A Phase II, Open-Label, Study of Subcutaneous Canakinumab, an Anti-IL-1β Human Monoclonal Antibody, for Patients With Low or Int-1 Risk IPSS/IPSS-R Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Inclusion Criteria:

• Age ≥ 18 years as MDS and CCUS are very rare conditions in the pediatric setting.

• Cohorts 1-3: Diagnosis of MDS according to WHO 2016 classification and low orintermediate-1 risk by IPSS or IPSS-R with a score of ≤ 3.5.

• Cohort 4: Diagnosis of CCUS defined as:

• Presence of a somatic pathogenic variant associated with hematological malignancywithout morphological evidence of myelodysplasia

• Variant allele fraction of greater than or equal to 2% in at least one identifiedsomatic pathogenic variant

• Bone marrow aspirate excluding hematological malignancy and MDS

• Presence of a cytopenia for >30 days. Cytopenia will be defined using acceptedCHRS (Clonal Hematopoiesis Risk Score) criteria (Weeks et al, NEJM Evidence inpress): ANC <1.8 or hgb <12 in females and <13 in males or a platelet count of <150.

• Cohort 1: Participants need to have not responded to prior therapy with ESAs orhypomethylating agents (HMAs). These could include azacitidine, decitabine, SGI-110,ASTX727, or CC-486. Patients will need to have received at least 4 cycles of HMA.Participants with relapse or progression after any number of cycles of HMA by IWG 2006 criteria will also be candidates. Participants with evidence of del 5qalteration also are required to have been treated with Lenalidomide.

• Cohort 1: Hemoglobin <10g/dL with symptomatic anemia or transfusion dependencydefined as the need for prior transfusion in the past 8 weeks for a hemoglobin levelless than 8g/dl.

• Cohort 2: Transfusion dependency defined as the need for prior transfusion in thepast 8 weeks of (1) at least 2 units of PRBC for a hemoglobin level less than 8g/dlor symptomatic anemia (hemoglobin <10g/dL), or (2) any platelet transfusion.

• Participants (or patient's legally authorized representative) must have signed aninformed consent document indicating that the patient understands the purpose of andprocedures required for the study and is willing to participate in the study.

• Adequate hepatic function with total bilirubin </=3 x ULN, AST or ALT </= 3xULN.

• Serum creatinine clearance >30mL/min and no end/stage renal disease (usingCockcroft-Gault).

• ECOG performance status </=2.

Exclusion Criteria:

• Active infection not adequately responding to appropriate antibiotics.

• Prior treatment with IL-1/IL-1r inhibitors

• Absolute neutrophil count (ANC) <0.5x109 k/ul; colony-stimulating factors can beadministered prior to study drug initiation.

• Female participants who are pregnant or lactating.

• Participants with reproductive potential who are unwilling to followingcontraception requirements (including condom use for males with sexual partners, andfor females: prescription oral contraceptives [birth control pills], contraceptiveinjections, intrauterine devices [IUD], double-barrier method [spermicidal jelly orfoam with condoms or diaphragm], contraceptive patch, or surgical sterilization)throughout the study. Reproductive potential is defined as no previous surgicalsterilization or females that are not post-menopausal for 12 months.

• Female participants with reproductive potential who do not have a negative urine orblood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.

• History of an active malignancy within the past 2 years prior to study entry, withthe exception of: a. Adequately treated in situ carcinoma of the cervix uteri b.Adequately treated basal cell carcinoma or localized squamous cell carcinoma of theskin or any other malignancy with a life expectancy of more than 2 years.

• Participants receiving any other concurrent investigational agent or chemotherapy,radiotherapy, or immunotherapy (within 14 days of initiating study treatment).

• Known history of testing positive for Human Immunodeficiency Virus (HIV) infections.

Participants requiring systemic steroids, methotrexate or other immunosuppressive drugs will not be included in the study.