CPX-351 in Higher Risk Myelodysplastic Syndromes

Inclusion Criteria: * Myelodysplastic syndrome (WHO 2016 classified) including CMML (even if white blood cell count (WBC) \> 13000/mm3). * For COHORT A: untreated patients except by erythropoiesis stimulating agents, Lenalidomide or non-chemotherapy during a phase of lower risk MDS; For COHORT B: absence of response (CR, CRi, PR or HI according to international working group (IWG) 2006 for MDS) after a minimum of 6 cycles of single hypomethylating agent or relapse after a response. * For COHORT A: less than 20% of marrow blasts. For COHORT B: less than doubling of marrow blasts compared with onset of hypomethylating agent. * Classical international prognostic scoring system (IPSS) int-2 or high risk score. * For COHORT A and B : age between 18 and 70 years * For COHORT A: Performance status (ECOG grading) ≤ 1; For COHORT B: Performance status ≤ 2. * Eligible for standard intensive chemotherapy. * Absence of concomitant severe cardiovascular disease which would make intensive chemotherapy impossible, i.e. arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, reduced left ventricular function assessed by multigated acquisition (MUGA) scan or echocardiogram. * Patient must have adequate organ function as indicated by the following laboratory values: Renal: Serum creatinine \< 2 mg/dl or calculated creatinine clearance ≥ 60 mL/min by MDRD (modification of the diet in renal disease) or CKD-EPI (chronic kidney disease epidemiology collaboration) equation for patients with creatinine levels \> 1.5xULN ; Hepatic: Serum total bilirubin ≤ 2.5xULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL, aspartate aminotransferase (ALT) and alanine aminotransferase (ALT) ≤ 2.5xULN, Alkaline Phosphatase ≤ 5xULN (if \> 2.5xULN, then liver fraction should be ≤ 2.5xULN). * Patients not known to be refractory to platelet transfusions. * Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles. Female patient is not actively breastfeeding at the time of study entry. * Female patients are either post-menopausal, free from menses for \> 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agree to abstain from becoming pregnant throughout the study, starting with Visit 1. Females of reproductive potential as well as fertile men and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use two highly effective forms of contraception from the time of giving informed consent, during the study and for 6 months (females and males) following the last dose of CPX-351. * Male patients agree to use an adequate method of contraception for the duration of the study. Men should be advised not to father a child while receiving CPX-351 and for 6 months post study. * Patients are available for regular blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study. * Patients have the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study. Exclusion Criteria: * Active and uncontrolled infection. * Last dose of hypomethylating agent given more than 4 months before entering the trial. * Uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance. * Current participation or participation in a study with an investigational compound or device within 30 days of initial dosing with study drug. * Known human immunodeficiency virus (HIV) infection or HIV-related malignancy. * Clinically active hepatitis B or hepatitis C infection. * Known allergy or hypersensitivity to any component of CPX-351. * "Currently active" second malignancy, other than non-melanoma skin cancer and in situ carcinoma of the cervix. * Subjects with a history of Wilson's disease or other copper-related disorder. * Treatment with growth factors such as erythropoietin alfa (EPO) or granulocyte colony-stimulating factor (G-CSF) or cytotoxic and non-cytotoxic agents (including low dose oral chemotherapy with the exception of hydroxyurea) in the 30 days before inclusion. * Treatment with systemic steroids that has not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs. * Clinical evidence of central nervous system leukemia. * Pregnancy or breastfeeding during the projected duration of the study. * Absence of social security.