FOLLICULAR LYMPHOMA; UPDATES ON TREATMENT STRATEGIES

2,500 views
2,158 views

Published on

Published in: Health & Medicine, Sports
0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,500
On SlideShare
0
From Embeds
0
Number of Embeds
6
Actions
Shares
0
Downloads
146
Comments
0
Likes
3
Embeds 0
No embeds

No notes for slide
  • .
  • .
  • Moving on to pts with HTB.
  • .
  • (2%, 3%, and 8% in R-CVP, R-CHOP, and R-FM, respectively).
  • 2 2
  • 2 2
  • 2 2
  • 2 2
  • 2 2
  • 2 2
  • 2 2
  • 2 2
  • Even in pts with high tum burder.
  • 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.
  • Some DLBCLs req tonic stimuation of the BCR-BCR signalling is hence an attractv target for amny agents.
  • FOLLICULAR LYMPHOMA; UPDATES ON TREATMENT STRATEGIES

    1. 1. MJRMJR 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. 2. MJRMJR Grade 1-2 Follicular Lymphoma Limited Stage Advanced Stage, Stage II bulky or ‘B’ Curative Intent Radiotherapy Asymptomatic, Low tumor burden Symptomatic, High tumor burden Watch and Wait Chemotherapy/ Immunotherapy CR or PR 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? Consolidation RIT or Maintenance Rituximab GELF Criteria
    3. 3. MJRMJR 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. 4. MJRMJR Horning S, SA Rosenberg. NEJM 1984;311:1471-76 Watch and Wait in FL
    5. 5. MJRMJR Tan D, Horning S, et al. ASH 2007. Abstract 3428 Overall Survival of 1,333 FL Patients at Stanford by Time to First Treatment P<0.001
    6. 6. MJRMJR
    7. 7. MJRMJR Median FU: 32 months
    8. 8. MJRMJR Time To Initiation of New Therapy Ardeshna KM et al. ASH 2010 Abstract 6
    9. 9. MJRMJR 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. 10. MJRMJR • progression within 6 months of Rtx • failure to respond to Rtx • inability to complete protocol • initiation of alternative therapy. wks
    11. 11. MJRMJR RESORT: Time to First Cytotoxic Therapy 3-yr Freedom from First Cytotoxic Chemo MR: 95% RR: 86% Median FU : 3.8 yrs
    12. 12. MJRMJR Ave Doses of Rtx Received 4.5 15.8
    13. 13. MJRMJR Grade 1-2 Follicular Lymphoma Advanced Stage, Stage II bulky or ‘B’ Symptomatic, High tumor burden Chemotherapy/ Immunotherapy Clinical Questions : •Is there still a role for watch and wait in rituximab era? •What is the optimal frontline therapy? •Role of maintenance rituximab?
    14. 14. MJRMJR RCTs on R-Chemo vs Chemo Marcus et al Salles et al Hiddeman et al Harold et alWhich R-Chemo for induction ?
    15. 15. MJRMJR Federico M, et al. ASCO 2012: Abstract 8006 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)
    16. 16. MJRMJR Time-to-Treatment Failure (R-CHOP vs R-CVP vs R-FM) Federico M, et al. ASCO 2012: Abstract 8006
    17. 17. MJRMJR Adverse Events (≥grade 3) (R-CHOP vs R-CVP vs R-FM) Federico M, et al. ASCO 2012: Abstract 8006 Second Malignancies: 2% 3% 8%
    18. 18. Bendamustine-Rituximab (B-R) vs CHOP-R Bendamustine-RituximabBendamustine-Rituximab (N=139)(N=139) - Bendamustine 90 mg/m- Bendamustine 90 mg/m22 day 1+2day 1+2 -Rituximab 375 mg/mRituximab 375 mg/m22 day 1day 1 CHOP-RituximabCHOP-Rituximab (N=140)(N=140) - Cyclophosphamide 750 mg/m- Cyclophosphamide 750 mg/m22 day 1day 1 - Doxorubicin 50 mg/m- Doxorubicin 50 mg/m22 day 1day 1 - Vincristine 1.4 mg/m- Vincristine 1.4 mg/m22 day 1day 1 - Prednisone 100 mg days 1-5Prednisone 100 mg days 1-5 - Rituximab 375 mg/mRituximab 375 mg/m22 day 1day 1 FollicularFollicular WaldenströmWaldenström’’ss Marginal zoneMarginal zone Small lymphocyticSmall lymphocytic Mantle cell (elderly)Mantle cell (elderly) RRRR StiL NHL 1-2003StiL NHL 1-2003 Courtesy of Mathias RummelLancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3)Lancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3) Median follow-up 45 monthsMedian follow-up 45 months
