Inclusion Criteria:

• Be greater than or equal to (>=) 18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever the greater) at the time of informed consent
• Positive for a calreticulin (CALR) driver mutation of essential thrombocythemia (ET) or myelofibrosis (MF)
• Participants with ET and MF with risk characteristics as described in the protocol
• Have an Eastern Cooperative Oncology Group (ECOG) performance status grade of less than or equal to (<=) 2
• For US sites: Eligible for ruxolitinib therapy as per drug label for participants naive to a janus kinase (JAK) inhibitor

Exclusion Criteria:

• Known allergies, hypersensitivity, or intolerance to the excipients of the study treatment
• Concurrent or recently diagnosed or treated malignancies present at the time of participant screening. Exceptions are squamous and basal cell carcinoma of the skin, carcinoma in situ of the cervix, and any malignancy that is considered cured or has minimal risk of recurrence within 1 year of first dose of study treatment in the opinion of both the investigator and sponsor's medical monitor. Participants cured of another malignant disease with no sign of relapse greater than or equal to (>=) 3 years after treatment ended are allowed to enter the study
• Prior solid organ transplantation
• Either of the following regarding hematopoietic stem cell transplantation: 1. Prior treatment with allogenic stem cell transplant less than or equal to (<=) 6 months before the first dose of JNJ-88549968 or 2. Evidence of graft versus host disease (GVHD) that requires immunosuppressant therapy
• History of clinically significant cardiovascular disease within 6 months prior to the first dose of study treatment

Inclusion Criteria

Patients eligible for inclusion in this study must meet all of the following criteria: 1. Age ≥ 18 years old 2. Diagnosis of CML-CP 3. Part A: Previously treated with at least two approved TKIs; Part B: T315I mutation at screening and previously treated with at least one approved TKI, with no other effective and/or tolerable therapies available 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 5. Patient has adequate organ function

Exclusion Criteria

Patients eligible for this study must not meet any of the following criteria: 1. For Part A only: T315I or V299L mutation at any time prior to starting study treatment 2. Active infection that requires systemic drug therapy 3. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of study drugs 4. Previous treatment with or known / suspected hypersensitivity to olverembatinib or any of its excipients 5. Previous treatment with or known / suspected hypersensitivity to bosutinib or any of its excipients 6. Pregnant or nursing (lactating) women

Inclusion criteria:

For Arm A:
• Have a diagnosis of: Acute myeloid leukemia (AML) per International Consensus Classification (ICC) 2022 or myelodysplastic syndromes (MDS) per world health organization (WHO) 2022 classified as moderate high, high, or very high-risk per the molecular international prognostic scoring system (IPSSM). All participants must have relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options
• Body weight greater than or equal to (>=) 40 kilograms (kg)
• Eastern cooperative oncology group (ECOG) performance status of 0 to 2For Arm B:
• All participants must have relapsed or refractory disease with no other approved therapies available that would be more appropriate in the investigator's judgement. Have a diagnosis of either: Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) meeting 2018 International workshop on chronic lymphocytic leukemia (iwCLL) National cancer institute (NCI) working group guidelines (Hallek 2018) that meet the following criteria: a. Participants must have received at least 2 prior lines of therapy; b. Have clinically measurable disease
• Body weight >= 40 kg
• ECOG performance status of 0 to 2
• Must sign an Informed consent form (ICF)
• For US sites: Have a diagnosis of CLL/SLL that meets iwCLL, NCI Working Group Guidelines which is relapsed or refractory and requires treatment with no other approved therapies available that would be more appropriate in the investigator's judgement. a. Participants must have received at least 2 prior lines of therapyExclusion criteria:For Arm A:
• Has acute promyelocytic leukemia according to world health organization (WHO) 2022 criteria or known active central nervous system (CNS) involvement of AML/MDS, unless in specific cohort (s) per study evaluation team (SET) decision
• Need for supplemental oxygen use to maintain adequate oxygenation
• Have evidence of uncontrolled systemic viral, bacterial, or fungal infection. Antimicrobial prophylaxis is permitted
• For US sites: Has acute promyelocytic leukemia according to WHO 2022 criteria or known active CNS involvement of AML/MDSFor Arm B:
• Need for supplemental oxygen use to maintain adequate oxygenation
• Have evidence of uncontrolled systemic viral, bacterial, or fungal infection requiring initiation of parenteral treatment as medical intervention
• Developed Richter's transformation or prolymphocytic leukemia
• Known active CNS or leptomeningeal involvement of CLL/SLL/Non-Hodgkin lymphoma (NHL)

