Efficacy and Pharmacogenomics of Cladribine Based Salvage Chemotherapy in Patients With Relapse/Refractory and Secondary Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

Inclusion Criteria:

1. Age ≥18 years at the time of informed consent.
2. Morphologically documented:

   * Primary Acute Myeloid Leukemia (AML) or
   * AML secondary to Myelodysplastic Syndrome (MDS) or myeloproliferative neoplasm (MPN), or
   * Therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria.
   * Subjects with high risk MDS after failure of hypomethylating agents are also eligible.
3. Subjects must meet one of the following criteria:

   * In first or subsequent relapse or refractory status, with or without prior hematopoietic stem cell transplant (HSCT) OR
   * Subjects with MDS or MPN transformed to AML will be eligible even if they had not received prior therapy for AML.
   * Subjects with high risk MDS after failure of hypomethylating agents.
4. Eastern Cooperative Oncology Group (ECOG) performance score 0-3.
5. It is not known what effects this treatment has on human pregnancy or development of the embryo or fetus. Therefore, female subjects participating in this study should avoid becoming pregnant, and male subjects should avoid impregnating a female partner. Non- sterilized female subjects of reproductive age and male subjects should use effective methods of contraception through defined periods during and after study treatment as specified below.

   Female subjects must meet one of the following:
   * Postmenopausal for at least one year before the screening visit, or
   * Surgically sterile, or if they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug, AND
   * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, or
   * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable contraception methods.)

   Male subjects, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:
   * Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose, OR
   * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
   * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)
6. Ability to understand a written informed consent document and the willingness to sign it.
7. Subjects must meet the following clinical laboratory criteria:

CLAG-M Arm Only:

For abnormalities in liver function tests, elevation thought to be due to hepatic infiltration by AML, Gilbert's syndrome or hemolysis would not be treated as exclusion criteria.

* Absolute neutrophil count ≥1,000/mm\^3 Unless related to AML
* Platelets ≥75,000/mm\^3 Unless related to AML
* Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) (if elevated, then complete direct bilirubin).
* AST(SGOT)/ALT Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
* Creatinine clearance ≥ 30 mL/min
* Resting left ventricular ejection fraction ≥ 45%

CLLDAC ARM ONLY:

* Absolute neutrophil count ≥ 1,000/mm\^3 unless related to AML
* Platelets ≥ 75,000/mm\^3 unless related to AML

Exclusion Criteria:

1. Acute Promyelocytic Leukemia.
2. Active infection not well controlled by antibacterial or antiviral therapy.
3. Pregnant or breast feeding women.
4. Participation in clinical trials with other investigational agents not included in this trial, throughout the duration of this trial. Participation of follow-up portion of another clinical trial will not exclude patient from participation.