R-DHAP vs POLA-R-DHAP Followed by Autologous Transplant as First Salvage Treatment in Patient With Relapsed or Refractory Diffuse Large B Cell Lymphoma

Inclusion Criteria: 1. Histologically documented diagnosis of Diffuse Large B-Cell Lymphoma Not otherwise specified (DLBCL-NOS) as defined in the 2022 edition of the World Health Organization (WHO) classification; are also admitted documented diagnosis of: * T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) * Epstein-barr virus (EBV)-associated DLBCL * Double-hit and triple-hit high grade B-cell lymphomas (HGBL DH/TH) * High-grade B-cell lymphoma, NOS (HGBL) * Transformed FL not previously untreated * Follicular large B-cell lymphoma (FLBL, former follicular 3b) 2. Known availability of biopsy material (at relapse/refractory or previous most recent). Re-biopsy highly encouraged even if not mandatory. Central pathology review required, but not mandatory for registration and treatment start; 3. Relapse or refractoriness after the first line R-chemo (R-CHOP o similar). Previous treatment with polatuzumab containing regimen is allowed as per clinician judgment; 4. CAR-T not indicated or unavailable; 5. Age 18-70 years. sGA mandatory for patients 65-70 years old: only category FIT admitted \[20\] (see Appendix A); 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 if not related to lymphoma disease (see Appendix B); 7. Measurable disease ≥ 1.5 cm in longest diameter, and measurable in 2 perpendicular dimensions; 8. Normal blood count defined as: neutrophils at least 1.500/mmc, platelets at least 75.000/mmc, haemoglobin at least 8,0 g/dL with transfusion independence, unless abnormalities due to underlying disease (bone marrow involvement), at the moment of signing informed consent; 9. Adequate liver function, assessed by baseline laboratory values; the increase to up to 2.5 ULN for transaminases and up to 1.5 ULN for bilirubin admitted for cases with documented liver involvement by lymphoma; 10. Adequate renal function defined as creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula; see Appendix C) 11. Subjects HBsAg negative but positive for antibodies to hepatitis B core antigen with undetectable HBV-DNA measured by real-time polymerase chain reaction (PCR). 12. Women of childbearing potential (WOCBP) and men must agree to use effective contraception if sexually active. Females of childbearing potential and males with female partners of reproductive potential should be advised to use effective contraception while receiving polatuzumab vedotin and for 9 months after the last dose of polatuzumab vedotin for female patients and for 6 months after the last dose of polatuzumab vedotin for male patients with female partners of reproductive potential. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control method (failure rate of less than 1%) e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner. The use of condoms by male patients is required (even if surgically sterilized, i.e., status post vasectomy) unless the female partner is permanently sterile. Full sexual abstinence is admitted when this is in line with the preferred and usual lifestyle of the subject, for the same time period planned for other methods of birth control (see above). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner) and withdrawal are not acceptable methods of contraception 13. WOCBP must have a negative serum (beta-human chorionic gonadotropin \[b-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study; 14. Life expectancy \> 6 months; 15. Subject understands and voluntarily signs an informed consent form approved by the National Ethics Committee prior to the initiation of any screening or study-specific procedures; 16. Subject must be able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: 1. Any histology other than DLBCL 2. Primary mediastinal lymphoma (PMBCL) 3. Known central nervous system lymphoma 4. Known history of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies 5. Contraindication to any drug in the chemotherapy regimen 6. Left ventricular ejection fraction (LVEF) \< 50% 7. Neuropathy ≥ grade 2 8. Subject is: * Seropositive for hepatitis B, defined by a positive test for hepatitis B surface antigen \[HBsAg\]. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (HBsAb positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR * Known to be seropositive for hepatitis C. EXCEPTION: Patients with presence of HCV antibody, but PCR negative for HCV-RNA are eligible * Positive for human immunodeficiency virus (HIV) infection 9. Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics 10. History of stroke or intracranial hemorrhage within the past 6 months. 11. History of clinically relevant liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic, hematologic, psychiatric, or metabolic disturbances 12. Clinically significant cardiovascular disease 13. Major surgical intervention prior 4 weeks to enrollment if not due to lymphoma and/or other disease life-threatening that can compromise chemotherapy treatment 14. Prior malignancies other than lymphoma in the last 5 years with exception of currently treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix 15. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety 16. If female, the patient is pregnant or breast-feeding 17. Patients participating in other clinical studies