    19. 19. MJRMJR Number (%) of patientsNumber (%) of patients Treatment groupTreatment group Grade 2Grade 2 Grade 3Grade 3 Grade 4Grade 4 Grade 3-4Grade 3-4 LeukocytesLeukocytes CHOP-RCHOP-R 39 (15)39 (15) 110 (44)110 (44) 71 (28)71 (28) 181 (72)181 (72) (10(1099 /L)/L) B-RB-R 80 (30)80 (30) 85 (32)85 (32) 13 (5)13 (5) 98 (37)98 (37) NeutrophilsNeutrophils CHOP-RCHOP-R 19 (8)19 (8) 70 (28)70 (28) 103 (41)103 (41) 173 (69)173 (69) (10(1099 /L)/L) B-RB-R 61 (23)61 (23) 53 (20)53 (20) 24 (9)24 (9) 77 (29)77 (29) LymphocytesLymphocytes CHOP-RCHOP-R 72 (29)72 (29) 87 (35)87 (35) 19 (8)19 (8) 106 (43)106 (43) (10(1099 /L)/L) B-RB-R 38 (14)38 (14) 122 (46)122 (46) 74 (28)74 (28) 196 (74)196 (74) HemoglobinHemoglobin CHOP-RCHOP-R 84 (33)84 (33) 10 (4)10 (4) 2 (<1)2 (<1) 12 (5)12 (5) (g/L)(g/L) B-RB-R 44 (16)44 (16) 6 (2)6 (2) 2 (<1)2 (<1) 8 (3)8 (3) PlateletsPlatelets CHOP-RCHOP-R 20 (8)20 (8) 11 (4)11 (4) 5 (2)5 (2) 16 (6)16 (6) (10(1099 /L)/L) B-RB-R 19 (7)19 (7) 15 (6)15 (6) 2 (<1)2 (<1) 13 (5)13 (5) Worst CTCAE Grades for Hematology Tests ResultsWorst CTCAE Grades for Hematology Tests Results Courtesy of Mathias Rummel
    20. 20. ToxicitiesToxicities (all CTC-grades)(all CTC-grades) B-R (n=261)B-R (n=261) CHOP-R (n=253)CHOP-R (n=253) (no. of pts)(no. of pts) (no. of pts)(no. of pts) PP valuevalue AlopeciaAlopecia -- ++++++ < 0.0001< 0.0001 ParesthesiasParesthesias 1818 7373 < 0.0001< 0.0001 StomatitisStomatitis 1616 4747 < 0.0001< 0.0001 Skin (erythema)Skin (erythema) 4242 2323 = 0.0122= 0.0122 Allergic reaction (skin)Allergic reaction (skin) 4040 1515 = 0.0003= 0.0003 Infectious complicationsInfectious complications 9696 127127 = 0.0025= 0.0025 - Sepsis- Sepsis 11 88 = 0.0190= 0.0190 Courtesy of Mathias Rummel
    21. 21. MJRMJR B-RB-R CHOP-RCHOP-R (n=261)(n=261) (n=253)(n=253) PP valuevalue ORRORR 92,7 %92,7 % 91,3 %91,3 % CRCR 39,8 %39,8 % 30,0 %30,0 % = 0.021= 0.021 SDSD 2,7 %2,7 % 3,6 %3,6 % PDPD 3,5 %3,5 % 2,8 %2,8 % Results Response ratesResults Response rates Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3)Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3)
    22. 22. MJRMJR PFS: follicular (n=279)PFS: follicular (n=279) 45 months follow-up45 months follow-up Median (months)Median (months) B-RB-R n. y. r.n. y. r. CHOP-RCHOP-R 40.940.9 0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 Hazard ratio, 0.61 (95% CI 0.42 - 0.87)Hazard ratio, 0.61 (95% CI 0.42 - 0.87) p = 0.0072p = 0.0072 0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel
    23. 23. MJRMJR PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)PFS: follicular, FLIPI low (0-2) (n=152; 54.5%) Median (months)Median (months) B-RB-R n. y. r.n. y. r. CHOP-RCHOP-R 46.646.6 Hazard ratio, 0.56 (95% CI 0.31 - 0.98)Hazard ratio, 0.56 (95% CI 0.31 - 0.98) p = 0.0428p = 0.0428 0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel
    24. 24. MJRMJR PFS: follicular, FLIPI high (3-5) (n=127; 45.5%)PFS: follicular, FLIPI high (3-5) (n=127; 45.5%) 0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 Hazard ratio, 0.63 (95% CI 0.38 - 1.04)Hazard ratio, 0.63 (95% CI 0.38 - 1.04) p = 0.0679p = 0.0679 Median (months)Median (months) B-RB-R 53.453.4 CHOP-RCHOP-R 34.934.9 0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel
    25. 25. MJRMJR 0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 Median (months)Median (months) B-RB-R 53.653.6 CHOP-RCHOP-R 31.531.5 Age: 61 yrs and older ( n = 315 )Age: 61 yrs and older ( n = 315 ) Hazard ratio, 0.62 (95% CI 0.45 - 0.84)Hazard ratio, 0.62 (95% CI 0.45 - 0.84) p = 0.0022p = 0.0022 0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel
    26. 26. MJRMJR 0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 Age: 60 yrs and younger ( n = 199 )Age: 60 yrs and younger ( n = 199 ) Median (months)Median (months) B-RB-R 71.671.6 CHOP-RCHOP-R 30.930.9 Hazard ratio, 0.52 (95% CI 0.33 - 0.79)Hazard ratio, 0.52 (95% CI 0.33 - 0.79) p = 0.0022p = 0.0022 0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel
