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Chemotherapy for PTCL

Chemotherapy for PTCL. Julie M. Vose, M.D. University of Nebraska Medical Center. Overall Survival. PTCL-NOS Cases by IPI. Test: p<0.001. 1.0. 0.9. 0.8. 0.7. 0.6. Proportion. 0.5. 0.4. 0.3. 0.2. 0.1. 0.0. 0. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

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Chemotherapy for PTCL

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  1. Chemotherapy for PTCL Julie M. Vose, M.D. University of Nebraska Medical Center

  2. Overall Survival PTCL-NOS Cases by IPI Test: p<0.001 1.0 0.9 0.8 0.7 0.6 Proportion 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time IPI CENSOR FAIL TOTAL MEDIAN 0/1 36 47 83 5.03 2 36 67 103 2.1 3 20 53 73 1.41 4/5 9 38 47 0.68

  3. Overall Survival PTCL-NOS Cases by Anthracycline Initial Tx 1.0 0.9 Test: p=0.14 0.8 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Anthracycline as part of initial tx CENSOR FAIL TOTAL MEDIAN yes 98 173 271 2.1 no 14 34 48 1.57

  4. Overall Survival PTCL-NOS Cases by Carbo/Cisplatin Initial Tx 1.0 0.9 Test: p=0.46 0.8 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Carbo/Cisplatin as part of initial tx CENSOR FAIL TOTAL MEDIAN yes 2 6 8 2.01 no 110 200 310 2.1

  5. PTCL - Therapy • Addition of novel agents to induction therapy • High-dose chemotherapy and autologous stem cell transplant in PR1/CR1 • Improved /novel agents for salvage therapy • ? Allogeneic stem cell transplantation to take advantage of GVL effect

  6. CD2 CD25 (IL-2Ra CD52 Malignant or Activated T Cell CD122 (IL-2R/IL-15Rb CD3 CD30 CD4 Receptor-directed Therapy in T cell Lymphoma

  7. ONTAK + CHOP First-line Treatment of PTCL • Phase II, Multicenter, Open-label, Single-arm • 48 subsites • Up to 50 newly diagnosed patients • Regimen • ONTAK 18 mcg/kg/d Days 1 & 2, followed by CHOP Days 3-7 of each cycle x 6 cycles • Objectives • ORR, TTP, Safety • Potential amendment • Consolidation ONTAK in patients who achieve CR

  8. DA-EPOCH-Alemtuzumab in Untreated Peripheral T-Cell Lymphoma • Study Rationale • Chemotherapy/monoclonal antibody combinations have improved survival in Diffuse Large B-Cell Lymphoma • EPOCH-A schedule 3 6 9 12 15 18 1 Dose level 1 30 mg Dose level 2 60 mg Dose level 3 90 mg EPOCH: Alemtuzumab: NCI

  9. A Phase II Study of Alemtuzumab in Combination with CHOP and ESHAP as a First-Line Treatment in PTCL Tanin Intragumtornchai, Udomsak Bunvorasate, Thanyaphong NaNakorn, Ponlapat Rotnuckkarin Division of Hematology Department of Medicine Faculty of Medicine Chulalongkorn University, Bangkok, Thailand

  10. M M M M M C E E C E C M = MabCampath 30 mg sc. D1-3; C= CHOP; E = ESHAP Treatment Schedule

  11. A Phase II Study of SGN-30 in Combination with CHOP in Anaplastic Large Cell LymphomaNCI-CTEP PI: Barbara Pro, MD M.D. Anderson Cancer Center

  12. Study Summary Within 4 weeks of initiation of therapy CTs H &P PS BM biopsy PET scan SGN-30 12 mg/kg Weekly for 3 weeks Restaging SGN-30 + CHOP q 21 days 6-8 cycles • Correlative studies • Serum CD30 before 1st dose of SGN-30 • Ln Bx before the 1st and after the 3rd dose of SGN-30

  13. Siplizumab in CD2 Lymphoproliferative Disease Deirdre O’Mahony, MD National Cancer Institute

  14. Cohort 8-10 Phase I MEDI-507 MEDI-507 Dosing Follow-up 1 2 3 4 5 6 7 8 9 10 12 14 16 Weeks Disease Evaluation Disease Evaluation Disease Evaluation Safety Evaluation for Dose Escalation *MEDI-507 administered week 1,3 and weekly thereafter for total 16 treatments or until PD, toxicity, or other reasons