Inclusion Criteria:

For patients in Phase I: 1. Have a diagnosis of relapsed or refractory AML, ALL or acute leukemia of ambiguous lineage according to World Health Organization (WHO) 2022 classification, or, in selected sites and regions, a diagnosis of MDS or MM as determined by pathology review at the treating institution, and whose disease has progressed after available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage or, in selected sites and regions, for MM or MDS. If acute leukemia patients are transformation from MDS or other hematologic malignancies, patients need to receive available standard therapies as acute leukemia after AML transformation and before enrolling this trial. In regions or countries where required by regulatory authorities, participants must have a documented KMT2A (MLL) fusion or NPM1 mutation, including those with coexisting FLT3 genomic alterations and/or IDH1/2 mutation. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option. For patients with MDS (selected sites and regions): 1. Patients with MDS must have bone marrow blasts ≥ 5% 2. Patients with MDS must have relapsed or refractory disease and have exhausted available standard therapies including at least 2 cycles of treatment with HMA For patients with MM (selected sites and regions): 3. 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 4. Have measurable disease as defined in the protocol 5. Meet the laboratory parameters set in the protocol For patients with relapsed/refractory AML in the venetoclax and azacitidine combination cohort (in countries and sites where permitted): 6. Have MLLr or NPM1m. For patients with relapsed/refractory AML in the gilteritinib combination cohort (in countries and sites where permitted): 7. Have MLLr or NPM1m AND any of the following FLT3 mutations: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836. For patients with relapsed/refractory AML with NPM1 enrolled in the RP2D confirmation cohort: 8. Must have ≥5% blasts in bone marrow by morphologic assessment 9. Must not have received prior treatment with a menin inhibitor For patients with newly diagnosed AML: 10. Must have AML as defined by WHO 2022 criteria with a documented MLLr or NPM1m (patients with AML characterized by MLL partial tandem duplications, MLL deletions, or trisomy 11 are not eligible) 11. Must not have received treatment for AML with the exception of hydroxyurea for control of white blood cell counts. For patients in Phase 2: 2. Have a confirmed diagnosis of relapsed AML or ALL according to WHO 2022 classification, as determined by pathology review at the treating institution, and who have ≥5% blasts by morphologic assessment in the bone marrow. Patients with extramedullary disease or peripheral blasts as the only manifestation of relapse are not eligible. Patients must have received clinically applicable standard therapies with confirmed survival benefit. Patients must not have had prior exposure to a menin inhibitor. 3. Have a documented KMT2A (MLL)-fusion assessed at relapse or immediately prior to the determination of refractory status. KMT2A genetic alterations other than fusions (eg, KMT2A-PTD, amplification, point mutation) are not permitted. For all patients: 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. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 6. For monotherapy, WBC below 30,000/μ at enrollment. 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 level ≥ 50 ml/min, assessed by the CPK-EPI formula (2021 version and Cystatin C not required) 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. Females of childbearing potential are defined as women who have (1) experienced menarche and have not undergone sterilization procedures (hysterectomy, or bilateral oophorectomy), or have (2) not experienced menopause as defined in the protocol. 15. All men and all women of childbearing potential and male patients' partners who are women of childbearing potential are required to use a highly effective method of contraception during the study and for 6 months (for females and males alike) after the last dose of study drug. Further guidelines noted in protocol. 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). For clinical sites in the UK, have abnormal ECGs at screening that are clinically significant, such as QTc ≥470 msec and ≥450 msec with QTc corrected according to Fridericia's formula (QTcF), for females and males, respectively. In addition, patients with a history of prolonged QT syndrome or who are required to take therapies associated with QT-interval prolongation are excluded. Note: In case of bundle branch block, QT interval correction can be performed. 5. Has an active and uncontrolled, 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. Had major surgery within 28 days prior to the first dose of DSP-5336 8. Has active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed). 9. 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. For clinical sites in the UK, underwent CAR-T therapy or other modified T-cell therapy within 6 months prior to the first dose of DSP-5336. 10. 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 11. 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 7 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336 12. 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; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.2); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months 13. 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. 14. 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 15. Have cognitive, psychological, or psychosocial impediment that would impair the ability of the patient to 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 16. 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 17. Have any history or complication of interstitial lung disease (for sites in Japan in Phase 1 dose escalation). 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. 18. Have a history of Torsades de Pointes 19. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336 20. Have plasma cell leukemia (>2.0 x 109 /L plasma cells in blood by standard differential) (for patients with MM) 21. 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) 22. Have a known intolerance of hypersensitivity reaction to components of the investigational medicinal product 23. For clinical sites in the UK: In Arm E (DSP-5336 + venetoclax/azacitidine), have received a live vaccine within 30 days prior to the first dose of DSP-5336

