Shortened vs Standard Chemotherapy Combined With Immunotherapy for the Initial Treatment of Patients With High Tumor Burden Follicular Lymphoma

Inclusion Criteria:

1. Histologically documented diagnosis of CD20+ Follicular lymphoma grade 1-2 or 3a, asdefined in the 2017 edition of the World Health Organization (WHO) classification;

2. Age ≥ 18 years;

3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix B);

4. No previous immunochemotherapy for the lymphoma (localized radiotherapy or rituximabmonotherapy with max of 4 doses are allowed);

5. Ann Arbor stage II-IV (Appendix A);

6. High tumor burden as per Groupe d'Etude des Lymphomes Folliculaires (GELF) criteriadefined as the presence of at least one of the following:

• systemic symptoms;

• Tumor bulk (any nodal or extranodal tumor mass with diameter > 7 cm);

• involvement of ≥ 3 nodal sites, each with a diameter ≥ 3 cm;

• splenomegaly;

• compressive syndrome (organ compression);

• serous effusion;

• circulant malignant cells;

• cytopenia;

• Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) > 1;

• Lactate dehydrogenase (LDH) > upper limit of normality (ULN);

• β2-microglobulin > 3 mg/L.

7. At least one site of measurable nodal disease at baseline ≥ 1.5 cm in the longesttransverse diameter as determined by CT scan (MRI is allowed if CT scan cannot beperformed); or evaluable disease at baseline FDG-PET (18F-fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET)) scan (at least one metabolic active siteof disease);

8. Adequate hematological counts (unless due to bone marrow involvement by lymphoma)defined as follows:

9. Absolute Neutrophil count (ANC) > 1.5 x 109/L;

10. Platelet count ≥ 80 x 109/L ;

11. Hemoglobin ≥ 10 g/dL.

12. Adequate renal function defined as creatinine ≤ 2 mg/dL, unless secondary tolymphoma;

13. Adequate hepatic function defined as bilirubin ≤ 2 mg/dL, unless secondary tolymphoma;

14. Left Ventricular Ejection Fraction (LVEF) > 50% at bidimensional echocardiogram (mandatory only for patients receiving R/G-CHOP);

15. Life expectancy ≥ 6 months;

16. Subject understands and voluntarily signs an informed consent form approved by anIndependent Ethics Committee (IEC) prior to the initiation of any screening orstudy-specific procedures;

17. Subject must be able to adhere to the study visit schedule and other protocolrequirements;

18. Women of childbearing potential (WOCBP) and men must agree to use effectivecontraception if sexually active. This applies for the time period between signingof the informed consent form and 12 months after last rituximab dose or 18 monthsafter last obinutuzumab dose. A woman is considered of childbearing potential, i.e.fertile, following menarche and until becoming postmenopausal unless permanentlysterile. Permanent sterilization methods include but are not limited tohysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausalstate is defined as no menses for continuous 12 months without an alternativemedical cause. A high follicle stimulating hormone (FSH) level in the postmenopausalrange may be used to confirm a postmenopausal state in women not using hormonalcontraception or hormonal replacement therapy. The investigator or a designatedassociate is requested to advise the patient how to achieve highly effective birthcontrol (failure rate of less than 1%) e.g., intrauterine device (IUD), intrauterinehormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner. Theuse of condoms by male patients is required (even if surgically sterilized, i.e.,status post vasectomy) unless the female partner is permanently sterile. Full sexualabstinence is admitted when this is in line with the preferred and usual lifestyleof the subject, for the same time period planned for other methods of birth control (see above). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner) and withdrawal are not acceptable methodsof contraception).

Exclusion Criteria:

1. Histological diagnosis different from FL grade 1-3a WHO 2017 classification;

2. Suspect or clinical evidence of Central Nervous System (CNS) involvement bylymphoma;

3. Contraindication to the use of anti-CD20 monoclonal antibodies;

4. Subject has received any anticancer therapy (chemotherapy, immunotherapy,investigational therapy, including targeted small molecule agents) within 14 daysprior to the first dose of study drug;

5. Noteworthy history of neurologic, psychiatric, endocrinological, metabolic,immunologic, or hepatic disease that would preclude participation in the study orcompromise ability to give informed consent;

6. Any history of other active malignancies within 3 years prior to study entry, withthe exception of: adequately treated in situ carcinoma of the cervix uterine; basalcell carcinoma of the skin or localized squamous cell carcinoma of the skin; limitedstage surgically removed breast cancer or adequately treated with radiation therapy;limited stage prostate carcinoma surgically removed or adequately treated withradiation therapy; previous malignancy confined and surgically resected withcurative intent;

7. Evidence of other clinically significant uncontrolled condition(s) including, butnot limited to:

• Uncontrolled and/or active systemic infection (viral, bacterial or fungal),including active ongoing infection from SARS-CoV-2;

• Chronic or acute hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.Note: subjects with serologic evidence of prior vaccination to HBV (i.e., HBsAgnegative, HBsAb positive and HBcAb negative) or positive HBcAb from previousinfection or intravenous immunoglobulins (IVIG) may participate; inactivecarriers (HBsAg positive with undetectable HBV- DNA) are eligible. Patientswith presence of HCV antibody are eligible only if Polymerase Chain Reaction (PCR) negative for HCV-RNA;

8. Women who are pregnant or breastfeeding.