    27. 27. MJRMJR 0.00.0 0.10.1 0.20.2 0.30.3 0.40.4 0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0 Overall survivalOverall survival 2 yrs2 yrs 3 yrs3 yrs 4 yrs4 yrs 5 yrs5 yrs 6 yrs6 yrs 7 yrs7 yrs 89.7%89.7% 85.6%85.6% 82.3%82.3% 80.1%80.1% 80.1%80.1% 75.9%75.9% 89.5%89.5% 86.7%86.7% 84.2%84.2% 77.8%77.8% 75.5%75.5% 59.5%59.5% B-RB-R CHOP-RCHOP-R 0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel
    28. 28. MJRMJR Grade 1-2 Follicular Lymphoma Advanced Stage, Stage II bulky or ‘B’ Symptomatic, High tumor burden 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 ? BR >RCHOP> RCVP – DO WE REALLY NEED CHEMO UPFRONT ? •Role of maintenance rituximab? •What is the optimal sequence of treatment?
    29. 29. MJRMJR ?
    30. 30. The Kiss of Death in Follicular Lymphoma Ramsay, et al. The Kiss of Death in FL. Blood 2011; 118: 5365-5366 Laurent, et al. Distribution, function, and prognostic value of cytotoxicT lymphocytes in FL. Blood 2011;118(20):5371-5379 CTL: Cytotoxic T lymphocyte, FL: follicular lymphoma
    31. 31. Lenalidomide: Mechanisms of Action in Lymphoma 1. 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):4713-4720. 2. 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;14:4650-4657
    32. 32. 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
    33. 33. Study Design Lenalidomide 20mg Days 1-21 Cycles 1-6* Months 1 2 3 4 5 6 Rituximab 375mg/M2 Day 1 of Cycles 1-6 If clinical benefit, can proceed to 12 cycles •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 R= RESTAGING R Lenalidomide 20mg Days 1-21 Cycles 7-12* Rituximab 375mg/M2 Day 1 of Cycles 7-12 R RR 7 8 9 10 11 12 *SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg)
    34. 34. Response Rates 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) 0 0 2(2) 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
    35. 35. PFS (months) Percentsurvival 0 12 24 36 0 20 40 60 80 100 Progression Free Survival N=103 36 mo PFS*:78% *Projected 3 year PFS All Evaluable Patients Courtesy of Nathan Fowler
    36. 36. Grade ≥ 3 Hematologic Toxicity 5 patients developed grade 3 neutropenic fever
    37. 37. 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
    38. 38. 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
    39. 39. Grade 1-2 Follicular Lymphoma Advanced Stage, Stage II bulky or ‘B’ Symptomatic, High tumor burden Chemotherapy/ Immunotherapy CR or PRClinical Question : •Role of maintenance rituximab? Consolidation RIT or Maintenance Rituximab
    40. 40. MJRMJR Salles G, et al. Lancet 2010; 377: 42–51 R-Maintenance vs Observation After R-Chemo Induction (PRIMA)
    41. 41. MJRMJR
    42. 42. MJRMJR Time to next lymphoma treatment Overall SurvivalTime to next Chemotherapy Progression Free Survival Median follow-up: 36 months 75% 58% Salles G, et al. Lancet 2010; 377: 42–51
    43. 43. MJRMJR
    44. 44. MJRMJR Salles G, et al. Lancet 2010; 377: 42–51 Grade 3 / 4 Adverse Events P=0.0026 Fulminant Hep B (n=1)
    45. 45. MJRMJR 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-RB-R is less toxic and more effective than CHOP-R • Impressive data with frontline IMiD + RImpressive data with frontline IMiD + R • Maintance rituximabMaintance 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
    46. 46. MJRMJR Thank You
    47. 47. MJRMJR
    48. 48. MJRMJR
    49. 49. MJRMJR Rituximab era Aggressive chemo/ Purine analogue Anthracycline Pre- anthracycline
    50. 50. MJRMJR Comparison of Observed vs Expected survival in follicular lymphoma Tan D, et al. J Clin Oncol 2008 (suppl; abstr 8535)J Clin Oncol 2008 (suppl; abstr 8535)
    51. 51. MJRMJR 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)J Clin Oncol 2008 (suppl; abstr 8535)
    52. 52. B-Cell Lymphomas Express Several Antigens that can be Targeted
    53. 53. Novel Strategies in B-cell Lymphoma: Targeting B-cell Receptor Signaling

    ×