Nivolumab With Chemotherapy in Refractory MDS

• Nivolumab (Drug), also known as Opdivo: 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle
• Azacitidine (Drug), also known as 5-azacitidine, Vidaza: 75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle
• Fludarabine (Drug): 25 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle. Dose reduction to 15 mg/m2 is permitted in cases of grade 4 hematological toxicity after first cycle.
• Cyclophosphamide (Drug): 300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.
• Cytarabine (Drug), also known as Ara-C, LDAC: 10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle
• all trans retinoic acid (Drug), also known as ATRA: 45 mg/m2 per os daily during the whole course of treatment
• Sildenafil (Drug): 20 mg per os three times a day during the whole course of treatment
• Melphalan (Drug): 2 mg per os daily during the whole course of treatment

Primary outcomes

• Overall response rate [6 months]: Overall response rate (ORR) defined as complete response plus partial response (CR + PR) and hematological improvement (HI). MDS International Working Group criteria will be used to assess response.

Secondary outcomes

• Treatment-related adverse events as assessed by CTCAE v4.03 [6 months]: Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment).
• Infectious complications [6 months]: Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Patients with myelodysplastic syndrome (MDS) (up to 20% blasts) of any risk. Patients with lower risk MDS (low and int-1 by IPSS) should have failed prior non-hypomethylating agent therapy (ie growth factors or lenalidomide). Patients with higher risk MDS (int-2 or high by IPSS) should have failed prior at least one therapy with a hypomethylating agent or Ara-C.
* Age 18 years or older.
* No severe organ dysfunction: creatinine <=2.5 x ULN; serum bilirubin <=2.5 x ULN; AST and ALT <=5 x ULN.
* Karnofsky index >=70%
* Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the first dose of treatment and must agree to use an effective contraception to avoid pregnancy for 24 weeks
* Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 24 weeks after the last dose of nivolumab.

Exclusion Criteria:

* Another malignancy requiring treatment at the time of inclusion
* History of interstitial lung disease or pneumonitis
* Patients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure NYHA Class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the study
* Active, known or suspected autoimmune disease requiring treatment at the time of inclusion
* Pregnancy or breastfeeding
* Patients unwilling or unable to comply with the protocol
* Somatic or psychiatric disorder making the patient unable to sign informed consent
* Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA4 therapy