RITUXIMAB PLUS LENALIDOMIDE IN FOLLICULAR LYMPHOMA

Rituxiamb plus Lenalidomide in advanced untreated Follicular Lymphoma journal presentation

1. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma ( RELEVANCE Trial) SPEAKER DR. KHUSHBOO GARG MEDICINE RESIDENT (BHU)

2. FOLLICULAR LYMPHOMA Follicular lymphoma are the second most frequent subtype of non- Hodgkin’s lymphoma. It constitute 22% of non- Hodgkin’s lymphoma worldwide. Median age of presentation is 59 years. These lymphoma have a chromosomal translocation of t(14;18) and abnormal expression of BCL-2 protein. The most common presentation for follicular lymphoma is with new, painless lymphadenopathy. B symptoms present in 28% patients. Bone marrow involvement in 42% patients. Staging is carried out by according to Ann Arbor Classification ranges from stage I to IV, with higher stage indicating more extensive disease. 10-15% patients are in stage I and II . Harrison’s Principle of Internal Medicine, 19 th edition

3. To be continued… Staging Evaluation for Follicular Lymphoma includes- Physical examination Documentation of B symptoms Laboratory evaluation- Complete blood counts Liver function tests Uric acid Calcium Serum β2- microglobulin Chest radiograph CT scan of abdomen, pelvis, and usually chest Bone marrow biopsy PET – CT is considered to confirm localized disease before involved – field radiotherapy or in the case of suspected transformation.

4. To be continued.. Evaluation of an adequate lymph node biopsy is sufficient to make a diagnosis of follicular lymphoma. The tumor is composed of small cleaved and large cells in varying proportion organized in a follicular pattern of growth. Patients with follicular lymphoma with predominantly large cells have a higher proliferative fraction, progress more rapidly, and have a shorter overall survival with simple chemotherapy regimens. Histological report of lymph node biopsies graded according to WHO classification . Grade 1, 2 and 3a should be treated as indolent disease. Grade 3b is considered an aggressive lymphoma treated as DLBCL . ESMO Clinical Practice Guidelines 2016

5. To be continued… For prognostic purposes , a ‘Follicular Lymphoma-specific International Prognostic Index’ (FLIPI) has been established. A revised FLIPI 2 has been suggested for patients requiring treatment which may be more informative on progression-free survival (PFS). Fewer than 10% patients have a high IPI score . ESMO clinical practice guidelines 2016

6. TREATMENT of FOLLICULAR LYMPHOMA The natural course of the disease is characterized by spontaneous regressions in 10%–20% of cases and varies significantly from case to case, therapy should be initiated according to GELF criteria for high tumour burden in FL . ESMO clinical practice guidelines 2016

7. ESMO clinical practice guidelines 2016

8. ESMO clinical practice guidelines 2016

9. ESMO clinical practice guidelines 2016

10. LENALIDOMIDE – MECHANISM OF ACTION Lenalidomide is an immunomodulatory agent that binds the cereblon E3 ubiquitin ligase complex, which results in degradation of transcription factors Aiolos (IKZF3) and Ikaros (IKZF1). In malignant lymphoma B cells, this degradation results in up-regulation of interferon stimulated genes and apoptosis. In T cells, the degradation results in enhanced IL-2 secretion, which leads to T-cell activation, thereby indirectly activating NK cells. Combining lenalidomide with rituximab enhances apoptosis and antibody-dependent cell-mediated cytotoxicity of B-cell non-Hodgkin’s lymphoma cells more effectively than monotherapy. American Society Of Haematology 2015

11. STUDY DESIGN Interventional study ( clinical trial) Phase 3 superiority trial Open label Multi- center (137 centers) Randomized 1030 patients underwent randomization from Dec 2011 to Nov 2014. 513 patients in the rituximab- lenalidomide group and 517 patients in the rituximab – chemotherapy group. Among the patients in the rituximab–chemotherapy group, 372 (72%) received R-CHOP, 117 (23%) received R-B, and 28 (5%) received R-CVP. To assess the efficacy and safety in previously untreated follicular lymphoma cases.

12. STUDY OBJECTIVES- Primary objectives – To compare efficacy in treatment groups. - Complete Response Rate (CR/ CRu ) at 120 weeks. - Progression free survival (PFS) by using the IWG ( Cheson , 1999) criteria.

13. 2. Secondary objectives- To compare the other parameters of efficacy in treatment groups: o Event Free Survival (EFS), o Time to Next Anti-Lymphoma Treatment (TTNLT), o Overall Survival (OS) Overall Response Rate (ORR) To compare the safety of rituximab plus lenalidomide versus rituximab plus chemotherapy .

