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Incidence: 2% to 8% Therapeutic strategies similar to those for NHL or ALL

Outcome In Patients With Richter′s Syndrome Treated With Chemotherapy And/or Immunotherapy With Or Without Stem Cell Transplantation. Richter’s Syndrome (RS) in CLL. Background. Incidence: 2% to 8% Therapeutic strategies similar to those for NHL or ALL Response rates: 5% to 43%

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Incidence: 2% to 8% Therapeutic strategies similar to those for NHL or ALL

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  1. Outcome In Patients With Richter′s Syndrome Treated With Chemotherapy And/or Immunotherapy With Or Without Stem Cell Transplantation

  2. Richter’s Syndrome (RS) in CLL. Background • Incidence: 2% to 8% • Therapeutic strategies similar to those for NHL or ALL • Response rates: 5% to 43% • Median survival with cytotoxic therapy: 5 to 8 months • Aim: to assess the incidence, presenting characteristics, treatment outcomes and prognostic factors

  3. Results N % CLL patients (1/1977 to 10/2004)3,986 100 Possible RS 204 5.1 Bx or FNA - proven RS (LCL) 148 3.7 Hodgkin’s Disease variant 13 0.3 CLL in accelerated phase 18 0.5 CLL with (+) Gallium scan 11 0.3 Prolymphocytic transformation 5 0.1 Other 9 0.2 LCL = large cell lymphoma

  4. Presenting Characteristics (n=148) Parameter  % Age > 60 yrs 53 Prior Rx > 1 48 LDH > 1.5 x ULN 47 Tumor size > 5cm 45 Platelets < 100K 42 Time to transformation > 5 yrs 38 β2-microglobulin > 3 x ULN 40

  5. Therapy in 130 Patients (I) • Therapy N % • Cytoreduction • Chemotherapy 79 61 • Chemo-immunotherapy 47 36 • Immunotherapy 4 3 • Subsequent SCT • Allo in remission 9 7 • Allo as salvage 8 6 • Auto in remission 3 2

  6. Therapy in 130 patients (II) Therapy N % Chemotherapy 79 61 Fludarabine or 2 - CDA - based 23 18 Hyper - CVAD & variants 21 16 CHOP 11 8 Other 24 19 Chemotherapy + Rituximab (R) 47 36 Hyper - CVAD & variants + R 35 27 FCR 7 5 CHOP + R 5 4 Immunotherapy 4 3 Rituximab / Campath 3/1 3

  7. Response by Treatment All RxChemoChemo+RImmRx Evaluable13079474 CR (%)15 (12)9 (11)6 (13)0 (0) CRu (%)3 (2)0 (0)2 (4)1 (25) PR (%)33 (25)18 (23)14 (30)1 (25) NR (%)79 (61)52 (66)25 (53)2 (50) CR+CRu+PR (%)*51 (39)27 (34)22 (47)2 (50) Chemo+R = Chemo+Rituximab; ImmRx = Immunotherapy *p=0.2 (Chemo vs. Chemo+R + ImmRx)

  8. Overall Survival in 143 Patients with RS

  9. Failure-Free Survival in 130 Treated Patients

  10. Response & Survival by Pre-Rx Features Response* Survival N=130 % PP PS 0-1 103 49 <0.001 <0.001 >1 27 4 LDH < 92767510.0050.001 (IU/L) > 9276126 b2M < 668540.0080.005 (mg/L) > 64522 Hgb < 1163240.0007 0.013 (g/dL) > 11 6653 PLT < 10053190.00010.001 (x109/L) > 1007653 Alb < 3.654240.003 <0.001 (g/dL) > 3.67450 Prior Rx0-1 63 49 0.045 0.012 > 2 63 32 Tumor <5 62 48 0.022 0.016 (cm) >5 60 28 TTT** < 5 79 47 0.027 0.027 (yrs) > 5 51 27 *Response = CR+CRu+PR; **TTT = Time to transformation

  11. Multivariate Analysis - Survival Poor risk factors P-Value P-value* PS >1 0.006 0.00002 LDH > 1.5 x ULN 0.003 0.058 PLT < 100K 0.012 NS Tumor size > 5cm 0.022 0.022 Prior therapies > 1 0.024 0.007 No allo-SCT in remission 0.002 *If SCT variable was included

  12. RS Score Tsimberidou, … Keating, JCO In Press

  13. Survival from Response to Initial Rx

  14. Conclusions • RS incidence was 3.9% in patients with CLL • Chemotherapy +/- immunotherapy followed by allogeneic SCT results in improved survival compared to other therapies • Factors predicting shorter survival are: Zubrod performance status , LDH , Platelets, tumor size , and >1 prior therapies • These above five factors were used to develop the RS score, which may be used to identify specific risk groups and to compare different therapeutic approaches

  15. Treatment Recommendations • Chemoimmunotherapy, e.g. hyper-CVAD+R, CHOP+R • Post-remission therapy with allo-SCT • Prognostic models identifying CLL patients at risk of RS should be developed and allo-SCT should be offered prior to RS transformation • Anti-viral therapy (?) (e.g. cidofovir EBV) • New approach: OFAR (oxaliplatin, fludarabine, cytarabine, rituximab)