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 (cumulative prenatal and postnatal age must be > 36 weeks) 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:

• All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to enrollment and treatment on AAML1831. Bone marrow and/or blood must have been submitted to the BPC via APEC14B1 for testing of FLT3 markers. Patients without samples submitted for FLT3 testing are not eligible
• Patients must be at least 6 months of age and 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 is pending or 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
• Patients < 8.3 kg at study enrollment are not eligible
• 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

Inclusion Criteria:

• In Cohorts I and II, patients must have R/R AML or MDS (venetoclax naïve or venetoclax exposed)
• Relapsed AML is defined as the appearance of 5% or greater myeloblasts in the bone marrow or peripheral blood after achieving a complete remission (CR), CR with partial hematologic recovery (CRh), or CR with incomplete hematologic recovery (CRi). Patients with a mutation in FLT3, IDH1 or IDH2 must have failed or been intolerant of a corresponding Food and Drug Administration (FDA) approved FLT3, IDH1 or IDH2 inhibitor before enrolling on study. The initial diagnosis of AML is defined by the ELN 2022 criteria, and therefore patients with either AML (peripheral blood or bone marrow blasts ≥ 20% or blasts ≥ 10% with recurrent genetic abnormalities) or MDS/AML (peripheral blood or bone marrow blasts 10-19%) are eligible
• Refractory AML is defined as failure to achieve a CR, CRh, or CRi after one of the following regimens: (i) ≥ 2 cycles of intensive induction chemotherapy with a cytarabine containing regimen (e.g., 7+3, mitoxantrone, etoposide, cytarabine [MEC], high-dose cytarabine [HIDAC], reinduction chemotherapy such as 5 + 2, etc.) or, (ii) ≥ 2 cycles of hypomethylating agent (HMA)/venetoclax or low-dose cytarabine (LDAC)/glasdegib or, (iii) ≥ 4 cycles of HMA monotherapy. The initial diagnosis of AML is defined by the ELN 2022 criteria, and therefore patients with either AML (peripheral blood or bone marrow blasts ≥ 20% or blasts ≥ 10% with recurrent genetic abnormalities) or MDS/AML (peripheral blood or bone marrow blasts 10-19%) are eligible
• Patients with MDS/AML (blasts 10-19%) who progress to AML (blasts ≥ 20%) after treatment will be considered relapsed or refractory MDS/AML, and not as newly-diagnosed AML (i.e. the patients' treatment history for eligibility purposes does not reset)
• Relapsed MDS is defined as: (i) Intermediate, high, or very high-risk disease by International Prognostic Scoring System-Revised (IPSS-R) and, (ii) Any relapse after achieving any 2023 IWG MDS defined response
• Refractory MDS is defined as: (i) Intermediate, high, or very high-risk disease by IPSS-R and > 5% blasts in the bone marrow or peripheral blood, (ii) Failure to achieve a response (as per IWG 2006 criteria) after ≥ 4 cycles of HMA monotherapy, or (iii) ≥ 2 cycles of HMA + venetoclax
• In Cohort III, patients must have prior untreated high-risk MDS
• MDS with > 5% blasts in the bone marrow or peripheral blood AND
• IPSS-R high or very high-risk disease OR
• Molecular International Prognostic Scoring System (IPSS-M) high or very high-risk disease
• No more than one single prior cycle of DNMTi therapy
• Prior use of erythropoiesis stimulating agents (ESA), thrombopoietin agonists, lenalidomide, and luspatercept are allowed
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of SM08502 (cirtuvivint) in combination with ASTX727 in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3
• Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin; in that case a cut off of ≤ 4 × institutional ULN will be used)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN (unless considered due to organ involvement by the patient's myeloid malignancy; in that case a cut off of ≤ 5 x institutional ULN will be used)
• Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73m^2
• If female, patient must be either:
• Postmenopausal (surgically sterile or age > 55 years with no menses for 12 or more months without an alternative medical cause or age equal to 55 or less with no menses for 12 or more months without an alternative medical cause and a follicle stimulating hormone [FSH] level > 40 IU/L); or
• Of children bearing potential. These patients 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. 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. Patient must agree to have a negative urine or serum beta-human chorionic gonadotropin (HCG) test result during screening and repeated within 7 days prior to study drug (local labs are allowed) to be eligible
