Inclusion Criteria:

• Patients eligible for treatment with azacitidine with one of the following diagnoses according to World Health Organization 2016:

• - MDS Higher-risk MDS according to the IPSS-R, i.e., intermediate- to very high-risk (IPSS-R score > 3) - CMML CMML with 10-29 percent marrow blasts without myeloproliferative disorder.

• - AML AML with 20-30 percent blasts (low-blast count AML) Note: Patients with therapy-related MDS are eligible if they have not received radiation or chemotherapy for six months.

Exclusion Criteria:

• - Patients eligible for allogeneic stem cell transplantation.

• - Prior therapy with hypomethylating agents.

• - Any matter constituting an exclusion criterion for treatment with azacitidine.

• - Patients receiving other active cancer treatment, including investigational agents, with the exception of hydroxyurea for white blood cell control and granulocyte colony-stimulating factor.

• - History of allergic reactions to ascorbic acid.

• - History of kidney or urinary tract stones requiring intervention within the past year.

• - Lack of ability to understand the information given, or lack of willingness to sign a written informed consent document.

• - Unwillingness to comply with the protocol.

• - Unwillingness to discontinue any and all use of vitamin C medication/supplementation including multivitamin at least 3 days (but preferably longer) prior to inclusion and baseline sampling.

- Planned azacitidine treatment after allogeneic stem cell transplantation

EVI-3 is a phase 2 international, multicentre, randomized, parallel-group, placebo-controlled, double-blind study of the efficacy and safety of oral vitamin C supplement in combination with azacitidine (AZA) in patients with higher-risk myeloid malignancies with or without mutations in genes recurrently affected in myeloid malignancies. Treatment allocation is in 1:1 ratio (vitamin C vs.#46; placebo) by block randomization stratified by clinical site. Study entry is staggered. Patients are randomized to either oral vitamin C 1000 mg daily or placebo from start of AZA treatment until end of study (EOS) or until AZA treatment is discontinued at the discretion of the treating physician, whichever occurs earlier. The accrual time is estimated to 48 months and 6 months follow-up, thus, maximum treatment duration will be approximately 54 months. A total of 196 patients is planned for enrollment. Study visits are scheduled at baseline, after 1st AZA treatment cycle, after 6 AZA treatment cycles, and, if AZA treatment is continued, at EOS or end of AZA treatment. Evaluations at study visits include bone marrow investigation, peripheral blood tests, patient-reported outcome measures, adverse events and compliance. Bone marrow aspirate and peripheral blood will be collected for biobank at each study visit. All patients will undergo follow-up once yearly from EOS. Follow-up will include information on duration of AZA therapy, survival and disease progression from myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) to acute myeloid leukemia (AML), if diagnosed following a clinical indication for a bone marrow test.

Arms

Experimental: Vitamin C

Oral vitamin C (ascorbic acid) will be given in a dose of 1000 mg daily (two capsules of 500 mg once daily) starting day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier.

Placebo Comparator: Placebo

Placebo will be administered orally as two capsules once daily that look and taste identical to the capsules containing vitamin C. Treatment will start day 1 in the 1st azacitidine (AZA) cycle (D1/C1) and continuing until discontinuation of AZA or end of study, whichever occurs earlier. The content of the placebo capsules is glucose monohydrate, potato starch, gelatin, magnesium stearate and talc.

Interventions

Dietary Supplement: - Vitamin C

Oral vitamin C (ascorbic acid) 1000 mg daily will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS as combination treatment.

Dietary Supplement: - Placebo

Placebo capsules (two capsules once daily) will be administered from day 1 in the 1st AZA cycle (D1/C1) and continued until discontinuation of AZA or EOS.