Inclusion Criteria:

• Participants who have received at least one dose of cilta-cel in a Company-sponsored clinical study
• Participants who have provided informed consent for this study

Inclusion Criteria:

• For Part A and B: Have relapsed/refractory NHL and >=2 prior systemic therapies, (including rituximab), and be ineligible for known therapies with demonstrated clinical benefit per investigator assessment or, histologically confirmed AITL that has recurred or progressed following institutional standard of care therapy.
• For Part C and D: Have R/R DLBCL, not otherwise specified [NOS (DLBCL, NOS)] or large B-cell lymphoma (LBCL) arising from follicular lymphoma and have received two or more lines of systemic therapy.
• Have at least one bi dimensionally measurable lesion >1.5-centimeter (cm) in largest dimension for nodal or >1.0 cm for extranodal lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (NOTE: For Part A only - ECOG PS of 2 is allowed for participants with secondary CNS lymphoma).
• Adequate bone marrow function
• Adequate kidney function
• Adequate Liver Function

Exclusion Criteria:

• Current or past history of peripheral eosinophilia, hypereosinophilic syndrome (HES), organ-specific eosinophilic disorder, or drug reaction with eosinophilia and systemic symptoms (DRESS).
• Prior allogeneic stem cell transplant (SCT) or solid organ transplantation.
• Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, melanoma in situ or carcinoma in situ of the breast or cervix, and prostate cancer with active surveillance.
• Any of the following in the previous 6 months:
• Myocardial infarction, long QT syndrome or family history of long QT syndrome, or Torsade de Pointes;
• Clinically important atrial or ventricular arrhythmias;
• Serious conduction system abnormalities, 3rd degree atrioventricular (AV block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF), New York Heart Association Class III or IV;
• Cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and/or other clinically significant episode of thromboembolic disease;
• Active inflammatory gastrointestinal (GI) disease, chronic diarrhea, previous gastric resection, or lap band surgery.
• Uncontrolled hypertension despite optimal medical treatment
• History of myocarditis.
• In ability to comply with listed prohibited treatments.
• Standard 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
• Cardiac ejection fraction <45%.

Inclusion Criteria:

• Adult 18 years of age and older.
• Histologically confirmed diagnosis of B-NHL before enrollment.
• Must have received prior CAR T or were unwilling/unable to receive prior CAR T.
• Must have refractory or relapsed disease after receiving 2 prior lines of therapies.
• If relapsed/refractory post-auto-SCT, then must have undergone auto-SCT at least 6 months prior to enrollment.
• If relapsed/refractory disease after allogeneic stem cell transplant (allo SCT) then must have undergone allo-SCT at least 6 months prior to enrollment and without evidence of graft versus host disease, and expectation to remain off immunosuppressive therapy through duration of trial
• Measurable disease at time of enrollment: At least one measurable lesion per Lugano Response Criteria (Cheson et al., 2014) or measurable disease per IWWM-11 response criteria (Treon 2023) for Waldenström macroglobulinemia patients.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

Exclusion Criteria:

• Previously treated with any investigational agent within 30 days prior to screening.
• Any previous or concurrent malignancy, with the following exceptions:Adequately treated non-melanoma skin cancer such as basal cell or squamous cellcarcinoma; carcinoma-in-situ (e.g., cervix, bladder, breast) treated curatively andwithout evidence of recurrence for at least 3 years prior to enrollment or adequatelytreated melanoma skin cancer in-situ; any other malignancy which has been completelytreated and remains in complete remission for ≥ 5 years prior to enrollment. Completelytreated prostate cancer with prostate-specific antigen (PSA) level < 1.0 may also bepermitted.
• Use of systemic immunosuppressive drugs within 4 weeks prior to study entry, or anticipated use of systemic immunosuppressive agents through end of study, with the exception of non-T cell targeting agents prior to leukapheresis
• Known immunodeficiency disease , with the exception of hypoglobulinemia
• History or presence of active or clinically relevant primary central nervous system (CNS) disorder, such as seizure, encephalopathy, cerebrovascular ischemia/hemorrhage, cerebellar disease, or any autoimmune disease with CNS involvement. For primary CNS disorders that have recovered or are in remission, participants without recurrence within 2 years of planned study enrollment may be included.
• Uncontrolled hypertension, history of myocarditis or congestive heart failure, unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial infarction within 6 months prior to study entry.
• Any active uncontrolled systemic fungal, bacterial or viral infection.Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Key Inclusion Criteria:

1. Have documented CD20+ aggressive B-NHL, with disease that has progressed after at least 2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent, as described in the protocol. 2. Measurable disease on cross sectional imaging as defined in the protocol 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 4. Adequate bone marrow, renal and hepatic function as defined in the protocol 5. Availability of tumor tissue for submission to central laboratory is required for study enrollment. Archival tumor tissue for histological assessment prior to enrollment is allowed 6. During dose expansion phase of the study, participant should be willing to undergo mandatory tumor biopsies, if in the opinion of the investigator, the participant has an accessible lesion that can be biopsied without significant risk to the participant.

