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What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy ? Radio

What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy ? Radioimmunotherapy ! . Matthew Matasar, MD MS Assistant Member, Lymphoma and Adult BMT Services Memorial Sloan-Kettering Cancer Center New York, NY.

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What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy ? Radio

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  1. What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy? Radioimmunotherapy! Matthew Matasar, MD MS Assistant Member, Lymphoma and Adult BMT Services Memorial Sloan-Kettering Cancer Center New York, NY

  2. Radioimmunotherapy consolidation of CR1 for FL • Observation • Rituximab maintenance • Radioimmunotherapy (RIT)

  3. Radioimmunotherapy consolidation of CR1 for FL • Observation • Rituximab maintenance • Radioimmunotherapy (RIT)

  4. RIT Background 90Y Ibritumomab tiuxetan 131I Tositumomab

  5. Principles of Radioimmunotherapy for Lymphoma • Highly sensitive to radiation therapy • Targeted delivery of radiation to tumor cells • Greater exposure of tumors vs surrounding normal organs • Crossfire of particle emissions • Continuous exposure of tumor cells • Retention of anti-tumor mechanisms of the antibody • Well characterized surface antigens • CD20 (CD22, CD19, CD25)

  6. Crossfire Effect of Radiolabeled Antibodies Radiolabeled “Hot” Antibody (cause damage to tumor cells as well as adjacent normal tissues) Unlabeled “Cold” Antibody Courtesy of Andrew Zelenetz, MD

  7. Weaknesses of alternative strategies Observation Rituximab maintenance Fails to prolong OS PRIMA dosing requires 12 treatments over 2 years Patient time, lost productivity At least $38,545 incremental cost increase: higher than that of single dose of RIT • Loss of opportunity to prolong PFS • Prolonging TTNT is a valid goal

  8. RIT consolidation of first remission

  9. RIT consolidation of first remission Available data: • SWOG 9911: Phase II CHOPx6  131I-tositumomab • FIT: Phase III Dealer’s choice  90Y-ibritumomab vs. observation • SWOG 0016: Phase III RCHOPx6 vs. CHOPx6 131I-tositumomab Awaiting data: • SWOG 0801: RCHOP  131I-tositumomab  R-maintenance q3m x 4y • Fol-BRITe: BR  90Y-ibritumomab

  10. RIT consolidation: SWOG 9911 BEXXAR Dosimetric Dose Cyclophosphamide 750 mg/m2 I.V. BEXXAR Therapeutic Dose Doxorubicin 50 mg/m2 I.V. Vincristine 1.4 mg/m2 I.V. Prednisone 100 mg PO qd x 5d Day 1 22 43 64 85 106 134 141 If PR or CR CHOP #3 CHOP #1 CHOP #2 CHOP #4 CHOP #5 CHOP #6

  11. RIT consolidation: SWOG 9911 100 10% 8% 90 2% 2% 80 23% 70 49% 60 50 40 66% 30 20 39% 10 0 After CHOP After BEXXAR • NE* • SD • PR • CR/ CRu * NE = Not Evaluable. 83/90 patients were evaluable for responses. Overall response (CR+CRu+PR) was 98% in evaluable patients including 59% CR, 13% CRu, and 25% PR.

  12. RIT consolidation: SWOG 9911 100% 100% 80% 80% 60% 60% 2-yr PFS Relapse At Risk Estimate or Death 40% 40% 90 18 81% 20% 20% Median FU = 2.3 yr. 0% 0% 0 1 2 3 0 1 2 3 Years from Registration

  13. RIT consolidation: FIT

  14. RIT consolidation: FIT Start of study 6-12 weeks after last dose of induction CONSOLIDATION INDUCTION 90Y-ibritumomab (n = 207) Rituximab 250 mg/m2 days −7, 0 90Y-ibritumomab (0.4 mCi/kg)[max 32 mCi] day 0 Patients with previously untreated FL First-line therapy with CVP, CHOP, CHOP-like, chlorambucil, fludarabine combination, or rituximab combination Response CR/CRu or PR RANDOMIZATION CONTROL No further treatment(n = 202) NR PD Not Eligible CVP = cyclophosphamide, vincristine, prednisone;CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CR = complete response; CR/u = unconfirmed CR; PR = partial response; NR = no response;PD = progressive disease. Morschhauser et al. J Clin Oncol. 2008;26:5156-5164.

  15. RIT consolidation: FIT The 5-year overall PFS was 29% in the control arm compared with 47% in the 90Y-ibritumomab arm: HR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001 100 75 90Y-ibritumomab: n = 207Median PFS: 49 mo Proportion Progression Free 50 Control: n = 202 Median PFS: 15 mo 25 N F 90Y-ibritumomab 207 108 Control 202 144 0 0 12 24 36 48 60 PFS From Time of Randomization (months) At risk: 90Y-ibritumomab 207 174 133 113 98 80 Control 202 117 83 67 65 46 Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594

  16. RIT consolidation: FIT F N 90Y-ibritumomab 207 18 Control 202 22 The 5-year OS was 89% in the control arm compared with 93% in the 90Y-ibritumomab arm: HR = 1.26 (95% CI: 0.68 – 2.35); P = 0.465 100 90Y-ibritumomab: n = 207 Median PFS: > 98 mo 75 Control: n = 202 Median PFS: > 101 mo Proportion Alive 50 25 0 0 12 24 36 48 60 OS From Time of Randomization (months) At risk: 90Y-ibritumomab 207 202 195 185 172 146 Control 202 194 192 182 171 135 Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594

  17. RIT consolidation: SWOG 0016 CHOP21 x 6 RANDOMIZE • Untreated follicular lymphoma • PS 0-2 • Stage III-IV CHOP21 x 6 + R x 6 (4 pre, 2 post) CHOP21 x 6 + 131I tositumomab post

  18. RIT consolidation: SWOG 0016 CHOP21 x 6 N=27 RANDOMIZE • Untreated follicular lymphoma • PS 0-2 • Stage III-IV CHOP21 x 6 + R x 6 (4 pre, 2 post) N=279 CHOP21 x 6 + 131I tositumomab post N=276

  19. RIT consolidation: SWOG 0016 (PFS) 100% 80% CHOP-RIT 60% Median FU 4.9y CHOP-R 40% Relapse 2-Year At Risk or Death Estimate CHOP I-131 265 86 80% 20% CHOP-R 267 106 76% 2-sided, multivariate p = .11 0% 0 2 4 6 8 10 Years from Registration S0016

  20. Overall Survival: S0016 100% CHOP-R 80% CHOP-RIT Median FU 4.9y 60% 40% 2-Year At Risk Deaths Estimate CHOP I-131 265 40 93% 20% CHOP-R 267 26 97% 2-sided, multivariate p = .08 0% 0 2 4 6 8 10 Years from Registration

  21. RIT consolidation: Safety • Toxicity: Largely hematologic • Neither FIT nor other studies of standalone RIT have shown statistically significantly increased risk of MDS

  22. Conclusions • RIT consolidation of first remission prolongs PFS • Favorable safety profile, less expensive than PRIMA R-maintenance • No OS benefit for any approach, including RIT • Future directions: • Clarify incremental utility of RIT consolidation after R-chemo • Clarify utility following more current induction (e.g., BR): Fol-BRITe • Compare to, or combine with, R-maintenance: SWOG 0801

  23. What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy? Radioimmunotherapy! Matthew Matasar, MD MS Assistant Member, Lymphoma and Adult BMT Services Memorial Sloan-Kettering Cancer Center New York, NY

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