This study will evaluate the efficacy of Pixantrone with rituximab, ifosfamide and etoposide as measured by the overall metabolic response rate after 2 cycles of treatment or at permanent treatment discontinuation.

This study will evaluate the efficacy of Pixantrone with rituximab, ifosfamide and etoposide as measured by the overall metabolic response rate after 2 cycles of treatment or at permanent treatment discontinuation.

Inclusion Criteria:

1. Histologically proven CD20+ aggressive non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL), de novo or transformed DLBCL from previously untreated low grade non-Hodgkin lymphoma or grade 3b follicular lymphoma) as per the World Health Organization (WHO) 2016 criteria

2. Relapsed or refractory disease, defined as follows:

   1. Patients eligible for ASCT who failed to achieve a Complete Response (CR) after at least one salvage therapy (eg, Rituximab-Etoposide- Methylprednisolone - Cytarabine - Cisplatin (R-ESHAP) or Rituximab- Dexamethasone- High-dose Cytarabine - Cisplatin (R-DHAP), patients who were previously refractory to Rituximab-Ifosfamide-Cytarabine-Etoposide (R-ICE) (stable disease or progressive disease) are not eligible to the study)
   2. Or patients in first relapse after Autologous Stem Cell Transplant (ASCT)
   3. Or patients not eligible for ASCT who failed to achieve a CR after at least one prior treatment (and no more than 4 previous lines) or in relapse after at least one prior treatment (and no more than 4 previous lines).

3. Age > or =18 years

4. Eastern Cooperative Oncology Group (ECOG) performance status < or = 2

5. Subjects must have evaluable disease based on positron emission tomography (PET-CT) scan

6. Minimum life expectancy of 6 months

7. Signed written informed consent

8. Patient covered by any social security system

9. Men must agree to use a barrier method of contraception during the treatment period and until 6 months after the last dose of chemotherapy

10. Women of childbearing potential must agree to use an adequate method of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception during the treatment period and until 12 months after the last dose of chemotherapy

Exclusion Criteria:

1. Any other histological type of lymphoma (Burkitt lymphoma, mantle-cell lymphoma…)

2. Any history of previously treated indolent non-Hodgkin lymphoma

3. Symptomatic central nervous system or meningeal involvement by the lymphoma

4. Contraindication to any drug contained in the Pixantrone with rituximab, ifosfamide and etoposide regimen

5. Treatment with any investigational drug within 28 days before the first study drug administration

6. Any of the following lab abnormalities unless related to the lymphoma or bone marrow infiltration:

   1. Absolute neutrophil count (ANC) < 1.0 G/L
   2. Platelet count < 100 G/L
   3. Creatinine clearance < 40 mL/min for patients < 70 y, or creatinine clearance < 60 mL/min for patients > or = 70 y, by Modification of Diet in Renal Disease (MDRD) method.
   4. Total bilirubin level > 1,5 x Upper Limit of Normal (ULN)
   5. Serum ASpartate Transaminase (AST) or ALanine Transaminase (ALT)> 2,5x ULN

7. Known Human Immunodeficiency Virus (HIV) positive

8. Active hepatitis C virus (HCV) (Positive HCV serology with positive Polymerase Chain Reaction (PCR) for HCV RNA)

9. Active hepatitis B (HB) :

   1. HBsAg positive
   2. HBsAg negative, Ac anti-HBs positive and/or Ac anti-HB core (HBc) positive (Patients who are seropositive due to a history of hepatitis B vaccine are eligible. Patients with Ac anti-HBs positive and/or Ac anti-HBc positive and no history of hepatitis B vaccine are eligible only if PCR for HB virus DNA is negative)

10. Cumulative dose of doxorubicine or equivalent > 450mg/m2

11. Left ventricular ejection fraction (LVEF) < 50% measured by echocardiography or isotopic method

12. Congestive heart failure (any stage from New York Heart Association (NYHA) classification)

13. Uncontrolled arterial hypertension

14. Severe rhythmic heart disease

15. Uncontrolled ischemic heart disease, including patients with stable angina

16. Significant valvular heart disease

17. History of a myocardial infarction within 6 months prior to enrolment

18. Pregnant or lactating females

19. Prior history of malignancies with the exception of non-melanoma skin tumors (basal cell or squamous cell carcinoma) or in situ cervical carcinoma

20. Any serious active disease or co-morbid medical condition according to the investigator's decision

21. Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness

22. Use of any standard or experimental anti-cancer drug therapy within 28 days before the first study drug administration

23. Use of corticosteroids prior to baseline PET-CT

24. Person deprived of his/her liberty by a judicial or administrative decision

25. Person hospitalized without consent

26. Adult person under legal protection