Follicular lymphoma

Oncology lecture about follicular lymphoma

1. Follicular lymphoma DR.Hatem Eletripy

2. Follicular lymphomas (FLs) are the second most frequent subtype of nodal lymphoid malignancies in Western Europe. The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5/100 000 recently. Mounier M, Bossard N, Remontet L et al .. Lancet Haematol 2015; 2: e481–e491. Incidence

3. Pathobiology FL is thought to arise from germinal center B cells, both centrocytes (small cleaved follicular center cells) and centroblasts ( large noncleaved follicular center cells ). The pathogenesis of FL is incompletely understood. Approximately 85 percent of FL have the t(14;18), which results in the overexpression of B cell leukemia/lymphoma 2 ( BCL2 ), an oncogene that blocks programmed cell death (apoptosis), leading to prolonged cell survival. Morin RD, et al. Nature. 2011

4. t(14;18)(q32;q21) This juxtaposes the bcl2 gene downstream from the immunoglobulin heavy chain promoter, resulting in overexpression of bcl2 protein Bcl-2 protein : antiapoptotic functions : Long lived accumulating lymphocytes t(14;18)(q32;q21) then predisposes to further oncogenic mutations

5. Grading of Follicular Lymphomas Centrocytes : small or medium-sized cells with cleaved nucleoli Centroblasts : large cells with round or oval nucleus and several membrane bound nucleoli

6. Grades: WHO Classification Grade Syn. % Centroblasts/HPF I FL, small cleaved 5% 0-5 II FL, mixed 31% 6-15 III FL, large noncleaved 64% >15 IIIa (14%): centrocytes are still present IIIb (50%): solid sheets of centroblasts, with no residual centrocytes.

7. Prognosis 1)FLIPI 2)FLIPI-2 3)M7 FLIPI

8. 1)Follicular Lymphoma International Prognostic Index (FLIPI) Characteristic RR (Death ) Solal-Céligny , et al. Blood. 2004;104:1258-1265.

9. Overall Survival According to FL-IPI

10. 2) FLIPI2  — The Follicular Lymphoma International Prognostic Index 2 (FLIPI2) FLIPI2 score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point) ● Age >60 years. ● Bone marrow involvement. ● Hemoglobin level <12.0  g/ dL . ● Greatest diameter of the largest involved node >6 cm. ● Serum beta-2 microglobulin level greater than the upper limit of norma l

11. Federico M, et al. J Clin Oncol . 2009;27:4555-4562. Subsequent studies have confirmed the prognostic value of the FLIPI2 in patients treated with rituximab-containing therapy . Bachy et al, Blood. 2018;132(1):49. Epub 2018 Apr 17

12. 3) m7-FLIPI The m7-FLIPI is a prognostic model that incorporates 1- the FLIPI 2-the Eastern Cooperative Oncology Group (ECOG) performance status. 3-the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11 ). Pastore A et al, Lancet Oncol. 2015 Sep;16(9):1111-22. Epub 2015 Aug 6.

13. a high risk group (28% of patients) with five-year (FFS) of 38% (enriched with mutations in EP300 and CREBBP.) a low-risk group (72% of patients) with a five-year FFS of 77% (mutations in EZH2,MEF2B & ARID1A ) Interestingly , approximately half of patients classified as high risk according to FLIPI were categorized as low risk using M7FLIPI(due to mut in EZH2 )

14. Staging

15. Risk groups Grade III (centroblasts > 15 /HPF) Stage III,IV Symptomatic Stage III,IV Asymptomatic Stage I,II FL grade 1-2 FL grade 3 Treated as DLCL

16. Management of early stages In the small proportion of patients with localized disease (stage I-II) at diagnosis, involved site RT (24-36 Gy ) is considered the standard due to its curative potential. In stage I–II patients with large tumour burden, adverse clinical or biological prognostic features or when local radiotherapy is not applicable (e.g. lung, liver), systemic therapy as indicated for advanced stages should be applied. Friedberg JW et,al . analysis of the National LymphoCare Study . J Clin Oncol 2012; 30: 3368–3375

17. Indications of Tratment in advanced disease( lll ,lV ).

18. Asymptomatic patients international phase III trial, 379 patients with advanced-stage, asymptomatic, non-bulky FL were randomly assigned to initial management with one of three strategies: watchful waiting;  Rituximab induction (rituximab 375 mg/m 2  weekly for four doses ) Rituximab induction followed by maintenance rituximab (administered every two months for two years ).

