Induction treatment (every 3 weeks, total 6 cycles)

• Azacitidine D-2, -1, 1 (level 1: 50mg/m2, level 2: 75mg/m2, level 3: 100mg/m2, level 4: 125mg/m2)
• Cyclophosphamide 750mg/m2 d1
• Doxorubicin 50 mg/m2 d1
• Vincristine 1.4 mg/m2 (Max: 2 mg) d1
• Prednisolone 100mg PO d1-5 Maintenance treatment (every 4 weeks, total 12 cycles)
• Azacitidine 75mg/m2 d1-5

1. Phase I Azacitidine will be administered intravenously from d-2 to d1, starting from dose level 1. Based on the BOIN design described above, if no DLT is identified in level 1, the dose will be escalated stepwise to levels 2, 3, and then 4.

   Subjects will receive intravenous azacitidine combined with CHOP regimen every 3 weeks as below:

   Level 1 - Azacitidine 50mg/m2 D-2, -1, 1 Level 2 - Azacitidine 75mg/m2 D-2, -1, 1 Level 3 - Azacitidine 100mg/m2 D-2, -1, 1 Level 4 - Azacitidine 125mg/m2 D-2, -1, 1

   Azacitidine at each level will be combined with the corresponding CHOP regimen as follows:

   • Cyclophosphamide 750mg/m2 d1
   • Doxorubicin 50 mg/m2 d1
   • Vincristine 1.4 mg/m2 (Max: 2 mg) d1
   • Prednisolone 100mg PO d1-5

2. Phase II

   • Azacitidine determined dose daily for D-2, -1, 1, Cyclophosphamide 750mg/m2 d1, Doxorubicin 50 mg/m2 d1, Vincristine 1.4 mg/m2 (Max: 2 mg) d1, Prednisolone 100mg PO d1-5 (6 cycles in total)
   • Use prophylactic trimethoprim-sulfamethoxazole 1T from the day of study drug administration to 21 days after the last dose of study treatment
   • Administer Peg-GCSF on study d2.
   • After Cycle 2, the study treatment can be administered if the ANC has been restored to ≥1,500/μL and platelets to ≥75,000/μL, and non-hematological toxicities that occurred in the previous cycle, except alopecia, have resolved to Grade 1 or less on d1 of each cycle.
   • If these hematological and non-hematological toxicities are not resolved, the clinical trial can be delayed for up to 21 days.

3. Consolidation therapy

   • After completing the planned first-line therapy in the clinical trial, the following consolidation therapy should be performed, regardless of the azacitidine dose level.
   • Azacitidine 75mg/m2 d1-5 (every 4 weeks, total 12 cycles)

Inclusion Criteria:

1. Treatment-naïve patients with newly diagnosed nodal T-cell lymphoma with T-follicular helper (TFH) phenotype as determined by the following 2016 WHO diagnostic criteria:

   • Angioimmunoblastic T-cell lymphoma
   • Follicular helper T-cell lymphoma
   • Peripheral T-cell lymphoma with follicular helper T-cell type

2. 20 to 85 years of age at diagnosis

3. ECOG performance status 0-2

4. Cardiac function suitable for chemotherapy: LVEF ≥45% on echocardiography or MUGA

5. Appropriate renal function: Serum Cr ≤2.0mg/dL or eGFR ≥ 30mL/min according to the Cockroft-Gault formula

6. Appropriate hepatic function: ALT ≤2.5x upper limit of normal (ULN) (or ≤5x ULN in the presence of liver involvement), total bilirubin ≤2x ULN (or ≤3x ULN in the presence of liver involvement)

7. Appropriate hematologic findings: absolute neutrophil count (ANC) ≥1,500/μL, platelets ≥100,000/μL (or ANC ≥500/μL and platelets ≥50,000/ μL in the presence of bone marrow involvement)

8. Written informed consent to participate in the study

9. Capable of following the study visit schedule and other requirements in the protocol

10. For women of childbearing potential, a negative pregnancy test

11. Women of childbearing potential must use an effective method of contraception (i.e., hormonal contraception, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the study period and for 3 months afterward. Men are to use an effective method of contraception during the study period and for 3 months afterward.

12. Life expectancy ≥90 days (3 months)

13. Hepatitis B or C infection: Hepatitis B carriers and subjects with inactive hepatitis C infection (normal levels of aminotransferases) are eligible if they take prophylactic antiviral drugs

Exclusion Criteria:

1. Other subtypes of non-Hodgkin's lymphoma
2. History of chemotherapy for Hodgkin's or other non-Hodgkin's lymphoma in the last 5 years
3. History of active cancer diagnosed within the last 3 years (with the exception of completely resected non-melanoma skin cancer, papillary thyroid cancer, carcinoma in situ of cervical cancer or breast cancer, and localized prostate cancer)
4. Uncontrolled hepatitis B (with the exception of asymptomatic HBsAg-positive or anti-HBcAb-positive cases receiving antiviral prophylaxis such as entecavir or tenofovir)
5. History of chronic hepatitis C (with the exception of HCV IgG positive with a negative HCV-RNA quantification)
6. History of human immunodeficiency virus (HIV) infection
7. Congestive heart failure (NYHA class ≥3)
8. Acute coronary syndrome (new-onset unstable angina or myocardial infarction) or ventricular tachycardia within 6 months prior to study entry
9. History of major neurological or psychiatric illness, including dementia or epilepsy
10. Severe chronic obstructive pulmonary disease with hypoxemia
11. Cerebrovascular disease within 3 months prior to study entry (including transient cerebral ischemia)
12. Unresolved wounds, ulcers, or bone fractures
13. Uncontrolled active infections (viral, bacterial, or fungal infections)
14. Concurrent use of other experimental drugs under investigation
15. Known hypersensitivity to the investigational drugs
16. History of major surgery or serious trauma within 21 days prior to study treatment. Open biopsy within 7 days prior to study treatment
17. Male subjects who had not undergone a vasectomy and have a partner who plans to become pregnant or are unable to use a medically acceptable method of contraception (partner's sterilization or intrauterine device placement, or barrier method combined with diaphragm or condom) during the subject's participation in the study
18. Pregnant or breastfeeding women or women of childbearing potential and men who are not willing to use appropriate methods of contraception during the study
19. Previously treated for T-cell lymphoma with immunotherapy or chemotherapy, except for short-term corticosteroids (for less than 8 days) prior to selection
20. Prior radiotherapy, except for those localized to a single lymph node
21. Central nervous system involvement
22. Contraindication to any of the drugs included in the chemotherapy
23. History of administration of doxorubicin at >200 mg/m²