  16. Platinum Compounds and Nucleoside Analogues in CLL • Cisplatin activates excision DNA repair mechanisms • Fludarabine and ara-C inhibit the resynthesis step of excision repair • Cisplatin is synergistic with ara-C and fludarabine • Fludarabine increases the accumulation of ara-CTP in leukemia cells • The combination of cisplatin, fludarabine and ara-C (PFA) has activity, but is toxic • Oxaliplatin is synergistic with fludarabine in vitro and has a different spectrum of clinical toxicity than cisplatin

  17. Untreated m 2.5 M fludarabine m 5 M oxaliplatin Combination Propidium Iodide Annexin V-FITC Synergistic Killing of CLL by Oxaliplatin and Fludarabine F 100 80 60 O O + F Apoptotic Cell Death (%) 40 20 0

  18. Analysis of Oxaliplatin-Induced DNA Inter-Strand Cross Links in DHFR of CLL CellsAction of Fludarabine + Fludarabine Control 0 100 200 400 100 200 400 mM oxaliplatin Double Strand Single Strand

  19. 1.4 100 1.2 75 1.0 0.8 % ICL remaining 50 0.6 0.4 25 0.2 0.0 0 0 4 8 0 400 200 Hr after drug removal Oxaliplatin-induced Interstrand Cross Links in DNA of CLL CellsAction of Fludarabine Fludarabine Fludarabine ICL/10 kb Oxaliplatin, mM

  20. Oxaliplatin-Induced Interstrand Cross Links in CLL DNAActions of Nucleoside Analogs

  21. O F C O Oxaliplatin in Therapy of Aggressive CLLActions ofFludarabine/ara-C Hours

  22. Course 1 OFAR Doses and Schedule Oxaliplatin 25 mg/m2 Fludarabine 30 mg/m2 Cytarabine 1000 mg/m2 Rituximab 375 mg/m2 1 2 3 4 8 15 22 29 Day Courses 2-6 1 2 3 4 8 15 22 29 Day

  23. OFAR • Current Accrual: 36 • Phase I / II • 17.5 mg/m2 = 4 (1 NE) • 20 mg/m2 = 8 • 25 mgm2 = 21 • Phase II ongoing at 25 mg/m2/day • Max phase II = 34

  24. Courses Administered OFAR – Phase I Updated 3/9/05

  25. OFAR-Related Non-Hematologic Toxicities by Dose Level Updated 3/9/05

  26. Hematologic Toxicities Updated 3/9/05

  27. Demographics of 10 Richter’s Syndrome Patients--OFAR Characteristic Value Median (range) Age Years 71 (46-78) LDH N<618 IU/L 900 (461-2074) b2Micro. N < 2 mg/L 4.9 (3.1-12.2) # Prior Rx 2 (0-10)

  28. Response to OFAR by Clinical Characteristics—Richter’s Syndrome Characteristic Value Pts. OR (%) Age <70 4 2 (50) >70 6 4 (67) LDH <2N 6 5 (83) >2N 4 1 (25) b2Micro. <2.5 N 5 4 (80) >2.5 N 5 2 (40)

  29. Response to OFAR by DoseRichter’s Syndrome Oxaliplatin Dose Pts. CR PR OR% 17.5 mg/m2 2 0 0 0 20.0 mg/m2 5 2 2 80 25.0 mg/m2 3 1 1 67

  30. Response to OFAR by Cytogenetics or FISH in Richter’s Syndrome (n=10) Category Pts. CR PR OR% Cytogenetics -17/17p- 3 0 2 67 +12 2 1 1 100 Complex 1 0 0 0 Not done 4 2 0 50 FISH 17p- 4 0 2 50 No 17p- 3 1 1 67

  31. Demographics of 19 Flu-Refractory CLL Patients--OFAR Characteristic Value Median (range) Age Years 60 (34-75) LDH N<618 IU/L 636 (311-1999) b2Micro. N < 2 mg/L 5.7 (2.2-8.6) # Prior Rx 4 (1-11)

  32. Response to OFAR by Clinical Characteristics—Flu-Refractory CLL Characteristic Value Pts. OR (%) Age <70 16 8 (50) >70 3 2 (67) LDH <N 9 5 (55) >N 10 5 (50.) b2Micro. <2.5 N 9 4 (44) >2.5 N 10 6 (60)

  33. Response to OFAR by DoseFlu-Refractory CLL Oxaliplatin Dose Pts. PR OR% 17.5 mg/m2 1 0 - 20.0 mg/m2 3 0 - 25.0 mg/m2 15 10 67

  34. Response to OFAR by Cytogenetics or FISH in Flu-Refractory CLL Category Pts. PR OR% Cytogenetics -17/17p- 6 3 50 +12 1 0 0 Complex 1 0 0 Not done 2 1 50 XY Simple 9 6 67 FISH 17p- 10 2 50 No 17p- 4 1 75 Not done 5 2 40

  35. Summary of OFAR in Richter’s Syndrome and Fludara Refractory CLL • Phase II dose of Oxaliplatin is 25 mg/m2 x4 • OFAR is active in Richter’s and Flu Refractory • Mechanism of action is confirmed • Cytoreduction is being followed by Allo-SCT • Dose intensity is justified by poor prognosis • Response is not affected by 17p deletion

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