19. Phase III Study: Rituximab vs Watchful Waiting in Asymptomatic FL Watchful waiting with regular clinic visits (n = 187) Rituximab 375 mg/m 2 wkly for 4 wks (n = 84) Mo 3 Pts with asymptomatic stage II, III, IV nonbulky FL (N = 463) Rituximab 375 mg/m 2 wkly for 4 wks (n = 192) Rituximab 375 mg/m 2 every 2 mos Mo 7 CT scan* Regular clinic visits Mo 13 CT scan if clinical CR* Mo 25 CT scan* *If CT shows CR, bone marrow assessed for histology and minimal residual disease. Continued follow-up Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.

20. Ardeshna KM, et al. Lancet Oncol . 2014;15:424-435.

21. Rituximab therapy was associated with improved ratings on quality of life measures, reflecting a decrease in anxiety. There was no difference in OS or rate of HT .

22. Maintenance Ritux imab Multicenter trial (RESORT) 408 patients with low tumor burden previously untreated FL received four weekly doses of  rituximab. The 299 patients (73 percent) who achieved a complete or partial response were randomly assigned to rituximab maintenance every three months until progression or to observation and re-treatment with rituximab at the time of progression

23. Kahl BS, et al. J Clin Oncol. 2014;32:3096-3102. Maintenance Rituximab vs Retreatment in Low Tumor Burden FL: Phase III E4402 (RESORT) Primary endpoint: time to treatment failure Secondary endpoints: time to first cytotoxic chemotherapy, safety/toxicity, QoL Pts with FL and low tumor burden who received frontline rituximab* (N = 408) Maintenance Rituximab 375 mg/m 2 every 3 mos (n = 146) Retreatment at Progression Rituximab 375 mg/m 2 /wk x 4 until Tx failure (n = 143) Pts with CR or PR (N = 289) Continue until rituximab treatment failure Median follow-up: 4.5 yrs *375 mg/m 2 /wk for 4 wks. Stratified by age (< 60 vs ≥ 60 yrs ) and time from diagnosis (< 1 vs ≥ 1 yr )

24. Kahl BS etal , J Clin Oncol . 2014 Oct;32(28):3096-102. Epub 2014 Aug 25.  Estimated OS at five years was similar in both groups (94 percent), and there was no difference in the rate of histologic transformation Wagner LI et al, J Clin Oncol . 2015;33(7):740. Epub 2015 Jan 20.

25. Choice of chemotherapy

26. Choice of Chemotherapy

27. Phase III StiL NHL 1-2003 Study: Frontline BR vs R-CHOP in MCL or CD20+ iNHL Primary endpoint: noninferiority of BR vs R-CHOP for PFS (decrease < 10% at 3 yrs ) Rummel MJ, et al. Lancet. 2013;381:1203-1210. Treatment-naive pts with MCL or indolent CD20-positive lymphoma (N = 514) BR (n = 274) R-CHOP (n = 275) bendamustine (90 mg/m2 on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1・4 mg/m2 on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles

28. Rummel MJ, et al. Lancet. 2013;381:1203-1210.

29. PFS (69.5 versus 31.2 months, with less toxicity, including lower rates of grade 3 and 4 neutropenia (29 versus 69 percent) and leukocytopenia (37 versus 72 percent), fewer infectious episodes (37 versus 50 percent), less paresthesia (7 versus 29 percent), less stomatitis (6 versus 19 percent), and no alopecia. There was no difference in OS (70 versus 66 percent at 10 years ). The number of second malignancies was similar between the two treatment arms (39 versus 47 cases). Rummel MJ ,et al J Clin Oncol . 2017;35 

30. New lines of treatment

31. The GALLIUM study international , open-label, randomized phase III trial comparing an obinutuzumab -based induction and maintenance strategy versus a rituximab-based induction and maintenance strategy in 1202 patients with previously untreated advanced stage FL. Participating treatment centers selected one of the following chemotherapy regimens to use with the antibody for induction:  bendamustine (57 percent), CHOP (33 percent), or CVP (10 percent). Patients responding to induction received up to two years of maintenance with the same antibody they received during induction.