• The effects of SM08502 (cirtuvivint) and ASTX727 on the developing human fetus are unknown. For this reason, and because these agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and during the treatment therapy. Women of childbearing age should agree to use adequate contraception for 7 months after completion of SM08502 (cirtuvivint) administration. For ASTX727, adequate contraception must continue for at least 6 months after last dose of ASTX727. 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 prior to the study and for the duration of the study and at least 4 months after the last dose of SM08502 (cirtuvivint) and 3 months after last dose of ASTX727. Women who are lactating must refrain from breastfeed during the study and at least for two weeks after last dose of ASTX727
• 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
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia or abnormal blood counts
• Patients who are receiving any other investigational agents
• Systemic anti-leukemic or other antineoplastic therapy within 14 days of first day of study treatment. Hydroxyurea may be continued through cycle 1 of treatment. Hydroxyurea is discouraged in subsequent cycles and should be discussed beforehand with principal investigator. If on venetoclax, then a wash-out period of at least five times the half-life of venetoclax is required. Exceptions: No wash-out required for intrathecal chemotherapy, hydroxyurea, cytarabine (Ara-C), or palliative radiation therapy to painful sites of leukemic disease. Patients are not allowed to receive concurrent therapy such as cytotoxic chemotherapy or radiation therapy for another cancer. Patients on hormonal adjuvant therapy for non-metastatic breast and prostate cancer or other minimally-myelosuppressive maintenance therapies for non-metastatic cancer may be eligible at the discretion of the study principal investigator (PI)
• Patient is receiving known inhibitors or activators of flavin-containing monooxygenases (FMO1 or FMO3), and these cannot be stopped at least 5 days prior to SM08502 (cirtuvivint) treatment start. Known inhibitors of FOMO are chlorpromazine and imipramine
• Patient is receiving strong inhibitors or strong inducers of CYP3A4/5 and these cannot be stopped at least 5 days prior to SM08502 (cirtuvivint) treatment start
• Strong inhibitors include grapefruit juice or grapefruit/grapefruit related citrus fruits (e.g., Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance
• Strong inducers include phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, and St. John's Wort. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance.
• While moderate inhibitors or moderate inducers of CYP3A4/5 are not an exclusion criteria for the trial, it is preferred that moderate inhibitors or moderate inducers of CYP3A4/5 be replaced prior to the first dose of SM08502 (cirtuvivint) and during study conduct where this is possible.
• Moderate inhibitors include erythromycin, ciprofloxacin, verapamil, diltiazem, atazanavir, fluconazole, darunavir, delavirdine, amprenavir, fosamprenavir, aprepitant, imatinib, tofisopam, and cimetidine. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance
• Moderate inducers include bosentan, efavirenz, etravirine, modafinil, and nafcillin. Examples may be found at the FDA website. Refer to the prescribing information of concomitant medications if in doubt or consult the sponsor for guidance
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to SM08502 (cirtuvivint) or ASTX727
• Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: patients with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Patients who had prior HCV that has been definitively treated with negative HCV viral load prior to study initiation and no evidence of cirrhosis, are allowed to participate. If there is no known history of HBV infection no HBV studies need to be obtained. If there is no known history of HCV infection, no HCV studies need to be obtained
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Pregnant and lactating women are excluded from this study because SM08502 (cirtuvivint) is a small molecule inhibitor of CLK DYRK with 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 SM08502 (cirtuvivint), breastfeeding should be discontinued if the mother is treated with SM08502 (cirtuvivint). These potential risks may also apply to other agents used in this study
• Patients with acute promyelocytic leukemia
• Subject has symptomatic central nervous system (CNS) involvement with AML
• Patient has immediate life-threatening, severe complications of their myeloid malignancy such as uncontrolled bleeding and/or uncontrolled infection
• Patient has significant active cardiac disease within 6 months prior to the start of study treatment, including uncontrolled New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke
• Left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 30 days prior to the start of study treatment
• Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Patient needs to be able to swallow pills
• Patient has 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)
• Subject has prolonged corrected QC (QTc) interval (Fridericia's correction [QTcF]) ≥ 480 ms or known family history of long QT interval syndrome at screening