14. INCLUSION CRITERIA Histologically confirmed CD 20 + follicular lymphoma grade 1, 2 or 3a. Have no prior systemic treatment for lymphoma Must be in need of treatment as evidenced by at least one of the GELF criteria. Age ≥18 years and sign an informed consent. Stage II, III or IV disease . Eastern Cooperative oncology group performance status 0-2. Willing to follow pregnancy precautions. Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow) within 28 days prior to signing informed consent, including: Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 /L Platelet count ≥ 75 x 10 9 /L Hemoglobin ≥ 8.0 g/dl

15. EXCLUSION CRITERIA Clinical evidence of transformed lymphoma . Grade 3b follicular lymphoma. Known seropositive for or active viral infection with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) Known sensitivity or allergy to murine products. Life expectancy < 6 months Presence or history of central nervous system involvement by lymphoma At high risk for a venous thromboembolic event (VTE) and not willing to take VTE prophylaxis. Pregnant or lactating females. Any of the following laboratory abnormalities: serum aspartate transaminase or alanine transaminase > 3x upper limit of normal (ULN), except in patients with documented liver involvement by lymphoma total bilirubin > 2.0 mg/dl (34 µmol/L) except in cases with documented liver or pancreatic involvement by lymphoma - creatinine clearance of < 30 mL/min

16. RANDOMIZATION, TREATMENT AND FOLLOW-UP

17. INTERVENTION 1030 patients were randomly assigned, in a 1:1 ratio, to the rituximab-lenalidomide group (513 patients) or rituximab – chemotherapy group (517 patients). Randomization was stratified according to the Follicular Lymphoma International Prognostic Index (FLIPI) score, age (≤60 vs. >60 years), lesion size (≤6 vs. >6 cm) and disease stage. EXPERIMENTAL ARM (Rituximab- Lenalidomide group) Lenalidomide dose 20-mg on days 2-22 every 28 days for 6 cycles, if CR then 10-mg on days 2-22 every 28 days for 12 cycles. PR after 6 cycles, continue 20 mg for 3~6 cycles and then 10 mg on days 2-22 every 28-day cycles for up to 18 cycles. Rituximab, 375 mg/m2 on days 1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.

18. to be continued…. STANDARD ARM (Rituximab – Chemotherapy group) Patients randomized to receive investigators choice will receive ONE of the following Rituximab-CHOP : with six cycles of R-CHOP in 21 day cycles followed by two 21 day cycles of 375 mg/m2 rituximab and 7 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles, OR Rituximab-CVP : with eight cycles of R-CVP in 21 day cycles; and 7 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles, OR Rituximab- Bendamustine : with rituximab 375 mg/m2 (day 1) plus bendamustine 90 mg/m2 (days 1 + 2) every 28 days for six cycles; and 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles. The total treatment duration was 120 weeks for both study arms.

19. EFFICACY OBJECTIVES OUTCOMES-

20. Kaplan-Meier Curve of Progression- free Survival and Overall Survival

21. Subgroup Analysis of Confirmed or Unconfirmed Complete Response at 120 weeks .

22. Subgroup Analysis of Progression Free Survival

23. HISTOLOGIC TRANFORMATION The rate of histologic transformation at first disease progression was evaluated as a prespecified exploratory end point. Among the 102 patients who had progression, a total of 17 patients (10 of 49 patients in the rituximab–lenalidomide group and 7 of 53 patients in the rituximab–chemotherapy group) had histologic transformation. Majority had transformations to DLBCL (9/10 in R 2 arm and 7/7 in R-chemo arm), and 1 patient had granulocytic sarcoma (R 2 arm).

24. ADVERSE EVENTS -

25. DISCUSSION Overall, the efficacy of rituximab plus lenalidomide was similar to that of rituximab plus chemotherapy in terms of complete response at 120 weeks and progression free survival at 3 years in previously untreated follicular lymphoma patients. Superiority was not shown for either regimen. Differences in safety profiles were noted between the two groups, with a higher incidence of grade 3 or 4 neutropenia and febrile neutropenia of any grade with rituximab plus chemotherapy and a higher incidence of grade 3 or 4 cutaneous reactions with rituximab plus lenalidomide. The rate of histologic transformation was less than 1% per year similar in both groups , which was well within the historical rate of 2 to 3% per year. At the time of the current follow-up, second primary cancers were reported in 38 patients (7%) in the rituximab– lenalidomide group and 48 patients (10%) in the rituximab–chemotherapy group. A limitation inherent to the current analysis is the limited follow-up time for time-to-event end points. Longer follow-up with more mature survival data will be needed to assess long-term outcomes

26. IWG (Cheson,1999) CRITERIA-

27. CTCAE GRADING Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical intervention/therapy required Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; no or minimal medical intervention/therapy required Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalization is possible Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care probable Grade 5 = Death - the event results in death]

28. The doses of CHOP components are: Cyclophosphamide, 750 mg/m2 IV on day 1 Doxorubicin, 50 mg/m2 IV on day 1 Vincristine, 1.4 mg/m2 (2 mg cap) IV on day 1 Prednisone, 100 mg/day PO on days 1-5