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Grade 1-2 Follicular Lymphoma

Follicular Lymphoma: Updates on Treatment Strategies Daryl Tan Raffles Cancer Center Visiting Consultant Singapore General Hospital Adjunct Assistant Professor, Duke-NUS Graduate Medical School. Grade 1-2 Follicular Lymphoma. Limited Stage. Advanced Stage, Stage II bulky or ‘ B ’.

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Grade 1-2 Follicular Lymphoma

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  1. Follicular Lymphoma: Updates on Treatment StrategiesDaryl TanRaffles Cancer CenterVisiting Consultant Singapore General HospitalAdjunct Assistant Professor,Duke-NUS Graduate Medical School

  2. Grade 1-2 Follicular Lymphoma Limited Stage Advanced Stage, Stage II bulky or ‘B’ GELF Criteria Symptomatic, High tumor burden Asymptomatic, Low tumor burden Curative Intent Radiotherapy Chemotherapy/ Immunotherapy Watch and Wait 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;311:1471-76

  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 2007. Abstract 3428

  6. Median FU: 32 months

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

  8. 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?

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

  10. RESORT: Time to First Cytotoxic Therapy 3-yr Freedom from First Cytotoxic Chemo MR: 95% RR: 86% Median FU : 3.8 yrs

  11. Ave Doses of Rtx Received 4.5 15.8

  12. 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

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

  14. 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 FondazioneItalianaLinfomi (N=534) Federico M, et al. ASCO 2012: Abstract 8006

  15. Time-to-Treatment Failure (R-CHOPvsR-CVPvsR-FM) Federico M, et al. ASCO 2012: Abstract 8006

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

  17. Bendamustine-Rituximab (B-R) vs CHOP-R StiL NHL 1-2003 • 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

  18. 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

  19. Toxicities(all CTC-grades) B-R (n=261) CHOP-R (n=253) (no. of pts) (no. of pts)P value Alopecia - +++ < 0.0001 Paresthesias 18 73 < 0.0001 Stomatitis 16 47 < 0.0001 Skin (erythema) 42 23 = 0.0122 Allergic reaction (skin) 40 15 = 0.0003 Infectious complications 96 127 = 0.0025 - Sepsis 1 8 = 0.0190 Courtesy of Mathias Rummel

  20. 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)

  21. Median (months) B-R n. y. r. CHOP-R 40.9 PFS: follicular (n=279) 45 months follow-up 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.61 (95% CI 0.42 - 0.87) p = 0.0072 0.1 0.0 0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel

  22. Median (months) B-R n. y. r. CHOP-R 46.6 PFS: follicular, FLIPI low (0-2) (n=152; 54.5%) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.56 (95% CI 0.31 - 0.98) p = 0.0428 0.1 0.0 0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel

  23. Median (months) B-R 53.4 CHOP-R 34.9 PFS: follicular, FLIPI high (3-5) (n=127; 45.5%) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.63 (95% CI 0.38 - 1.04) p = 0.0679 0.1 0.0 0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel

  24. Median (months) B-R 53.6 CHOP-R 31.5 Age: 61 yrs and older ( n = 315 ) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.62 (95% CI 0.45 - 0.84) p = 0.0022 0.1 0.0 0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel

  25. Median (months) B-R 71.6 CHOP-R 30.9 Age: 60 yrs and younger ( n = 199 ) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.52 (95% CI 0.33 - 0.79) p = 0.0022 0.1 0.0 0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel

  26. Overall survival 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 0 12 24 36 48 60 72 84 96 months Courtesy of Mathias Rummel

  27. 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

  28. ?

  29. 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: 5365-5366 Laurent, et al. Distribution, function, and prognostic value of cytotoxicT lymphocytes in FL. Blood 2011;118(20):5371-5379

  30. 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):4713-4720. 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

  31. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study Nathan Fowler, SattvaNeelapu, 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

  32. Study Design 7 8 9 10 11 12 Lenalidomide 20mg Days 1-21 Cycles 1-6* Months 1 2 3 4 5 6 Lenalidomide 20mg Days 1-21 Cycles 7-12* Rituximab 375mg/M2 Day 1 of Cycles 1-6 Rituximab 375mg/M2 Day 1 of Cycles 7-12 R R R= RESTAGING R R 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

  33. Response Rates • *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

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

  35. Grade ≥ 3 Hematologic Toxicity 5 patients developed grade 3 neutropenic fever

  36. 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

  37. RELEVANCE Study Design(Rituximab and LEnalidomide versus Any ChEmotherapy) R2 R2 Maintenance 1st line FL N=1000 R R+ Chemo RituximabMaint. • 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

  38. 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

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

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

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

  42. 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

  43. Thank You

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