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Follicular Lymphoma: Updates on Treatment Strategies Daryl Tan Raffles Cancer Center Visiting Consultant Singapore General Hospital Adjunct.

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Presentation on theme: "Follicular Lymphoma: Updates on Treatment Strategies Daryl Tan Raffles Cancer Center Visiting Consultant Singapore General Hospital Adjunct."— Presentation transcript:

1 Follicular Lymphoma: Updates on Treatment Strategies Daryl Tan Raffles Cancer Center Visiting Consultant Singapore General Hospital Adjunct Assistant Professor, Duke-NUS Graduate Medical School

2 Grade 1-2 Follicular Lymphoma
Limited Stage Advanced Stage, Stage II bulky or ‘B’ GELF Criteria Curative Intent Radiotherapy Asymptomatic, Low tumor burden Symptomatic, High tumor burden Watch and Wait Chemotherapy/ Immunotherapy Clinical Questions : Is there still a role for watch and wait in rituximab era? What is the optimal frontline therapy? Which R-Chemo? Role of maintenance rituximab? . CR or PR Consolidation RIT or Maintenance Rituximab

3 Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’ Asymptomatic, Low tumor burden Watch and Wait Clinical Questions : Is there still a role for watch and wait in rituximab era? .

4 Watch and Wait in FL Horning S, SA Rosenberg. NEJM 1984;311:

5 Overall Survival of 1,333 FL Patients at Stanford
by Time to First Treatment P<0.001 Tan D, Horning S, et al. ASH Abstract 3428

6

7 Median FU: 32 months

8 Time To Initiation of New Therapy
Ardeshna KM et al. ASH 2010 Abstract 6

9 Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’ Asymptomatic, Low tumor burden Watch and Wait Clinical Questions : Is there still a role for watch and wait in rituximab era? Role of maintenance rituximab?

10 wks progression within 6 months of Rtx failure to respond to Rtx inability to complete protocol initiation of alternative therapy.

11 RESORT: Time to First Cytotoxic Therapy
3-yr Freedom from First Cytotoxic Chemo MR: % RR: % Median FU : 3.8 yrs

12 Ave Doses of Rtx Received
4.5 15.8

13 Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’ Symptomatic, High tumor burden Clinical Questions : Is there still a role for watch and wait in rituximab era? What is the optimal frontline therapy? Role of maintenance rituximab? Chemotherapy/ Immunotherapy Moving on to pts with HTB.

14 RCTs on R-Chemo vs Chemo Which R-Chemo for induction ?
Marcus et al Salles et al Which R-Chemo for induction ? Hiddeman et al Harold et al

15 Phase III Study of R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: final results of the FOLL05 trial from the Fondazione Italiana Linfomi (N=534) . Federico M, et al. ASCO 2012: Abstract 8006

16 Time-to-Treatment Failure (R-CHOP vs R-CVP vs R-FM)
Federico M, et al. ASCO 2012: Abstract 8006

17 Adverse Events (≥grade 3) (R-CHOP vs R-CVP vs R-FM)
Second Malignancies: 2% % % (2%, 3%, and 8% in R-CVP, R-CHOP, and R-FM, respectively). Federico M, et al. ASCO 2012: Abstract 8006

18 Bendamustine-Rituximab (B-R) vs CHOP-R
StiL NHL Bendamustine-Rituximab (N=139) - Bendamustine 90 mg/m2 day 1+2 Rituximab 375 mg/m2 day 1 Follicular Waldenström’s Marginal zone Small lymphocytic Mantle cell (elderly) R CHOP-Rituximab (N=140) - Cyclophosphamide 750 mg/m2 day 1 - Doxorubicin 50 mg/m2 day 1 - Vincristine 1.4 mg/m2 day 1 Prednisone 100 mg days 1-5 Rituximab 375 mg/m2 day 1 Median follow-up 45 months Lancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3) Courtesy of Mathias Rummel

19 Worst CTCAE Grades for Hematology Tests Results
Number (%) of patients Treatment group Grade 2 Grade 3 Grade 4 Grade 3-4 Leukocytes CHOP-R 39 (15) 110 (44) 71 (28) 181 (72) (109/L) B-R 80 (30) 85 (32) 13 (5) 98 (37) Neutrophils CHOP-R 19 (8) 70 (28) 103 (41) 173 (69) (109/L) B-R 61 (23) 53 (20) 24 (9) 77 (29) Lymphocytes CHOP-R 72 (29) 87 (35) 19 (8) 106 (43) (109/L) B-R 38 (14) 122 (46) 74 (28) 196 (74) Hemoglobin CHOP-R 84 (33) 10 (4) 2 (<1) 12 (5) (g/L) B-R 44 (16) 6 (2) 2 (<1) 8 (3) Platelets CHOP-R 20 (8) 11 (4) 5 (2) 16 (6) (109/L) B-R 19 (7) 15 (6) 2 (<1) 13 (5) Courtesy of Mathias Rummel 2 2

