are noteligible. 1. Patients must not have had prior exposure to a menin inhibitor 2. Patients for Arms G and H are limited to a total of 3 prior lines of therapy, with induction chemotherapy, consolidation chemotherapy, and stem cell transplantation with or without subsequent maintenance treatment considered to be 1 line. 3. Have a documented KMT2A (MLL)-fusion for Arm G and I or NPM1 mutation for Arm H assessed at relapse or immediately prior to the determination of refractory status. For Arms G and I, KMT2A genetic alterations other than fusions (eg, KMT2A-PTD, amplification, point mutation) are not permitted. 4. Be > 18 years of age. For countries and sites where approved, for DSP-5336 monotherapy, acute leukemia patients ≥12 years of age who weigh ≥40 kg may be enrolled. 5. ECOG < 2; For Phase 2 only, patients must have an ECOG performance status 0 or 1. 6. For monotherapy, WBC below 30,000/μ. For the combination arms, WBC count must be below 25,000/uL at enrollment and prior to starting treatment. (Hydroxyurea and steroids for cytoreduction purposes are allowed prior to enrollment and during study treatment) 7. Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gault formula 8. Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients with known Gilbert's syndrome) 9. Aspartate aminotransferase (AST) ≤3.0 times ULN 10. Alanine aminotransferase (ALT) ≤3.0 times ULN 11. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia or neuropathy. 12. Be willing to attend study visits as required by the protocol 13. Have an estimated life expectancy ≥3 months, based on the investigator's assessment 14. Females of childbearing potential must have a negative serum pregnancy test. 15. Must agree to use a highly effective contraception method or 2 acceptable methods of birth control (each partner must use one method) or use prevention of pregnancy measures (ie, agreement to refrain completely from heterosexual intercourse) during the study and for 6 months (for females and males alike) after the last dose of study drug, if male or female patient is of child-producing potential For sites in Japan only: Implantable hormonal contraceptives, a diaphragm with spermicide, cervical cap with spermicide and contraceptive sponge (spermicide is already in the contraceptive sponge) included in the barrier contraceptive method are not approved and cannot be used in Japan. 16. Have AML/ALL/MDS/MM bone marrow material suitable for genomic analysis of AML,ALL, MDS, or MM genetic alterations. Note: If a bone marrow material is insufficient, an alternative suitable tissue (ex: peripheral blood) must be provided.

Exclusion Criteria:

1. Has a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO 2. Histological diagnosis of acute promyelocytic leukemia 3. Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336 4. Have abnormal ECGs at screening that are clinically significant, such as (QTc >480 msec, with QTc corrected according to Fridericia's formula (QTcF). Note: In case of bundle branch block, QT interval correction can be performed. 5. Has an active anduncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy. Note: Patients must be afebrile with negative blood cultures at least 72 hours prior to Cycle 1 Day 1. 6. Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, isavuconazole and itraconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted. If a patient is on one of the excluded azole class antifungals, he/she can be taken off or switched to a permitted azole 7 or more days prior to first dose, then the patient could be allowed on study (Arm B) with approval of the medical monitor. 7. Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days prior to the first dose of DSP-5336 8. Had major surgery within 28 days prior to the first dose of DSP-5336 9. Has active central nervous system leukemia. Patients with a history of any CNS leukemia involvement are excluded from Phase 2 Arms G and H. 10. Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336. Patients who have received >1 prior HSCT are excluded from Phase 2 Arms G and H. 11. Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP-5336, or receiving immunosuppressive therapy post-HSCT at the time of screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD 12. Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336 13. In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results 14. Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of hepatitis B surface antigen, all being indicative of active infection. For sites in Japan, Taiwan, and Korea only: Hepatitis B core (HBc) antibody or hepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. If HBc antibody or HBs antibody test is positive, HBV DNA quantification test should be performed to confirm that HBV DNA is negative. 15. Have severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication 16. Have cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient o receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures 17. Are pregnant or breastfeeding or planning to become pregnant. Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug 18. Have any history or complication of interstitial lung disease (for sites in Japan in Phase 1 dose escalation only). For clinical sites in the EU, have a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment. 19. Have a history of Torsades de Pointes 20. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336 21. Have plasma cell leukemia (>2.0 x 109 /L plasma cells in blood by standard differential) (for patients with MM only) 22. For patients intending to enroll into the combination cohort with gilteritinib: Patients must be gilteritinib-naïve or sensitive and have not received a FLT3 inhibitor in the relapsed refractory setting (prior FLT3 inhibitor in front line therapy is allowed) 23. Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product 24. Patients with LDH >500 U/L (>8.3 µkat/L) are excluded from Phase 2 Arms G and H

