Recombinant EphB4-HSA Fusion Protein and Azacitidine or Decitabine for Relapsed or Refractory Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Patients Previously Treated With a Hypomethylating Agent

Inclusion Criteria:

* Adult subjects with advanced MDS requiring treatment with HMA and either refractory to at least 4 cycles or progressing after previously documented response

  * Patient must be treated within 6 months of the last HMA treatment and must be willing to be treated with the same agent they last received on this study
  * Prior treatment with novel HMA analog of decitabine on clinical trial is allowed; in such cases, decitabine will be used as the standard of care agent
* MDS classified as intermediate 1-risk or high risk according to the international prognostic scoring system (IPSS) or revised-IPSS
* Chronic myelomonocytic leukemia (CMML)
* Acute myeloblastic leukemia (AML) that was previously treated with HMA and is unfit for intensive chemotherapy

  * Patient must be within 6 months of prior treatment with HMA and must be willing to be treated with the same agent on this study
* During the 8 weeks prior to inclusion in study, subjects must have a baseline bone marrow examination including all of the following:

  * Cytomorphology to confirm bone marrow blasts
  * Cytogenetics
* Eastern Cooperative Oncology Group (ECOG) status 0-2
* Subject is able to understand and willing to comply with protocol requirements and instructions
* Subject has signed and dated informed consent
* Total bilirubin (except for Gilbert's syndrome) =\< 2.5 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN
* Creatinine =\< 2.5 x ULN
* Women of childbearing potential (WOCBP) and male patients with WOCBP as partners must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of the investigational agent; subject is practicing an acceptable method of contraception (documented in case report form \[CRF\]); WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal; post menopause is defined as:

  * Amenorrhea \>= 12 consecutive months without another cause or
* For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL
* Women who are using oral contraceptives, other hormonal contraceptives (vagina products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential
* WOCBP must have a negative serum test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 72 hours prior to the start of investigational product
* Patients with uncontrolled hypertension

Exclusion Criteria:

* Patients with AML whose white blood cell count exceeds 25,000
* Corrected QT (QTc) (Fridericia Correction Formula) \> 480 on electrocardiogram (ECG)
* Patients whose electrolytes (sodium, potassium, calcium, magnesium) are abnormal or cannot be normalized with standard intervention on the day of treatment with study drug
* Patients who are actively receiving any other anticancer therapy
* Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to HMAs
* Patients with a diagnosis of acute promyelocytic leukemia
* Patients with short life expectancy (less than 3 months) due to comorbidity other than MDS
* Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin \[B-hCG\] pregnancy test)
* Patients with current alcohol or drug abuse
* Patients who have received treatment with an investigational drug within 30 days preceding the first dose of study medication
* Patients with uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Patients infected with hepatitis B, C or human immunodeficiency virus (HIV), unless they are on stable and effective antiviral treatment
* Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization; inhaled or topical steroids and adrenal replacement steroid doses \> 10mg daily prednisone equivalent, are permitted in the absence of uncontrolled autoimmune disease
* MEDICATION-RELATED EXCLUSION CRITERIA
* Patients with uncontrolled hypertension (HTN) (\> 160/90) will not be admitted onto the study