• Time to response (TTR) associated with CPX-351 [ Time Frame: day 28 +/- 7 days of induction ]
  TTR associated with CPX-351 in participant with MDS at the end of induction. TTR defined by the time between starting the treatment and the time of achieving best response.
• Duration of response (DOR) in participants achieving a response [ Time Frame: At the end of cycle 1 (each cycle is 28 days), up to 1 year after end of treatment ]
  DOR in participants achieving a response defined by the time between first response (day C1 D28 +/-7 days from induction) and the day of loss of response
• Event-free survival (EFS) [ Time Frame: up to 1 year after end of treatment ]
  EFS probability of all participants enrolled in this trial from start of treatment and up to 1 year after the end of treatment.
• Overall survival (OS) [ Time Frame: up to 1 year after end of treatment ]
  OS probability of all participants enrolled in this trial from start of treatment and up to 1 year after the end of treatment.

This study will evaluate efficacy of treatment with CPX-351in participants with MDS while using a new stratification tool to predict outcomes of patients following HMA failure in order to gain a better understanding and insight into identifying new opportunities for drug approvals in this setting.

CPX-351is an investigational (experimental) drug for the indication of myelodysplastic syndrome that works by delivering two chemotherapy medications (daunorubicin and cytarabine) together which are then concentrated into the bone marrow (the part of the body that makes blood cells). CPX-351 is experimental because it is not approved by the Food and Drug Administration (FDA) for the indication of myelodysplastic syndrome. This drug is approved by theFDA for the indication of acute myeloid leukemia. One or more of the Investigators conducting this study serve as consultants for the company that makes products used in this study. These financial interests are within permissible limits established by the local institutional Conflict of Interest Policy.

Prior to beginning treatment, all eligible participants will be grouped into low risk versus high risk based on a stratification tool used to determine their disease. Group 1 will be low risk participants and group 2 will be high risk participants. All study participants will get the same study drug, CPX-351. Participants will receive the CPX-351 on days 1, 3 and 5 of the first 28 day cycle. After participants finish the first round of treatment and based on their response they may be eligible for another 4 cycles of treatment. The participant's doctor will inform them if this is an available option when the time comes. Once participant have finished treatment, their doctor will continue observe for side effects and follow their condition for 1 year.

Inclusion Criteria:

• Patients must give voluntary written consent before performance of any study related procedures not part of standard medical care
• Diagnosis of MDS or MDS/MPN according to 2016 WHO criteria12
• Primary therapy failure with either hypomethylating agents (decitabine or azacitidine) defined as:
• Progression (according to 2006 IWG criteria)13 after initiation of azacitidine or decitabine treatment; or
• Failure to achieve complete or partial response or hematological improvement (according to 2006 IWG)13 after at least 4-6 cycles (4-weeks cycle) of azacitidine or decitabine; or
• Relapse after initial complete or partial response or hematological improvement (according to 2006 IWG criteria)13 observed after at least 4 cycles of azacitidine or decitabine.
• Eastern Cooperative Oncology Group (ECOG) Performance Status < 2
• Subjects must have normal organ and marrow function defined as:
• If total bilirubin < 2x upper limit of normal (</= 3 x ULN if considered to be due to leukemic involvement or Gilbert's syndrome) at the discretion of the treating physician following discussion with PI)
• Calculated creatinine clearance value of > 30ml/min AND a serum creatinine < 1.5mg/dL
• LVEF >/= 50%
• Female patients who:
• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• Agree to practice true abstinence from heterosexual contact or agree to use effective contraception without interruption during the study therapy and 90 days after the last dose
• Male patients who:
• Are surgically sterile, OR
• Agree to practice true abstinence from heterosexual contact or agree to use effective contraception without interruption during the study therapy and 90 days after the last dose

Exclusion Criteria:

• Prior treatment with CPX-351, or known hypersensitivity to CPX-351 or its components.
• Prior treatment with intensive chemotherapy.
• Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent.
• Any active malignancy (unrelated, non-hematological malignancy) diagnosed within the past 6 months of starting the study drug (other than curatively treated carcinoma-in-situ of the cervix or non-melanoma skin cancer).
• Patients with uncontrolled intercurrent 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.
• Known history of HIV or active hepatitis B or C.
• Major surgery within 2 weeks prior to study enrollment.
• Pregnant or lactating females
• Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence or 2 forms of contraception) to avoid pregnancy while receiving study treatment.