Inclusion Criteria:

• All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrollment on AALL2321
• Infants (aged 365 days or less) on the date of diagnosis are eligible; infants must be > 36 weeks gestational age at the time of enrollment
• Patients must have newly diagnosed B-acute lymphoblastic leukemia (B-ALL, 2017 World Health Organization [WHO] classification), also termed B-precursor ALL, or acute leukemia of ambiguous lineage (ALAL), which includes mixed phenotype acute leukemia. For patients with ALAL, the immunophenotype of the leukemia must comprise at least 50% B lineage
• Diagnostic immunophenotype: Leukemia cells must express CD19

Exclusion Criteria:

• Patients with Down Syndrome
• Patients with secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy
• Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of infant ALL or for any cancer diagnosis prior to the initiation of protocol therapy, with the exception of:
• Steroid pretreatment:
• PredniSONE, prednisoLONE, or methylPREDNISolone for ≤ 72 hours (3 days) in the 7 days prior to enrollment. The dose of predniSONE, prednisoLONE or methylPREDNISolone does not affect eligibility
• Inhaled and topical steroids are not considered pretreatment
• Note: Pretreatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone used during or within 6 hours prior to or after sedation to prevent or treat airway edema. However, prior exposure to ANY steroids that occurred > 28 days before enrollment does not affect eligibility
• Intrathecal cytarabine or methotrexate:
• An intrathecal dose of cytarabine or methotrexate in the 7 days prior to enrollment does not affect eligibility
• Note: The preference is to defer the diagnostic lumbar puncture with intrathecal chemotherapy to day 1 of induction to allow for cytoreduction of circulating blasts and decrease the potential for central nervous system (CNS) contamination due to a traumatic tap. If done prior to day 1 of induction, these results will be used to determine CNS status
• Hydroxyurea:
• Pretreatment with ≤ 72 hours (3 days) of hydroxyurea in the 7 days prior to enrollment does not affect eligibility
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA) and National Cancer Institute (NCI) requirements for human studies must be met

Inclusion Criteria:

• Patients must be >= 1 year and < 22 years of age at the time of enrollment
• Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL), with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease
• NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL) are eligible if they have an M2 or M3 marrow at the time of enrollment on this study
• Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing or other molecular method
• Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended)
• In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate is unable to be performed due to patient clinical status, flow cytometry of peripheral blood specimen may be substituted if the patient has at least 1,000/uL circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
• Patients with one of the following:
• Second or greater relapse;
• Primary refractory disease with at least 2 prior induction attempts;
• First relapse refractory to at least one prior re-induction attempt
• Any relapse after HSCT (Cohort 1 ONLY)Patients with Down syndrome are eligible ONLY for Cohort 1 with:
• Any of above disease status, OR
• First relapse with no prior re-induction attempt NOTE: Patients with Down syndrome or prior HSCT are NOT eligible for Cohort 2 combination therapy
• Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy, defined as resolution of all such toxicities to =< grade 2 or lower per the inclusion/exclusion criteria prior to entering this study. Apply to Cohort 2:
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment.
• A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, 6MP, and/or methotrexate).
• A waiting period is not required for patients receiving a single dose of intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior to enrollment
• >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. For patients who previously received calaspargase pegol, >= 21 days must have elapsed after the last dose. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy.
• Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy.
• Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment.
• Anti-cancer agents that are antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. A waiting period prior to enrollment is not required for patients receiving corticosteroid for leukemia therapy/cytoreduction.
• Radiotherapy: >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); >= 3 months must have elapsed if prior cranial or craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given.
• Stem cell transplant or rescue without TBI: For Cohort 1, at least 90 days must have elapsed since stem cell transplant and at least 30 days from donor lymphocyte infusion. Patient must have had no more than one previous HSCT and currently have no evidence of active graft vs. host disease (GVHD). For Cohort 2, no prior HSCT is allowed.
• Chimeric antigen receptor (CAR) T cell therapy: At least 30 days must have elapsed from the last CAR-T cell infusion
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
• Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x ULN for age; for the purpose of this study, the ULN for ALT will be 45 U/L