  15. Cohort 1-7 Phase I MEDI-507 MEDI-507 Dosing Follow-up LTFU 1 2 3 4 5 6 7 8 9 10 11 13 14 15 16 12 Weeks Disease Evaluation Disease Evaluation Disease Evaluation Disease Evaluation Safety Evaluation for Dose Escalation *MEDI-507 received over 2-3 consecutive days per week (depending on cohort), every other week for 16 weeks or until PD, toxicity, or other reasons

  16. Cohort 8-10 Phase I MEDI-507 MEDI-507 Dosing Follow-up 1 2 3 4 5 6 7 8 9 10 12 14 16 Weeks Disease Evaluation Disease Evaluation Disease Evaluation Safety Evaluation for Dose Escalation *MEDI-507 administered week 1,3 and weekly thereafter for total 16 treatments or until PD, toxicity, or other reasons

  17. GELA LNH T1st line V-ACVBP – Velcade GELA (A. Delmer, B. Coiffier) 18 – 60 yrs R A I L (GELA) C. Haioun CHOP - Mab-CHOP Intergroup – Schering (NLG ) F. D’Amore 60 – 80 yrs Genetic randomisation Auto/allo < 60 yrs In preparation « CHOP » « CHOP » Auto Mini-Allo German High Grade (N. Schmitz)

  18. Gemcitabine • Analog of ara-C with > membrane permeability and affinity for deoxycytidine kinase   cellular uptake • Self-potentiating mechanism of action  enhanced accumulation and prolonged retention within malignant cells  inhibits DNA synthesis • Expanded anti-tumor activity, including in solid tumors and lymphoma.

  19. GDP • GDP = gemcitabine (D1, D8), dexamethasone (D1-4), cisplatin (D1) - outpatient administration - in vitro evidence of synergy with cisplatin • NCIC 2 Ph II trials Relapsed aggressive NHL RR 53% Relapsed HL RR 70%

  20. Primary Treatment of PTCL with GDP • Study proposal: Primary therapy of PTCL with GDP • Eligibility: all patients with advanced stage* PTCL and limited stage PTCL with > 2 IPI RFs Histology: PTCLUS, AILT, ALK neg ALCL, ETTL, HSTCL, SCPTCL • Exclude: Cut ALCL, ALK pos ALCL and NK/T cell lymphoma to receive primary radiotherapy * Advanced = stage III/IV, bulky, B sxs

  21. N N H2N H 1 8 METHOTREXATE H H N 4 5 N 9 CH2 NH 2 COO- O = 10 H3C C - N - C - CH2 - CH2 - COO- N H H N N H2N H 1 Pralatrexate (PDX) 8 H H N 4 5 N 9 CH NH 2 COO- O H3C = 10 C - N - C - CH2 - CH2 - COO- HC H H H C – CH2

  22. TUMOR CELL cMOAT/ MRP ATPase RFC-1 Plasma membrane ATP PDX PDX PDX (& Natural Folates) FPGS PDX(G)n ATP + MgCl2 Lysosome ADP Gn PDX(G)n PDX FPGH + SH ? cysteine cysteine cysteine TMTX cysteine Compared to MTX PDX more efficiently enters tumor cells (RFC-1) and is more readily retained (FPGS)

  23. Overall Survival PTCL-NOS Cases by Stem Cell Transplant 1.0 0.9 Test: p=0.0076 0.8 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Time Hi-dose therapy (transplant) CENSOR FAIL TOTAL MEDIAN yes 21 27 48 3.5 no 63 148 211 1.95

  24. Failure-free Survival PTCL-NOS Cases by Transplant Reason 1.0 0.9 Test: p<0.001 0.8 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 Time Transplant reason CENSOR FAIL TOTAL MEDIAN inital tx 8 15 23 1.46 subseq. to recur. 0 24 24 0.71

  25. Auto PSC for PTCL and ALCL: UNMC 1 . 0 . 9 . 8 PTCL CR2+ / Rel 1 (n=8) . 7 . 6 Anaplastic CR2+ / Rel 1 (n=15) . 5 PFS Probability . 4 PTCL CR1 / PR1 (n=18) . 3 . 2 . 1 0 0 2 4 3 6 4 8 6 0 1 2 Months

  26. Auto PSC for PTCL and ALCL: UNMC 1 . 0 Anaplastic CR2+ / Rel 1 (n=15) . 9 . 8 . 7 . 6 PTCL CR1 / PR1 (n=18) Survival Probability . 5 . 4 PTCL CR2+ / Rel 1 (n=8) . 3 . 2 . 1 0 0 2 4 3 6 4 8 6 0 1 2 Months

  27. Future for PTCL Therapy • Addition of novel agents to induction therapy • New agents for salvage therapy • Directed therapy by IHC or gene expression? • ? Stem cell transplantation in CR1 • Allogeneic stem cell transplantation

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