Azacitidine and Rituximab-GDP Immunochemotherapy in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Inclusion Criteria: 1. age from 19 to 75 years 2. diagnosed as diffuse large B-cell lymphoma according to the World Health Organization 2016 criteria 3. with any measurable lesion by radiologic studies (direct measurement is allowed in cases of (sub)cutaneous lesions) 4. patients who were initially treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other rituximab-containing immunochemotherapy and relapsed or refractory to prior treatment 5. previously treated with from1 to 4 lines of therapy * autologous stem cell transplant (ASCT) will be counted as 1 line of therapy * in cases of previously treated with ASCT, patients 1) who elapsed at 60 days and 2) who have lower risk of severe bone marrow suppression and infectious complication, judged by physician 6. ASCT ineligible or no further plan of ASCT due to previous transplantation 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0\~2 8. Hb ≥ 8.0 g/dL, absolute neutrophil count (ANC) ≥ 1,000/mm3, Platelet ≥ 100,000/mm3 prior to enrollment * correction of Hb by transfusion will be allowed * in cases of bone marrow involvement, patients will be included if they have ANC ≥ 500/mm3, Platelet ≥ 50,000/mm3 and no significant infection risk or transfusion dependency 9. Glomerular Filtration Rate \> 60 mL/min calculated according to Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) equation, and total bilirubin \< 2.5 mg/dL, aspartate amino-transferase (AST) and alanine amino- transferase (ALT) \< x3 upper limit of normal (ULN) * In cases of hepatic involvement of DLBCL, AST or ALT \< x5 ULN will be allowed * In cases of Gilbert syndrome, Direct bilirubin \< 2.5 ULN will be allowed 10. patients who agree to do highly effective contraception during and 3 months after treatment 11. patients who agree not to be pregnant or breast-feeding and had a negative result for screening pregnancy test 12. life expectancy \> 3 months Exclusion Criteria: 1. primary or secondary central nervous system DLBCL 2. patients with or strongly suggestive of lymphomatous involvement on eye, epidural area, kidney/adrenal gland, breast, testes, or uterus 3. intravascular DLBCL 4. DLBCL transformed from low grade lymphoma 5. high grade B-cell lymphomas other than DLBCL: primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma not otherwise specified (NOS), high-grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and/or B-cell lymphoma 6 (BCL6) rearrangements, B-cell lymphoma, unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma 6. human immunodeficiency virus (HIV) associated DLBCL 7. patients with liver cirrhosis of Child-Pugh Classification B or higher, or active hepatitis B (HBV) or hepatitis C (HCV) infection * in cases of patients who are positive for HBsAg or HBcAb immunoglobulin G (IgG) but no evidence of active infection, patients who are negative for HBV DNA will be allowed only with adequate anti-viral prophylaxis * in cases of patients who are positive for hepatitis C antibody, patients will be allowed if they satisfy all other inclusion criteria and without evidence of liver cirrhosis (irrespective of HCV RNA titer) * patients who were diagnosed HCV less than 6 months before screening period will be excluded unless they have negative result for HCV RNA 8. patients with active infection treated with anti-microbial agents 9. patients who were diagnosed malignancy other than lymphoma, either actively treated or have been received chemotherapy or radiation therapy less than 3 years from the time of enrollment 10. Major surgery within 21 days (open laparotomy for diagnostic biopsy will be exempted) 11. patients who underwent hypersensitivity, severe allergic reaction or anaphylaxis to rituximab or other chimeric/humanized antibodies 12. patients who underwent hypersensitivity, severe allergic reaction or anaphylaxis gemcitabine, azacitidine, or cisplatin 13. severe congestive heart failure, unstable heart or pulmonary diseases 14. pregnant or lactating women 15. during radiation therapy to chest area (considering previous reports of severe esophagitis and pneumonitis after concurrent chemoradiation with gemcitabine) 16. with any prior experience of posterior reversible encephalopathy syndrome or progressive multifocal leukoencephalopathy due to rituximab 17. with any prior experience of Stevens-Jones syndrome or toxic epidermal necrosis