Exclusion Criteria:

• Patients with any prior history of SOS irrespective of severity
• Patients with isolated central nervous system (CNS), testicular, or any other extramedullary site of relapse
• Patients who have been previously treated with inotuzumab ozogamicin
• Patients who have previously received HSCT (Cohort 2 only)
• Patients with Down syndrome (Cohort 2 only)
• History of allergic reaction attributed to compounds of similar or biologic composition to inotuzumab ozogamicin or other agents in the study
• Note: Patients with history of allergy to pegaspargase/calaspargase pegol are eligible for enrollment on Cohort 2 if Erwinia formulation of asparaginase can be obtained
• Patients with active optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal involvement
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving or plan to receive other anti-cancer agents (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy, and intrathecal chemotherapy)
• Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are receiving cyclosporine, tacrolimus, or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial; at least 3 half-lives must have elapsed after the last dose of GVHD or anti-rejection medications
• Patients who are currently receiving or plan to receive corticosteroids except as described below
• Systemic corticosteroids may be administered for cytoreduction up to 24 hours prior to the start of protocol therapy, (Cohort 1 only) for all patients, corticosteroids may be administered as a premedication for inotuzumab ozogamicin and as treatment for allergic reactions or for physiologic replacement/stress dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids are not allowed for other indications
• Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections; testing to prove negative status is not required for enrollment unless it is deemed necessary for usual medical care of the patient
• Patients who have an active uncontrolled infection defined as:
• Positive bacterial blood culture within 48 hours of study enrollment;
• Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with clinical signs of infection; fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability
• A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
• Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved; for patients with clostridium (C.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline
• Active viral or protozoal infection requiring IV treatment
• Patients known to have one of the following concomitant genetic syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Schwachman (Schwachman-Diamond-Blackfan) syndrome or any other known bone marrow failure syndrome
• There have been no human studies of inotuzumab ozogamicin in pregnant women and no reports of exposure in utero; based on nonclinical safety studies, inotuzumab ozogamicin has the potential to impair human male and female fertility and to adversely affect human embryo fetal development; women of childbearing potential should be advised to avoid becoming pregnant while receiving inotuzumab ozogamicin; there is no information regarding the presence of inotuzumab ozogamicin in human milk, the effects on the breast-fed infant, or the effects on milk production; because of the potential for adverse reactions in breast-fed infants, women should not breast-feed during treatment with inotuzumab ozogamicin and for at least 2 months after the final dose
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within 7 days prior to enrollment
• Female patients who are sexually active and of reproductive potential are not eligible unless they agree to use an effective contraceptive method for the duration of their study participation and for 8 months after the last dose of inotuzumab ozogamicin
• Men with female partners of childbearing potential should use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose of inotuzumab ozogamicin
• Lactating females are not eligible unless they agree not to breastfeed their infants

Inclusion Criteria:

