Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)

Inclusion Criteria: Myelodysplastic Syndromes (MDS) :

1. Understand and voluntarily provide permission (subjects and/or when applicable,parental/legal representative) to the informed consent form/informed assent form (ICF/IAF) prior to conducting any study-related assessments/procedures.

2. Able to adhere to the study visit schedule and other protocol requirements.

3. Male or female age 1 month to less than 18 years old at the time of informedconsent/informed assent.

4. Newly diagnosed advanced primary or secondary Myelodysplastic Syndromes (MDS), withlatest peripheral blood (PB) and bone marrow (BM) biopsy confirming diagnosis withinthe 14 days prior to informed consent signature, with one of the following:

5. RAEB (Refractory anemia with excess blasts): 2% to 19% blasts in PB or 5% to 19%blasts in BM.

6. RAEB-t (Refractory anemia with excess blasts in transformation): 20% to 29% ofblasts in PB or BM.

7. Secondary Myelodysplastic Syndromes presenting as chronic myelomonocytic leukemia (CMML) without increase in blasts but with chromosomal abnormality

8. Lansky play score at least equal to 60; or Karnofsky performance status at least equalto 60.

9. Life expectancy of at least 3 months.

10. Normal renal function defined as less than or equal to NCI CTCAE (National CancerInstitute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) v 4.0 Grade 1 (maximum 1.5 x Upper Limit of Normal [ULN]).

11. Normal liver function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 2.5 x ULN for transaminases and bilirubin).

12. Females of childbearing potential and male subjects that have reached puberty and areyounger than 18 years of age must agree to undergo physician-approved reproductiveeducation and discuss the side effects of the Investigational Product (IP) onreproduction with parent(s) and/or guardian(s).

13. Females of childbearing potential, defined as females who have achieved menarcheand/or 8 years or older and have not undergone a hysterectomy or bilateraloophorectomy, must meet the following conditions below. (Note: Amenorrhea followingcancer therapy does not rule out childbearing potential):

14. Have a negative serum pregnancy test within 72 hours prior to starting IP asverified by the Investigator. Agree to ongoing pregnancy testing during thecourse of the study

15. Female subjects must, as appropriate to age and the discretion of the studyphysician, either commit to true abstinence1 from heterosexual contact (whichmust be reviewed on a monthly basis) and/or agree to the use of approvedcontraceptive method (eg. oral, injectable, or implantable hormonalcontraceptive; tubal ligation; intra-uterine device; or vasectomized partner)while on azacitidine; and for 3 months following the last dose.

16. Male subjects must, as appropriate to age and the discretion of the study physician:

17. Agree to use a condom during sexual contact with a pregnant female or a female ofchildbearing potential (FCBP) while participating in the study, during doseinterruptions, and for at least 3 months following azacitidine discontinuation,even if he has undergone a successful vasectomy. Juvenile Myelomonocytic Leukemia Subjects (JMML):

18. Understand and voluntarily provide permission (subjects and/or when applicable,parental/legal representative) to the ICF/IAF prior to conducting any study-relatedassessments/procedures.

19. Able to adhere to the study visit schedule and other protocol requirements.

20. Male or female age 1 month to less than 18 years old at the time of informedconsent/informed assent.

21. Newly diagnosed Juvenile Myelomonocytic Leukemia (JMML), with PB and BM confirmingdiagnosis prior to informed consent signature, with one of the following

22. somatic mutation in PTPN11

23. somatic mutation in KRAS

24. somatic mutation in NRAS and HbF % > 5x normal value for age

25. clinical diagnosis of neurofibromatosis Type 1.

26. Lansky play score at least equal to 60; or Karnofsky performance status at least equalto 60.

27. Life expectancy of at least 3 months.

28. Normal renal function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 1.5 x ULN).

29. Normal liver function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 2.5 x ULN for transaminases and bilirubin).

30. Females of childbearing potential and male subjects that have reached puberty and areyounger than 18 years of age must agree to undergo physician-approved reproductiveeducation and discuss the side effects of the IP on reproduction with parent(s) and/orguardian(s).

31. Females of childbearing potential, defined as females who have achieved menarcheand/or 8 years or older and have not undergone a hysterectomy or bilateraloophorectomy, must meet the following conditions below.

32. Have a negative serum pregnancy test within 72 hours prior to starting IP asverified by the Investigator. Agree to ongoing pregnancy testing during thecourse of the study

33. Female subjects must, as appropriate to age and the discretion of the studyphysician, either commit to true abstinence2 from heterosexual contact (whichmust be reviewed on a monthly basis) and/or agree to the use of approvedcontraceptive method (eg. oral, injectable, or implantable hormonalcontraceptive; tubal ligation; intra-uterine device; or vasectomized partner)while on azacitidine; and for 3 months following the last dose.

34. Male subjects must, as appropriate to age and the discretion of the study physician: a. Agree to use a condom during sexual contact with a pregnant female or a female ofchildbearing potential (FCBP) while participating in the study, during doseinterruptions, and for at least 3 months following azacitidine discontinuation, evenif he has undergone a successful vasectomy.

35. SO2 greater than 92% (without additional supply of O2).

36. Peripheral blood monocyte count of at least 1.0 x 109/L.

37. Blast percentage in PB and BM less than 20%.

38. Splenomegaly.

Exclusion Criteria: Myelodysplastic Syndromes (MDS):

1. Any significant medical condition, laboratory abnormality, or psychiatric illness thatwould prevent the subject from participating in the study.

2. Any condition including the presence of laboratory abnormalities, which places thesubject at unacceptable risk if he/she were to participate in the study.

3. Any condition that confounds the ability to interpret data from the study.

4. Treated by any investigational agent in a clinical study within 4 weeks prior tosigning of informed consent / informed assent.

5. Any central nervous system (CNS) involvement.

6. Isolated extramedullary disease.

7. Current uncontrolled infection.

8. Cardiac toxicity (shortening fraction below 28%).

9. Concurrent treatment with another anticancer therapy.

10. Pregnancy or lactation.

11. Prior treatment with a demethylating agent.

12. Allergy to azacitidine or mannitol.

13. Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with theadministration of the therapy according to this protocol.

14. Genetic abnormalities indicative of Core Binding factor AML; t(8;21), inv16, t(16;16),and t(15;17).

15. Subjects with inherited BM failure syndromes (ie, Fanconi's anemia, congenital severeneutropenia, Shwachman-Diamond syndrome). Juvenile Myelomonocytic Leukemia Subjects:

16. Any significant medical condition, laboratory abnormality, or psychiatric illness thatwould prevent the subject from participating in the study.

17. Any condition including the presence of laboratory abnormalities, which places thesubject at unacceptable risk if he/she were to participate in the study.

18. Any condition that confounds the ability to interpret data from the study.

19. Treated by any investigational agent in a clinical study within 4 weeks prior tosigning of informed consent / informed assent.

20. Any CNS involvement.

21. Isolated extramedullary disease.

22. Current uncontrolled infection.

23. Cardiac toxicity (shortening fraction below 28%).

24. Concurrent treatment with another anticancer therapy.

25. Pregnancy or lactation.

26. Prior treatment with a demethylating agent.

27. Allergy to azacitidine or mannitol.

28. Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with theadministration of the therapy according to this protocol.

29. Germline molecular aberrations in CBL, PTPN11, NRAS, or KRAS.