CPI-613 and Hydroxychloroquine for Patients With High Risk Myelodysplastic Syndrome

Inclusion Criteria: Patients must meet all of the following inclusion criteria before enrollment: * Histologically documented high risk MDS whose disease has failed to respond, progressed or relapsed while on a hypomethylating agent. * IPSS-R score of Intermediate, high or very high at time of enrollment * ECOG Performance Status of ≤3. * Men and women 18 years of age or older. * Expected survival \>2 months. * Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device \[IUD\], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation. * Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists. * Patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities. Patients with persisting, non-hematologic, non-infectious toxicities from prior treatment ≤ Grade 2 are eligible, but must be documented as such. * Laboratory values obtained ≤2 weeks prior to enrollment must demonstrate adequate hepatic function, renal function, and coagulation as defined below: * Aspartate aminotransferase \[AST/SGOT\] ≤3x upper normal limit \[UNL\] * Alanine aminotransferase \[ALT/SGPT\] ≤3x UNL * Bilirubin ≤1.5x UNL * Serum creatinine ≤1.5 mg/dL or 133 μmol/L * Albumin ≥ 2.0 g/dL or ≥ 20 g/L. * Mentally competent, ability to understand and willingness to sign an IRB-approved written informed consent form. * Have access via central line (e.g., portacath). Exclusion Criteria: * Patients with the following characteristics are excluded: * Serious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, symptomatic coronary artery disease, myocardial infarction within the past 3 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association Class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients' risk for toxicity. * Patients with active central nervous system (CNS) or epidural tumor. * Any active uncontrolled bleeding or bleeding diathesis (e.g., active peptic ulcer disease). * Any condition or abnormality which may, in the opinion of the investigator, compromise his or her safety. * Pregnant women, or women of child-bearing potential not using reliable means of contraception. * Fertile men unwilling to practice contraceptive methods during the study period. * Lactating females. * Life expectancy less than 2 months. * Unwilling or unable to follow protocol requirements. * Evidence of ongoing uncontrolled serious infection. * Requirement for immediate palliative treatment of any kind including surgery. * Patients with uncontrolled HIV infection. (Note: Patients with known HIV infection are excluded because patients with an immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, and because there may be unknown or dangerous drug interactions between CPI-613 and anti-retroviral agents used to treat HIV infections). * Patients who have received radiotherapy, surgery, treatment with cytotoxic agents (except a hypomethylating agent, i.e. azacytidine or decitabine), treatment with biologic agents, immunotherapy, or any other anti-cancer therapy of any kind, or any other standard or investigational treatment for their cancer, or any other investigational agent for any indication, within the past 2 weeks prior to initiation of CPI-613 treatment. * Patients that have received a chemotherapy regimen with stem cell support in the previous 6 months.