• All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to enrollment and treatment on AAML1831
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must be newly diagnosed with de novo AML according to the 2016 World Health Organization (WHO) classification with or without extramedullary disease
• Patient must have 1 of the following:
• >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)
• In cases where extensive fibrosis may result in a dry tap, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy
• < 20% bone marrow blasts with one or more of the genetic abnormalities associated with childhood/young adult AML as provided in the protocol (sample obtained within 14 days prior to enrollment)
• A complete blood count (CBC) documenting the presence of at least 1,000/uL (i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells (blasts) if a bone marrow aspirate or biopsy cannot be performed (performed within 7 days prior to enrollment)
• ARM C: Patient must be >= 2 years of age at the time of Late Callback
• ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular Oncology
• ARM C: Patient does not have any congenital long QT syndrome or congenital heart block
• ARM C: Females of reproductive potential must agree to use effective contraception during treatment and for at least 6 months after the last dose of gilteritinib
• ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib and for 2 months after the last dose of gilteritinib
• ARM C: Males of reproductive potential must agree to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib
• ARM D: Patient must be >= 2 years of age at the time of Late Callback
• ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating mutations as reported by Foundation Medicine
• ARM D: Females of reproductive potential must agree to use effective contraception during treatment and for at least 6 months after the last dose of gilteritinib
• ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib and for 2 months after the last dose of gilteritinib
• ARM D: Males of reproductive potential must agree to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib
• NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who transfer to Arm C or Arm D are not eligible
• NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment
• NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking
• NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental retardation)
• NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would prevent computer use or recognition of visual test stimuli
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Fanconi anemia
• Shwachman Diamond syndrome
• Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21
• Telomere disorders
• Germline predispositions known, or suspected by the treating physician to increase risk of toxicity with AML therapy
• Any concurrent malignancy
• Juvenile myelomonocytic leukemia (JMML)
• Philadelphia chromosome positive AML
• Mixed phenotype acute leukemia
• Acute promyelocytic leukemia
• Acute myeloid leukemia arising from myelodysplasia
• Therapy-related myeloid neoplasms
• Patients with persistent cardiac dysfunction prior to enrollment, defined as ejection fraction (EF) < 50% (preferred method Biplane Simpson's EF) or if EF unavailable, shortening fraction (SF) < 24%. *Note: if clinically safe and feasible, repeat echocardiogram is strongly advised in order to confirm cardiac dysfunction following clinical stabilization, particularly if occurring in the setting of sepsis or other transient physiologic stressor. If the repeat echocardiogram demonstrates an EF >= 50%, the patient is eligible to enroll and may receive an anthracycline-containing Induction regimen
• Administration of prior anti-cancer therapy except as outlined below:
• Hydroxyurea
• All-trans retinoic acid (ATRA)
• Corticosteroids (any route)
• Intrathecal therapy given at diagnosis
• In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be avoided from the time of enrollment until it is determined whether the patient will receive gilteritinib. Patients receiving gilteritinib will be required to avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the study treatment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• ARM D: Patient does not have any congenital long QT syndrome or congenital heart block

Key Inclusion Criteria:

• Previously untreated with histological confirmation of AML by World Health Organization 2022 criteria and are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age, or comorbidity.
• Participant has any level of CD123 expression on blasts.
• Participants must be considered ineligible for intensive chemotherapy, defined by the following:
• ≥75 years of age; or
• ≥18 to 74 years of age with at least 1 of the following:
• Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3.
• Diffusing capacity of the lung for carbon monoxide of ≤65% or forced expiratory volume in 1 second ≤65%.
• Baseline creatinine clearance ≥30 to <45 milliliters/minute calculated by the Cockcroft Gault formula or measured by 24-hour urine collection.
• Hepatic disorder with total bilirubin >1.5 x upper limit of normal.
• Any other condition for which the physician judges the participant to be unsuitable for intensive chemotherapy.
• ECOG performance status:
• 0 to 2 for participants ≥75 years of age, or
• 0 to 3 for participants ≥18 to 74 years of age.

Key Exclusion Criteria:

• Participant has received prior therapy for AML.
• Participant is willing and able to receive standard induction therapy.
• Participant has received treatment for an antecedent hematologic disease with a hypomethylating agent, venetoclax, tagraxofusp, purine analogue, cytarabine, intensive chemotherapy, SCT, chimeric antigen receptor-T therapy, or other experimental therapies.
• Participant has AML with central nervous system involvement.Note: Other inclusion/exclusion criteria may apply.