Inclusion criteria

1. Confirmed acute myeloid leukemia per 2022 WHO (≥20 % blasts or genetically-definedAML) 2. Age ≥ 18 years on the date of consent Disease status 3. Phase I:Relapsed/refractory (R/R) or newly-diagnosed, overy high risk defined as p53 mutation orsecondary AML after MPN or chemotherapy/radiation exposure 4. An ECOG performance statusof 0-2 5. Acceptable Organ function within 14 days of cycle 1 day 1 6. AST/ALT ≤ 3× ULN;total bilirubin ≤ 1.5× ULN (unless Gilbert's) 7. Creatinine clearance > 60 mL/min(Cockcroft-Gault) 8. Subjects must have a baseline QTc interval of less than 450milliseconds (<450 ms) White blood cells < 25 × 10⁹/L before first dose ofhypomethylating agent - debulking with hydroxyurea/leukapheresis or up to 6 doses ofcytarabine 100mg-200mg if needed is acceptable.9. HIV, HBV, and HCV patients are eligible if viral load is undetectable on stabletherapy Wash-out from prior therapies should be ≥14 days from the last cytotoxic ortargeted agent, and recovery to ≤Grade 1 non-hematologic toxicity 10. Reproductiveprecautions 11.Negative serum β-hCG for WOCBP; agreement to use highly effectivecontraception during treatment and ≥ 90 days after last dose Signed written informedconsent and willingness to comply with study procedures