32.   At a median follow-up of 41 months : Superior PFS (83 versus 79 percent at three years; in the group as a whole and, on post-hoc subset analysis, among those receiving a backbone of  bendamustine  or CHOP.

33. Lenalidomide plus rituximab  

34. International , open-label phase III trial (RELEVANCE) 1030 patients with treatment-naïve advanced FL were randomly assigned to R 2  or chemoimmunotherapy . In each arm, treatment was given for a total of 30 months. R 2  was administered for 18 months and followed by one year of  rituximab  maintenance. Chemoimmunotherapy with R-CHOP (72 percent), BR (23 percent), or R-CVP (5 percent) was administered for approximately six months and followed by two years of maintenance therapy.

35. At a median follow-up of 38 months, R 2   ● Similar rates of complete remission (48 versus 53 percent ). ●Higher rates of dose reduction (36 versus 14 percent), dose interruption (59 versus 35 percent), or early treatment discontinuation (11 versus 3 percent ). ●More rash (43 versus 24 percent), diarrhea (37 versus 19 percent), and tumor flare (6 versus <1 percent ). ●Fewer episodes of severe neutropenia (32 versus 50 percent) and febrile neutropenia (2 versus 7 percent), less growth factor use (23 versus 68 percent), and less nausea, vomiting, and neuropathy.

36. Maintenance Rituximab

37. Untreated pts with high-tumor burden FL Induction Immunochemotherapy 8 cycles R-CHOP or R-CVP or R-FCM Rituximab maintenance 375 mg/m 2 q8w for 2 yrs (n = 505) Observation (n = 513) Response* (N = 1019) *Only pts with CR/ CRu /PR randomized to maintenance therapy; 1 pt died during randomization. Stratified by response to induction, chemotherapy regimen, and geographic location prior to 1:1 randomization Salles GA, et al. ASH 2013. Abstract 509. PRIMA: Rituximab Maintenance vs Observation in Pts With FL

38. Rituximab Maintenance vs Observation in Patients With FL: Survival Salles GA, et al. ASH 2013. Abstract 509. Rituximab Observation PFS According to Maintenance (ITT Pts) OS According to Maintenance (ITT Pts) 6 yrs = 42.7% 6 yrs: 59.2% HR: 0.57 P < .0001 1.0 0.8 0.6 0.4 0.2 Probability 10 20 30 40 50 60 70 80 90 Mos + Censored Log-rank P < .0001 6 yrs: 87.4% 6 yrs: 88.7% HR: 1.027 P = .885 1.0 0.8 0.6 0.4 0.2 Probability 10 20 30 40 50 60 70 80 90 Mos + Censored Log-rank P = .8846

39. Relapsed or Refractory follicular lymphoma A biopsy should be taken. the previous lines of treatment. What is the current situation? Patient age/comorbidities Disease-related symptoms Tumor burden

40.  relapsed or refractory follicular lymphoma

41. Lines of treatment

42. -Immunotherapy with single agent rituximab - Chemoimmunotherapy with an anti-CD20 antibody as   obinutuzumab  or  rituximab plus chemotherapy -Novel agents ( eg ,  lenalidomine ,   idelalisib ,   copanlisib ). Radioimmunotherapy (RIT) with radiolabeled antibodies. The main treatment options for patients with symptomatic late relapse include :

43. Choice of anti-CD20 antibody For most patients with relapsed or refractory FL being treated with chemotherapy, obinutuzumab suggested rather than rituximab. This preference is largely based on a randomized trial ( GADOLIN ) that demonstrated an OS benefit for   bendamustine plus obinutuzumab when compared with single agent bendamustine in the relapsed setting