Inclusion Criteria:

• Patient must be ≥ 60 years of age or adults ˂ 60 who in the opinion of the treating physician are better served by azanucleoside-based therapy rather than intensive, cytarabine-based induction based on clinical status (i.e., performance status, age > 75 years), organ dysfunction, or disease biology
• Patient must have a morphologically confirmed diagnosis of AML according to the World Health Organization (WHO) 2016 classification excluding acute promyelocytic leukemia (APL) with PML-RARA, AML with RUNX1-RUNX1T1, or AML with CBFB-MYH11
• Patient must have no prior therapy for AML with the exception of hydroxyurea and all-trans retinoic acid (ATRA), or leukapheresis. Patients with cytarabine-based emergency therapy prior to the start of therapy on this trial are eligible
• Patient must have no prior therapy with hypomethylating agents or FLT3 inhibitors
• Patient must have the FLT3-ITD or D835 mutation based on MyeloMATCH Master Screening and Reassessment Protocol (MSRP)
• Patient must be assigned to this protocol by the myeloMATCH MSRP
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.
• All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
• A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patient of childbearing potential and/or sexually active patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Contraception measures must continue for 30 days after the last dose of venetoclax for all patients and for 6 months after the last dose of gilteritinib for patients of childbearing potential and for 4 months after the last dose of gilteritinib for male patients with partners of childbearing potential. Patient must not breastfeed during treatment and for 2 months after treatment ends
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
• Total bilirubin 2X ≤ institutional upper limit of normal (ULN) (unless thought to be elevated due to disease involvement or Gilbert's syndrome)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN
• Either measured or estimated by Cockcroft-Gault equation
• Creatinine clearance of ≥ 30 mL/min/1.73m^2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration/randomization are eligible for this trial
• Patients must not have a baseline corrected QT interval ≥ 480 msec using Fredericia correction (QTcF).NOTE: Since older patients are at risk for prolonged QTc and many will require supportivecare with agents that affect the QTc, an ECG is recommended if clinically indicated. Ifthe QTc is prolonged, they should be treated on tier advancement process (TAP) instead ofEA02
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patient must not have the medical necessity for ongoing treatment with a strong CYP3A4 inducing drug
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Patients must not have an active or uncontrolled infection

Inclusion Criteria:

• >= 15 and < 40 years at time of diagnosis
• Newly diagnosed B-ALL, T-ALL, lymphoblastic lymphoma (LLy), or mixed-phenotype acute leukemia/lymphoma (MPAL)
• Note: Philadelphia chromosome (PH)+ and PH-like acute leukemia are eligible (use of tyrosine kinase inhibitors [TKI] or CRLF2- targeted concomitant medication must be documented, if used)
• Conjugated bilirubin =< 1.5 x upper limit of normal (ULN) for age, regardless of baseline bilirubin (within 7 days prior to enrollment), and
• Serum glutamate pyruvate transaminase (SGPT) (ALT) =< 225 U/L (=< 5x ULN) (within 7 days prior to enrollment), and
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L and serum glutamic oxaloacetic transaminase (SGOT) (AST) to 50 U/L regardless of baseline
• SGOT (AST) =< 250 U/L (=< 5x ULN) (within 7 days prior to enrollment)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L and SGOT (AST) to 50 U/L regardless of baseline
• For patients receiving ursodiol prior to enrollment, laboratory values must meet above criteria off ursodiol for 7 days
• PEDIATRIC PATIENTS (AGE 15-17 years):
• A 24-hour urine creatinine clearance >= 30 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR
• A glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2. GFR must be performed using one of the following methods (within 7 days prior to enrollment):
• 1. Estimated GFR (eGFR) >= 30 mL/min/1.73 m^2.
• An online calculator is available through the National Kidney Foundation at https://www.kidney.org/professionals/kdoqi/gfr_calculatorped
• 2. Measured GFR >= 30 mL/min/1.73 m^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard).
• ADULT PATIENTS (AGE 18 YEARS OR OLDER): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection (within 7 days prior to enrollment). Estimated creatinine clearance is based on actual body weight
• An online calculator is available through the National Kidney Foundation at https://www.kidney.org/professionals/kdoqi/gfr_calculatorcoc
• Berlin-Frankfurt-Munich (BFM), Children's Oncology Group (COG), or C10403-based Induction regimen and must be inclusive of >= 1 dose of pegaspargase or calaspargase pegol, and
• First dose of asparaginase must be planned within the first week of induction therapy, and
• Dose of pegaspargase or calaspargase pegol must be >= 1,000 IU/ m^2 (dose-capping permitted per primary regimen)
• Note: Co-enrollment on a therapeutic consortia trial is not required
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Down syndrome
• Known inherited or autoimmune liver disease impacting conjugated bilirubin (e.g., Alagille syndrome, primary sclerosing cholangitis, other)
• Known biopsy (or imaging) proven severe liver fibrosis (Batts-Ludwig >= stage 3)
• Unable to tolerate oral formulation of study drug at enrollment
• Patients who received chemotherapy or treatment for a prior malignancy are not eligible
• The following are permitted: steroid prophase, hydroxyurea, or other cytoreduction prior to initiation of Induction chemotherapy (must be documented) and chemotherapy for current diagnosis (i.e. initiation of Induction therapy within enrollment window). Chemotherapy prior to enrollment for treatment of a non-malignancy (e.g., steroid or methotrexate for autoimmune disease) is also permitted and must be documented
• Female patients who are pregnant since fetal toxicities and teratogenic effects in humans are unknown for study drug. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Inclusion Criteria:

