Inclusion Criteria:

1. Aged ≥ 18 years of age.

2. Patient has a confirmed diagnosis of recurrent or refractory AML or MDS:

   Parts A, B, C:

   i. AML either de novo or secondary ii. MDS with at least 5% blasts that is relapsed after or refractory to hypomethylating agent (HMA) therapy iii. Patient has received, and has progressed, recurred, or is intolerant of approved therapeutic options that are available or declines treatment with these therapies

   Part D:

   i. Confirmed diagnosis of de novo or secondary R/R AML (includes patients with MDS/AML) ii. Patient has received no more than 2 prior lines of therapy iii. Patients must have exhausted, be ineligible for, be intolerant of, or otherwise not be considered appropriate candidates for available therapies considered suitable for the individual patient (including targeted therapies) iv. Patients must have a recent assessment of TP53 mutation status by an approved local laboratory.

   Part E:

   i. Patient has a confirmed diagnosis of de novo or secondary newly diagnosed AML (includes patients with MDS/AML) with no prior lines of AML-directed therapy ii. Patient must have evidence of a positive recent assessment of TP53 mutation status

3. White blood cell (WBC) count at the time of the first dose is < 20,000/uL
4. Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 2.
5. Toxicities related to prior study therapy should have resolved to Grade 1 or less according to criteria of NCI CTCAE v5.0

6. The patient's laboratory values meet the following criteria:

   1. Creatinine clearance (CrCl) as calculated by the Cockcroft-Gault formula must be ≥ 45 mL/min;
   2. Total bilirubin ≤ 1.5 × ULN.
   3. AST and ALT ≤ 3.0 × ULN (unless attributed to leukemic involvement).

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL)
2. Active central nervous system (CNS) leukemia.
3. Isolated extramedullary relapse
4. Prior organ allograft

5. Prior history of allogeneic hematopoietic transplantation:

   1. In Parts A, B, and C: Prior history of allogeneic hematopoietic transplantation within six months of treatment or with clinical or laboratory evidence of GVHD, or requiring ongoing treatment with immune suppression
   2. In Parts D and E: Prior history of allogeneic hematopoietic transplantation within twelve months of treatment or with clinical or laboratory evidence of GVHD, or requiring ongoing treatment with immune suppression

6. Treatment with any of the following:

   1. Radiation therapy (XRT) within 28 days of the first dose of CLN-049, or craniospinal XRT within 8 weeks of the first dose of CLN-049, or history of total body irradiation (TBI).
   2. Prior immunotherapy with checkpoint inhibitors ≤ 42 days prior to the first dose of CLN-049.
   3. Prior history of chimeric antigen receptor (CAR-T) cell therapy or other modified T cell therapy.
   4. Anti-leukemic therapy except hydroxyurea for cytoreduction, and intrathecal chemotherapy ≤ 14 days or 5 half-lives, whichever is shorter, prior to the first dose of CLN-049.
   5. Short-acting hematopoietic growth factors ≤ 7 days prior to the first dose of CLN-049
   6. Long-acting growth factors ≤ 14 days prior to the first dose of CLN-049.
   7. Systemic glucocorticoid therapy (except equivalent of < 10 mg prednisone daily) or other immune-suppressive drugs ≤ 14 days prior to the first dose of CLN-049
   8. Prior treatment with a FLT3-directed bispecific molecule, or a FLT3-targeted antibody.
7. Currently participating/previously participated in an interventional study and received an investigational drug within 14 days (or five half-lives, whichever is longer) prior to the first dose of CLN-049.
8. Patients with concomitant second malignancies requiring active treatment in the past 12 months, or if additional therapy is required or anticipated during study participation.
9. Patients with any active autoimmune disease or a history of known or suspected autoimmune disease, or history of a syndrome that requires systemic corticosteroids or immunosuppressive medications
10. A serious uncontrolled medical disorder that would impair the ability of the patient to receive protocol therapy or whose control may be jeopardized by the complications of this therapy.
11. Any concurrent condition, therapy, or laboratory abnormality that, in the opinion of the investigator, might compromise patient safety or interfere with the evaluation of the safety of the drug.
12. Active uncontrolled infection within seven days of first dose of CLN-049.
13. Has a history of, or a positive test for Human Immunodeficiency Virus (HIV) 1/2 or primary immunodeficiency disease such as HIV.
14. Known history of hepatitis B (with positive testing for either hepatitis B surface antigen [HBsAg] or hepatitis B core Ab), hepatitis C (HCV) infection (with positive testing for HCV antibody and/or HCV ribonucleic acid [RNA] in serum), or acute hepatitis A (with positive testing for hepatitis A IgM).
15. Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
16. History of the following events in conjunction with prior treatment with immunotherapy: Grade 3 or greater neurotoxicity, ocular toxicity, pneumonitis, myocarditis, or colitis; liver dysfunction meeting the laboratory criteria for Hy's Law.
17. Live virus vaccines within 28 days of the first dose of CLN-049, during treatment, and until the end of last dose of CLN-049.
18. QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥ 480 milliseconds.
19. Patient has history of drug-related anaphylactic reactions to any components of CLN-049. History of Grade 4 anaphylactic reaction to any bispecific molecule or monoclonal antibody therapy.
20. Known history of prior human anti-human antibody response. Patients will not be screened for human anti-human antibody prior to study participation.