20 Toxicities (all CTC-grades)
B-R (n=261) CHOP-R (n=253) (no. of pts) (no. of pts) P value Alopecia < Paresthesias < Stomatitis < Skin (erythema) = Allergic reaction (skin) = Infectious complications = - Sepsis 1 8 = Courtesy of Mathias Rummel

21 Results Response rates
B-R CHOP-R (n=261) (n=253) P value ORR 92,7 % 91,3 % CR 39,8 % 30,0 % = 0.021 SD 2,7 % 3,6 % PD 3,5 % 2,8 % Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3) 2 2

22 PFS: follicular (n=279) 45 months follow-up
1.0 Median (months) B-R n. y. r. CHOP-R 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.61 (95% CI ) p = 0.1 0.0 months Courtesy of Mathias Rummel 2 2

23 PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)
1.0 Median (months) B-R n. y. r. CHOP-R 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.56 (95% CI ) p = 0.1 0.0 months Courtesy of Mathias Rummel 2 2

24 PFS: follicular, FLIPI high (3-5) (n=127; 45.5%)
1.0 Median (months) B-R CHOP-R 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.63 (95% CI ) p = 0.1 0.0 months Courtesy of Mathias Rummel 2 2

25 Age: 61 yrs and older ( n = 315 ) Median (months) 1.0 B-R 53.6
CHOP-R 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.62 (95% CI ) p = 0.1 0.0 months Courtesy of Mathias Rummel 2 2

26 Age: 60 yrs and younger ( n = 199 )
1.0 Median (months) B-R CHOP-R 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.52 (95% CI ) p = 0.1 0.0 months Courtesy of Mathias Rummel 2 2

27 Overall survival 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 1.0 0.9 0.8 B-R
0.7 0.6 CHOP-R 0.5 0.4 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 89.7% 85.6% 82.3% 80.1% 80.1% 75.9% 89.5% 86.7% 84.2% 77.8% 75.5% 59.5% 0.3 0.2 0.1 0.0 months Courtesy of Mathias Rummel 2 2

28 Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’ Symptomatic, High tumor burden Clinical Questions : Is there still a role for watch and wait in rituximab era? What is the optimal frontline therapy? Which R-Chemo ? BR >RCHOP> RCVP DO WE REALLY NEED CHEMO UPFRONT ? Role of maintenance rituximab? What is the optimal sequence of treatment? Chemotherapy/ Immunotherapy Even in pts with high tum burder.

29

30 ?

31 The Kiss of Death in Follicular Lymphoma
CTL: Cytotoxic T lymphocyte, FL: follicular lymphoma Ramsay, et al. The Kiss of Death in FL. Blood 2011; 118: Laurent, et al. Distribution, function, and prognostic value of cytotoxicT lymphocytes in FL. Blood 2011;118(20):

32 Lenalidomide: Mechanisms of Action in Lymphoma
Ramsay AG, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21): Lei W, et al. Lenalidomide Enhances Natural Killer Cell and Monocyte-Mediated Antibody-Dependent Cellular Cytotoxicity of Rituximab-Treated CD20+ Tumor Cells. Clin Cancer Res 2008;14:

33 Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study
Nathan Fowler, Sattva Neelapu, Frederick Hagemeister, Peter McLaughlin, Larry W Kwak, Jorge Romaguera, Michele Fanale, Luis Fayad, Robert Orlowski, Michael Wang, Francesco Turturro, Yasuhiro Oki, Linda Lacerte, Felipe Samaniego Department of Lymphoma/Myeloma MD Anderson Cancer Center, Houston, Texas Courtesy of Nathan Fowler

34 Lenalidomide 20mg Days 1-21 Cycles 1-6*
Study Design Months Lenalidomide 20mg Days 1-21 Cycles 1-6* Lenalidomide 20mg Days 1-21 Cycles 7-12* Rituximab 375mg/M2 Day 1 of Cycles 7-12 R Rituximab 375mg/M2 Day 1 of Cycles 1-6 R R R= RESTAGING If clinical benefit, can proceed to 12 cycles *SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg) Phase II, single institution Planned Enrollment N= 50 Follicular lymphoma (grade I/II) N=30 Small lymphocytic lymphoma N=30 Marginal zone lymphoma Groups analyzed independently for response and toxicity