• Patients must be > 365 days and < 18 years (for AIEOP-BFM), > 365 days and < 22 years (for Children's Oncology Group [COG]) and > 365 days and < 46 years (for ALLTogether sites) at the time of enrollment
• Newly-diagnosed Ph+ or ABL-class Ph-like B-ALL. Leukemic blasts must express CD19. ABL-class fusions are defined as rearrangements involving the following genes predicted to be sensitive to imatinib and/or dasatinib: ABL1, ABL2, CSF1R, and PDGFRB
• Evidence of BCR::ABL1 should be documented by a clinically-validated assay prior to study entry on day 15 from the first dose of vinCRIStine during Induction therapy. ABL-class Ph-like B-ALL gene rearrangements should be documented by a clinically-validated assay and enrolled on study by day 1 of Blinatumomab Block 1. Accepted methods of detection include fluorescence in situ hybridization (FISH) using break-apart of colocalization signal probes, singleplex or multiplex reverse-transcription polymerase chain reaction (RT-PCR), whole-transcriptome or panel-based ribonucleic acid (RNA) sequencing (e.g., Hematologic Cancer Fusion Analysis, TruSight RNA Pan-Cancer Panel or equivalent). Confirmation of 5' fusion partner genes is not required for study enrollment
• Patients with Ph+ B-ALL must have previously started Induction therapy, which includes vinCRIStine, a corticosteroid, pegaspargase or calaspargase pegol, with or without anthracycline, and/or other standard cytotoxic chemotherapy
• Patients with Ph+ B-ALL have not received more than 14 days of systemic Induction therapy beginning with the first Induction dose of vinCRIStine
• Patients with ABL-class Ph-like B-ALL must have previously completed 4 or 5 weeks of multiagent Induction chemotherapy (Induction 1A)
• Patients may have started either imatinib or dasatinib prior to study entry but should have received no more than 14 days of TKI for Ph+ B-ALL or no more than 35 days of TKI for ABL-class Ph-like B-ALL
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of ≤ 2 or Karnofsky and Lansky performance scores ≥ 50%. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age
• For pediatric patients (age 1-17 years): a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2, as determined by one of the following methods (must be performed within 7 days prior to enrollment unless otherwise indicated):
• Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m2
• Measured GFR ≥ 50 mL/min/1.73 m^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard
• For adult patients (age 18 years or older): Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on body weight
• Direct bilirubin < 2.0 mg/dL (34.2 micromoles/L) (must be performed within 7 days prior to enrollment unless otherwise indicated)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 10 x upper limit of normal (ULN) (must be performed within 7 days prior to enrollment unless otherwise indicated)
• * Shortening fraction of ≥ 27% by echocardiogram (must be obtained within 21 days prior to enrollment and start of protocol therapy [repeat if necessary]) OR
• Left Ventricular Ejection fraction of ≥ 50% by radionuclide angiogram or echocardiogram (must be obtained within 21 days prior to enrollment and start of protocol therapy [repeat if necessary]) AND
• Corrected QT Interval, QTc < 480mSec (must be obtained within 21 days prior to enrollment and start of protocol therapy [repeat if necessary])
• Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis before study enrollment

