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

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

What this study is about