44. Phase III GADOLIN: Bendamustine ± Obinutuzumab in Refractory CD20+ iNHL Open-label, international trial Primary endpoint: PFS assessed independently Secondary endpoints: investigator-assessed PFS, OS, responses, safety, PK, PROs Sehn LH et,al Lancet Oncol. 2016;17(8):1081. Epub 2016 Jun 2 Rituximab-refractory CD20-positive indolent NHL (N = 413) Up to 6 28-day cycles Bendamustine 90 mg/m 2 /day IV Days 1, 2 + Obinutuzumab 1000 mg IV Days 1, 8, 15 cycle 1; Day 1 cycles 2-6 Bendamustine 120 mg/m 2 /day IV Days 1, 2 CR/PR/SD Obinutuzumab maintenance 1000 mg IV q2m For 2 yrs or until PD Stratified by NHL subtype (FL vs other), prior therapies (≤ 2 vs > 2), refractory type, and geographic region

45. Cheson et al, journa of clinical oncology VOLUME 36 NUMBER 22 AUGUST 1, 2018

46. Lenalidomide Lenalidomide  plus  rituximab  (R 2 ) and lenalidomide plus   obinutuzumab  (O-R) are acceptable alternatives for the treatment of late or early relapse. In a phase II trial, 91 patients with relapsed or refractory FL were randomly assigned to single agent  lenalidomide  or to R 2   . The addition of  rituximab  improved the response rate (76 versus 53 percent) and median time to progression (2 versus 1.1 years) but did not improve survival Leonard JP et,al J Clin Oncol . 2015 Nov;33(31):3635-40. Epub 2015 Aug 24. 

47. CALGB 50401: Study Design Randomized phase II trial Median follow-up: 2.5 yrs (range: 0.1-4.8) Primary endpoint: ORR Secondary endpoints: TTP, OS Leonard J, et al. J Clin Oncol . 2015;33:3635-3640 . Pts with FL who relapsed following ≥ 1 rituximab-based regimen (N = 91) Rituximab + Lenalidomide (n = 46) Lenalidomide (n = 45) 12 x 28-day cycles Lenalidomide  plus  Rituximab  (R 2 )

48. Pi3k inhibitors

49. Idelalisib Idelalisib  is approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with relapsed FL who have received at least two prior systemic therapies.

50. Phase II Study 101-09: Idelalisib Monotherapy in Refractory iNHL Key eligibility criteria: Previously treated iNHL (FL, MZL, SLL, WM) Refractory to BOTH rituximab and an alkylating agent Defined as less than PR or PD within 6 mos Documented radiologically Primary endpoint: ORR Secondary endpoints: DOR PFS OS Time to response Safety Quality of life Idelalisib 150 mg BID Therapy maintained until progression, toxicity, or death Enrolled April 2011 to October 2012 Long-term follow-up Gopal A, et al. N Engl J Med. 2014;370:1008-1018. Single-arm study (N = 125)

51. Other pi3k inhibitors copanlisib  is   is an intravenous inhibitor of PI3K alpha and delta approved by the US Food and Drug administration as a single agent for the treatment of patients with relapsed FL who have received at least two prior systemic therapies. Duvelisib  is approved by the US Food and Drug Administration as a single agent for the treatment of patients with relapsed FL who have received at least two prior systemic therapies

52. A meta-analysis of nine trials including 2586 adult patients with FL reported that patients who received maintenance   rituximab demonstrated superior rate of OS compared with patients who were observed or treated with rituximab at the time of relapse but not for those with previously untreated FL. Higher rates of severe (grade 3 or 4) toxicities, especially infection related adverse events. Maintenance Rituximab in relapsed refrctory follicular lymphoma

53. Maintenance after second line

54. Radioimmunotherapy   Ibritumomab tiuxetan is a murine anti-CD20 monoclonal antibody conjugated to the radioisotope yttrium-90 that is approved by the US Food and Drug Administration for the treatment of patients with relapsed or refractory Follicular lymphoma

55. Prospective trials of RIT demonstrate response rates of 60 to 80 percent in previously treated disease Median PFS is less than one year, but patients who achieve a CR have a median time to progression of close to four years . Witzig TE et al, Cancer . 2007;109(9):1804.

56. Thank you