Exclusion Criteria:

• Known history of chronic myeloid leukemia (CML)
• ABL-class Ph-like B-ALL who are CNS2 or CNS3 at end of Induction phase
• ALL developing after a previous cancer treated with cytotoxic chemotherapy
• Active, uncontrolled infection or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
• Down syndrome (trisomy 21)
• Pregnancy and breast feeding
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A negative pregnancy test is required for female patients of childbearing potential within 7 days prior to enrollment
• Lactating females who plan to breastfeed their infants
• Sexually active male and female patients of reproductive potential who have not agreed to use an effective contraception method for the duration of treatment according to protocol
• NOTE: Patients who could become pregnant or could father a child must use effective contraception during protocol treatment and for 30 days after the last dose of dasatinib or 14 days after the last dose of imatinib dose or per institutional standard of care for multiagent chemotherapy, whichever is longer
• Prior treatment with TKIs before study entry with the exception of imatinib or dasatinib
• Patients with congenital long QT syndrome, history of ventricular arrhythmias, or heart block
• Patients with known Charcot-Marie-Tooth disease
• Patients with significant central nervous system pathology that would preclude treatment with blinatumomab, including history of severe neurologic disorder or autoimmune disease with central nervous system (CNS) involvement
• Note: Patients with a history of seizures that are well controlled on stable doses of anti-epileptic drugs are eligible. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible. Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved
• HIV-infected patients are eligible if on effective anti-retroviral therapy that does not interact with planned study agents and with undetectable viral load within 6 months of treatment
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Main Inclusion Criteria:

• Diagnosis of primary AML or AML with myelodysplasia-related changes (AML-MRC)
• Patient is in first or second relapse or has refractory disease. Patients must have had histologic verification of AML at the original diagnosis.
• Patient must be positive for the following FLT3 mutations in bone marrow or PB: FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD) D835 or I836 or FLT3-ITD and specified FLT3-TKD.
• ECOG performance status 0-2
• Life expectancy of at least 3 months in the opinion of the investigator.
• Normal hepatic and renal function.
• Patient is able to swallow oral medications.
• Female patients are postmenopausal, documented as surgically sterile, use two methods of contraception or practice true abstinence and have a negative urine pregnancy test at screening.
• Male patients even if surgically sterilized agree to practice true abstinence or use highly effective barrier contraception.

Main Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia.
• Known BCR-ABL-positive leukemia.
• AML secondary to prior chemotherapy for other neoplasms (except for MDS).
• AML that has relapsed after or is refractory to more than 2 lines of therapy.
• Clinically active central nervous system leukemia or prior history of NCI CTCAE Grade ≥ 3 drug-related CNS toxicity.
• Major surgery or radiation therapy within 4 weeks prior to the first study dose.
• Prior treatment with iadademstat is not allowed. Treatment with any other agents with KDM1A/LSD1 inhibitory activity is only allowed if treatment finalized at least 3 weeks prior to first dose on study. Previous treatment with FLT3 inhibitors is allowed in the following cases: midostaurin and sorafenib are allowed when used in first-line therapy regimen as part of induction, consolidation and/or maintenance: quizartinib and gilteritinib are allowed when used in first-line therapy regimen, as part of induction, consolidation and/or maintenance, ONLY if patients were not refractory to the drugs or if responding, relapse did not occur while on these drugs.
• Patients not eligible to receive gilteritinib per label.
• Prior treatment with 3 or more lines of AML therapy.
• Treatment with any investigational products within 3 weeks prior to first dose of study treatment.
• Uncontrolled hypertension or poorly controlled diabetes.
• Evidence of active uncontrolled viral, bacterial, or systemic fungal infection.
• Pregnant or lactating women.