Key Exclusion Criteria:

1. Prior treatments with allogeneic stem cell transplantation or solid organ transplantation, treatment with anti-CD20 x anti- CD3 bispecific antibody, such as odronextamab 2. Diagnosis of Mantle Cell Lymphoma (MCL) 3. Primary Central Nervous System (CNS) lymphoma or known involvement by non-primary CNS lymphoma, as described in the protocol 4. Treatment with any systemic anti-lymphoma therapy within 5 half-lives or within 14 days prior to first administration of study drug, whichever is shorter, as described in the protocol 5. Standard radiotherapy within 14 days of first administration of study drug, as described in the protocol 6. Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or corticosteroid equivalent within 72 hours of start of odronextamab 7. Co-morbid conditions, as described in the protocol 8. Infections, as described in the protocol 9. Allergy/hypersensitivity: Known hypersensitivity to both allopurinol and rasburicaseNOTE: Other protocol defined inclusion / exclusion criteria apply

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance of 0 or 1.
• Must have confirmed diagnosis of Relapsed/Refractory Multiple Myeloma (RRMM) after the participant's last treatment, as outlined in the protocol.
• All participants must have measurable diseases per central laboratory as outlined in protocol

Exclusion Criteria:

• Has received prior etentamig treatment.
• Prior exposure to BCMA-targeted therapy as noted in the protocol.
• Has received prior cereblon E3 ligase modulatory drug (CELMoD) (iberdomide or mezigdomide).

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

• Documented diagnosis of multiple myeloma (MM) as per International Myeloma Working Group (IMWG) criteria.
• Received at least 4 classes of MM treatment [including immunomodulatory drug (IMiD), proteasome inhibitor (PI), anti CD38 mAb, anti-BCMA therapy, and at least 3 prior lines of therapy (LOT).
• Documented disease progression during or after their last anti-myeloma regimen as per IMWG 2016 criteria.
• Participants must have measurable disease during screening.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion Criteria

• Active or history of central nervous system involvement with MM.
• Active systemic fungal, bacterial, viral, or other infection despite appropriate anti-infective treatment at the time of leukapheresis. Participants with severe infection, severe sepsis or bacteremia in the last 28 days prior to leukapheresis are excluded.
• Received any prior therapy directed at G protein-coupled receptor class C, group 5, member D (GPRC5D) or has received other prior treatment for MM without the required washout prior to leukapheresis.
• Other protocol-defined Inclusion/Exclusion criteria apply.

Key Inclusion Criteria:

1. Previously untreated participants for lymphoma with documented Cluster of Differentiation 20+ (CD20+) DLBCL, as described in the protocol OR relapsed or refractory DLBCL, for whom next available standard of care therapy is not available or deemed ineligible according to the investigator (Part 1A only) 2. Measurable disease with at least one nodal lesion or at least one extranodal lesion, as described in the protocol 3. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 4. Life expectancy ≥ 12 months 5. International Prognostic Index (IPI) of 3 to 5 (part 1 only) and ≥2 (part 2) for untreated DLBCL only 6. Adequate hematologic and organ function, as defined in the protocol.

Key Exclusion Criteria:

1. Primary Central Nervous System (CNS) lymphoma or known involvement by non-primary CNS NHL and history or current relevant CNS pathology 2. Another active malignancy, significant active disease or medical condition, as described in the protocol 3. Peripheral neuropathy Grade ≥3 4. Treatment with any systemic anti-lymphoma therapy, except for participants with Relapsed/Refractory (R/R) DLBCL and participants with DLBCL transformed from an indolent lymphoma after treatment with systemic anti-lymphoma therapy. 5. Any other therapy or investigational treatment within 28 days or 5 half-lives of the drug, whichever is shorter, prior to the start of study treatment 6. Recent major surgery, prior organ transplantation, or standard radiotherapy, as described in the protocol 7. Allergy/hypersensitivity to study drugs, as described in the protocol 8. Infections such as any active infection (bacterial, viral, fungal, mycobacterial, parasitic or other), active Coronavirus Disease (COVID-19) infection, uncontrolled infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV), Cytomegalovirus (CMV) infection, as described in the protocol.Note: Other protocol-defined Inclusion/ Exclusion criteria apply

Inclusion Criteria:

• ≥ 12 years of age at the time of informed consent.
• New-onset moderate or severe cGVHD, as defined by the 2014 NIH Consensus Development Project Criteria for Clinical Trials in cGVHD, requiring systemic therapy.
• History of allo-HCT from any donor HLA type (related or unrelated donor with any degree of HLA matching) using any graft source (bone marrow, peripheral blood stem cells, or cord blood). Recipients of myeloablative, nonmyeloablative, or reduced-intensity conditioning are eligible.
• Adequate hematologic function with ANC ≥ 0.5 × 109/L independent of growth factors for at least 7 days prior to study entry.
• Willingness to avoid pregnancy or fathering children.

Exclusion Criteria:

• Received more than 1 prior allo-HCT. Prior autologous HCT is allowed.
• Has overlap cGVHD, defined as simultaneous presence of features or characteristics of aGVHD in a patient with cGVHD.
• Received more than 7 days of systemic corticosteroid treatment for cGVHD or unable to begin a prednisone dose ≥ 1.0 mg/kg per day (or methylprednisolone equivalent) for cGVHD.
• Received previous systemic treatment for cGVHD, including extracorporeal photopheresis.
• Systemic treatment with CNIs or mTOR inhibitors started within 2 weeks prior to C1D1.
• Prior treatment with CSF-1R targeted therapies.
• Active, uncontrolled bacterial, fungal, parasitic, or viral infection.
• Evidence of relapse of the primary hematologic disease or treatment for relapse after the allo-HCT was performed, including DLIs for the treatment of molecular relapse.
• History of acute or chronic pancreatitis.
• Active symptomatic myositis.
• History or current diagnosis of cardiac disease indicating significant risk of safety for participation in the study, such as uncontrolled or significant cardiac disease.
• Severe renal impairment, that is, estimated CrCl < 30 mL/min measured or calculated by Cockcroft-Gault equation in adults and Schwartz formula in pediatric participants, or endstage renal disease on dialysis.
• Impaired liver function, defined as total bilirubin > 1.5 × ULN and/or ALT and AST > 3 × ULN in participants with no evidence of liver cGVHD.
• Pregnant or breastfeeding.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

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