35 Response Rates *7 pts not evaluable for response:
SLL (N=30) Marginal (N=27)* Follicular (N=46)* All Patients Eval (N=103) ITT (N=110) ORR, n (%) 24 (80) 24(89) 45(98) 93(90) 93(85) CR/Cru 8(27) 18(67) 40(87) 66(64) 66(60) PR 16(53) 6(22) 5(11) 27(26) 27(25) SD, n (%) 4(13) 3(11) 1(2) 8(8) 8(7) PD, n (%) 2(7) 2(2) *7 pts not evaluable for response: 5 due to adverse event in cycle 1 1 due to non-compliance 1 due to withdrawal of consent Courtesy of Nathan Fowler

36 Progression Free Survival
All Evaluable Patients N=103 36 mo PFS*:78% *Projected 3 year PFS Courtesy of Nathan Fowler

37 Grade ≥ 3 Hematologic Toxicity
5 patients developed grade 3 neutropenic fever

38 Grade ≥ 3 Non Hematologic Adverse Events (>1 pt.)
Five secondary malignancies reported 75 yo: recurrent bladder cancer 53 yo: localized melanoma 53 yo: stage 0 DCIS of breast 81 yo: multiple myeloma 75 yo: recurrent localized prostate cancer

39 RELEVANCE Study Design (Rituximab and LEnalidomide versus Any ChEmotherapy)
1st line FL N=1000 R R2 R + Chemo R2 Maintenance Rituximab Maint. R+Chemo: Investigator’s choice of R-CHOP, R-CVP, BR Lenalidomide 20mg for 6 cycles, then 10mg if CR LYSA (PI: Morschhauser) + North America (PI: Fowler) Courtesy of Nathan Fowler

40 Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’ Symptomatic, High tumor burden Chemotherapy/ Immunotherapy Clinical Question : Role of maintenance rituximab? CR or PR Consolidation RIT or Maintenance Rituximab

41 R-Maintenance vs Observation After R-Chemo Induction (PRIMA)
Salles G, et al. Lancet 2010; 377: 42–51

42

43 Median follow-up: 36 months
Progression Free Survival Time to next lymphoma treatment 75% 58% Time to next Chemotherapy Overall Survival Salles G, et al. Lancet 2010; 377: 42–51

44

45 Grade 3 / 4 Adverse Events Salles G, et al. Lancet 2010; 377: 42–51
P=0.0026 Fulminant Hep B (n=1) Salles G, et al. Lancet 2010; 377: 42–51

46 Conclusions -BTG 2013 Certainly still a role for watchful waiting
R-FM a/w increased toxicity B-R is less toxic and more effective than CHOP-R Impressive data with frontline IMiD + R Maintance rituximab Observed improvements in PFS and Time to Next Tx not been shown to translate into OS benefit MR should be weighed against increased risk of toxicity, other potential complications, resources and pt’s preference

47 Thank You

48 This is the 2013 NCCN hot off the press
This is the 2013 NCCN hot off the press. Prob not surprising that flu now no longer recommended upfront . Options have been narrowed down. In terms of efficacy, we know that BR> RCHOP> RCVP, Before we jump in and hail BR king of the hill, let me ask a more provocative question.

49

50

51 Rituximab era Aggressive chemo/ Purine analogue Anthracycline Pre- anthracycline

52 Comparison of Observed vs Expected survival in follicular lymphoma
Tan D, et al. J Clin Oncol 2008 (suppl; abstr 8535)

53 Impacts of Frontline and Salvage Tx on OS- The Stanford Experience
EFS1 OS-post first relapse Tan D, et al. J Clin Oncol 2008 (suppl; abstr 8535)

54 B-Cell Lymphomas Express Several Antigens that can be Targeted

55 Novel Strategies in B-cell Lymphoma:
Targeting B-cell Receptor Signaling Some DLBCLs req tonic stimuation of the BCR-BCR signalling is hence an attractv target for amny agents.

56 Follicular Lymphoma Response: Tumor Burden, Molecular Response
BY GELF CRITERIA N=46 GELF (+) HIGH TUMOR BURDEN N=22 (48%) GELF (-) HIGH TUMOR BURDEN N=24 (52%) SD PR CR/Cru ORR 1 (5%) 21(95%) 100% 1(4%) 4(17%) 19 (79%) 96% BY BULK OF DISEASE N=46 BULKY N=13 (28%) NON-BULKY N=33 (72%) SD PR CR/CRu ORR 1(8%) 12(92%) 100% 1(3%) 4 (12%) 28 (85%) 97% MOLECULAR RESPONSE N=44 (eval) PCR POSITIVE PCR NEGATIVE PRETREATMENT 17(41%) 26(59%) POST CYCLE 3 5(11%) 39(89%) POST CYCLE 6 2(5%) 42(95%) Bone marrow and peripheral blood for major or minor breakpoint 1. Brice P, et al. JCO 1997: 15:1110–1117.


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