Inclusion Criteria:

• Patient must have enrolled onto MYELOMATCH and must have been given a treatment assignment to MyeloMATCH to MM1YA-CTG01 based on the presence of an actionable mutation as defined in MYELOMATCH
• Participants must have been registered to master screening and re-assessment protocol (myeloMATCH MSRP) prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study. Participants must have agreed to have specimens submitted for translational medicine (MRD) and must be offered the opportunity to submit biosamples for banking for future research as per the myeloMATCH MSRP
• Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP
• Previously untreated, de novo acute myeloid leukemia (AML) defined by > 20% myeloblasts in the peripheral blood or bone marrow (refer to the 2016 updated World Health Organization [WHO] classification of myeloid neoplasms and acute leukemia) excluding all the following categories of AML:
• Favorable cytogenetics: (t(8;21)q22;q22.1); RUNX1-RUNX1T1, inversion 16(p13.1;q22), t(16;16)(p13.1;q22); CBFB-MYH11
• CEBPA biallelic mutations
• NPM1 mutation
• AML with PML-RARalpha
• AML with any adverse cytogenetics, TP53 mutation, RUNX1 mutation, ASXL1, 11q23/KMT2 rearrangements
• AML with FLT3-ITD or FLT3-TKD mutations
• Therapy related AML, or AML following a diagnosis of myelodysplasia or myeloproliferative neoplasm Participants with central nervous system (CNS) disease are eligible for this trial and will be treated according to institutional guidelines with intrathecal chemotherapy for this aspect of their disease
• Age 18-59 years at time of induction therapy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 3
• Total bilirubin =< 2 x institutional upper limit of normal (ULN) (must be done within 7 days of enrollment)
• Aspartate aminotransferase (AST) (serum glutamate pyruvate transaminase [SGPT]) +/or alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 × institutional ULN (must be done within 7 days of enrollment)
• Cardiac ejection fraction >= 50% (echocardiography or multigated acquisition scan [MUGA]) (must be done within 7 days of enrollment)
• Calculated creatinine clearance >= 30 mL/min/ 1.73m^2; Clearance to be calculated using Cockcroft formula (must be done within 7 days of enrollment)
• White blood cells (WBC) must be < 25 x 10^9/L. Hydroxyurea and leukapheresis are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped at least 24 hours prior to the initiation of protocol therapy
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method while on treatment and for 6 months after stopping study drug. A woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.Women of childbearing potential will have a pregnancy test to determine eligibility aspart of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy ifa false-positive is suspected. Patient will be considered eligible if an ultrasound isnegative for pregnancy
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate
• Patients must be accessible for treatment, response assessment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.Patients must agree to return to their primary care facility for any adverse events whichmay occur through the course of the trial
• In accordance with Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 7 working days of patient enrollment
• Participants receiving strong or moderate CYP3A inhibitors must agree to discontinue use at least 48 hours prior to start of study treatment if assigned to arm 1 or 2
• Patients with known human immunodeficiency virus (HIV) infection who are on effective anti-retroviral therapy and have undetectable viral load within 6 months of enrollment are eligible for this trial
• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days of enrollment. Patients need to be on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection who have been treated and cured are eligible. Patients who with active HCV infection who are currently being treated must have an undetectable HCV viral load within 28 days of enrollment to be eligible

Exclusion Criteria:

• Prior therapy for AML except for hydroxyurea and leukapheresis to control blood counts. The use of all-trans retinoic acid (ATRA) is permitted until a diagnosis of acute promyelocytic leukemia, if suspected, is ruled out
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cytarabine, daunorubicin, azacitidine, venetoclax
• Pregnant women are excluded from this study because venetoclax, cytarabine and azacitidine have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, cytarabine and azacitidine breastfeeding should be discontinued if the mother is treated with venetoclax, cytarabine and azacitidine. These potential risks may also apply to other agents used in this study
• Patients with isolated myeloid sarcoma are not eligible
• Any other serious intercurrent illness, life threatening condition, organ system dysfunction, or medical condition judged by the local investigator to compromise the subject's safety (for example):
• Active, uncontrolled bacterial, fungal, or viral infection