- Exclusion Criteria

1. Leukemia subtype - Acute promyelocytic leukemia (APL, PML-RARA) 2. CNS leukemia not cleared (<5 WBC/µL & no blasts), or symptomatic CNS involvement 3. Recent or uncontrolled transplant-related complications Allogeneic HSCT ≤ 90 days before Day 1 Active grade ≥ 2 GVHD or systemic immunosuppression >10 mg/day prednisone-equivalent 4. Concurrent malignancies requiring active therapy. Any adequately treated in-situ cancers or those not expected to interfere with endpoints are allowed. 5. Active, uncontrolled infection (bacterial, viral, or fungal) despite appropriate antimicrobial therapy 6. Cardiac risk, NYHA class III/IV heart failure, unstable angina, recent MI (< 6 months), clinically significant arrhythmia, Concomitant use of QT-prolonging medications that cannot be discontinued, or history of torsades de pointes 7. Pregnant or breastfeeding. 8. Patients with known G6PD deficiency. 9. Investigational drug or major surgery within 28 days. 10. Bleeding diathesis/coagulopathy that would preclude required marrow aspirates or lumbar puncture. 11. Psychiatric or social condition that, in the investigator's judgment, would impair compliance with protocol-mandated visits/procedures.

Inclusion Criteria:

• Newly diagnosed AML (WHO 2022 classification or ICC 2022 classification)
• Participants must be considered Ineligible for intensive induction defined by the following: 1. Age 75 years or older, or 2. Age 18 to 74 years with at least one of the following comorbidities: i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina). ii) Severe pulmonary disorder (eg, DLCO ≤65% or FEV1 ≤65%). iii) Creatinine clearance ≥30 mL/min to <45 mL/min iv) Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN).
• Must have achieved CR,CRh, CRi, following induction with maximum 3 cycles of standard IV HMAs and venetoclax.
• Able to provide informed consent
• Prior and concomitant hydroxyurea is permitted
• ECOG performance status 0 to 3

Exclusion Criteria:

• Progression or relapse after induction standard HMAs + Venetoclax therapy
• Pregnancy or breastfeeding
• Uncontrolled infection, active CNS disease, or concurrent malignancy requiring systemic therapy
• Inability to take oral medication or presence of malabsorption syndrome or any other uncontrolled gastrointestinal condition
• Candidate for intensive chemotherapy
• Uncontrolled infection, active CNS disease, or concurrent malignancy requiring systemic therapy
• Candidate for stem cell transplant

Inclusion Criteria:

• Patient must have documented T cell ALL and must be in first or later hematologic CR or CRi after a minimum of 2 blocks of intensive chemotherapy.
• Patients in hematologic CR or CRi must have persistent or recurrent MRD ≥ 10-4.
• Institution must have received central MRD status test results confirming persistent or recurrent MRD ≥ 10-4 by flow cytometry.
• Patient may have undergone a prior allogeneic stem cell transplant, but patient may not have Grafts Versus Host Disease (GVHD) that requires ongoing immunosuppressive therapy. Patient may receive prednisone if the dose is ≤ 10 mg per day.
• Patient must have an ECOG performance status 0-2.
• All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 registration to rule out pregnancy.
• 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 and continue to 3 months after the last dose of protocol treatment. Patients must also agree to abstain from donating sperm, even if they have had a successful vasectomy, or donating eggs while on study treatment and for 3 months after the last dose of protocol treatment.
• 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.
• Patient must have adequate organ and marrow function as defined below (these labs must be obtained ≤ 7 days prior to Step 1 registration).
• Absolute neutrophil count (ANC) ≥ 750/μL
• Platelets ≥ 75,000/μL
• Total or Direct bilirubin ≤ 2 mg/dL
• AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional ULN
• Creatinine ≤ 1.5 x institutional ULN or Creatinine Clearance > 30 ml/min
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
• 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.
• Patients with prior CNS involvement are eligible as long as they do not have active CNS involvement at time of Step 1 registration.
• 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.

Exclusion Criteria:

• Patient must not be pregnant or breast-feeding due to the potential harm to an unbornfetus and possible risk for adverse events in nursing infants with the treatment regimensbeing used

Inclusion Criteria:

• Male or female participants:
• Pediatric formulation group: ≥ 1 and less than 18 years of age at study entry.
• Adult formulation group: ≥ 14 and less than 18 years of age and body weight of ≥ 40 kg at study entry.
• Participants with Ph+ CML-CP must meet all of the following laboratory values at the screening visit. In the case where bone marrow blast and promyelocyte counts are available, these will be accepted if done within 56 days prior to the screening visit, to avoid unnecessary repetition of this test. 1. < 15% blasts in peripheral blood and bone marrow 2. < 30% combined blasts plus promyelocytes in peripheral blood and bone marrow 3. < 20% basophils in the peripheral blood 4. Neutrophils ≥ 1.5 x 10^9/L (or WBC ≥ 3 x 10^9/L if neutrophils are not available) and platelet count ≥ 100 x 10^9/L 5. No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
• Prior treatment with a minimum of one TKI
• Failure (adapted from the 2020 European Leukemia Net (ELN) Guidelines Hochhaus et al 2020 and 2013 ELN Guidelines Baccarani et al 2013) or intolerance to the most recent TKI therapy at the time of screening.
• Performance status: Karnofsky ≥ 50% for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years of age at the time of screening
• Participants must have adequate renal, hepatic, pancreatic and cardiac function
• Participants must have electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication:
• Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] at the time of screening which are amenable to standardized RQ-PCR quantification.

Exclusion Criteria:

• Known presence of the T315I mutation prior to study entry or a BCR::ABL mutation with known resistance to study treatment any time prior to study entry.
• Known second chronic phase of CML after previous progression to AP/BC.
• Previous treatment with a hematopoietic stem-cell transplantation.
• Patient planning to undergo allogeneic hematopoietic stem cell transplantation.
• Cardiac or cardiac repolarization abnormality
• Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator could cause unacceptable safety risks or compromise compliance with the protocol
• History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
• History of acute or chronic liver disease.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
• Pregnant or nursing (lactating) females.Other protocol-defined inclusion/exclusion 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), organ dysfunction, or disease biology
• Patient must have a morphologically confirmed diagnosis of AML as determined by the site and confirmed by the treatment verification team, 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, all-trans retinoic acid (ATRA), cytarabine-based emergency therapy or leukapheresis to ensure white blood cells (WBC) < 25,000/mm^3 prior to starting venetoclax treatment
• Patient must have no prior therapy with hypomethylating agents or FLT3 inhibitors
• Patient must have the FLT3-ITD, D835, or I836del mutation based on MYELOMATCH Protocol
• Patient must be assigned to this protocol by the MYELOMATCH Protocol
• 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 randomization to rule out pregnancy A patient of childbearing potential is defined as anyone, regardless of 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)
• Patients must not expect to conceive or father children by using 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 who are able to conceive or father children 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 ≤ 2 X institutional upper limit of normal (ULN), unless thought to be elevated due to disease involvement or Gilbert's syndrome, in which case bilirubin ≤ 3 x ULN is allowed (must be obtained ≤ 14 days prior to randomization)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN (must be obtained ≤ 14 days prior to randomization)
• Creatinine clearance ≥ 30 mL/min (must be obtained ≤ 14 days prior to randomization)
• Either measured or estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (2021)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
• Patients who meet the criteria below must have had an electrocardiogram (ECG) performed with a corrected QT interval using Fridericia's correction (QTcF) interval within normal limits:
• History of cardiac arrythmia, atrial fibrillation, or irregular QTcF interval OR
• Known genetic predisposition to long QT syndrome OR
• Risk for electrolyte abnormalities, including tumor lysis syndrome
• Normal limits are QTcF ≤ 450 ms for males and QTcF ≤ 460 ms for females. Corrected QT interval method (QTcF) may follow institutional standards
• NOTE: Since older patients and patients with cardiac disease are at risk for prolonged QTcF and many will require supportive care with agents that affect the QTcF, an ECG is recommended if clinically indicated as noted above. If the QTcF is prolonged (> 450 ms for males and > 460 ms for females), they should be treated on the Tier Advancement Pathway (TAP) instead of MM1OA-EA02. In patients where ECG is not clinically indicated, QTcF does not need to be documented
• 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 2 or better
• Patient must not have an uncontrolled infection