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Current Phases of Clinical Trials in CLL

Current Phases of Clinical Trials in CLL. Induction phase Eradication of minimal residual disease Salvage therapy Allogeneic Cellular Immunotherapy. ?How do we decide therapy at each phase?. Comparison of Response Rates by Regimen. Regimen Pts. %CR %OR

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Current Phases of Clinical Trials in CLL

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  1. Current Phases of Clinical Trials in CLL • Induction phase • Eradication of minimal residual disease • Salvage therapy • Allogeneic Cellular Immunotherapy ?How do we decide therapy at each phase?

  2. Comparison of Response Rates by Regimen Regimen Pts. %CR %OR “CHOP-like” 80 24 63 Fludarabine 201 32 85 Flu + Cyclo 110 37 88 Flu/Cyclo/Rit 300 72 95 (FCR)

  3. Survival CLL by Front-lineTreatment } p<.01 } p= ns } p<.001 Proportion Alive } }

  4. Chemosensitization By Rituximab And Vice Versa Rituximab • Increases cytotoxicity of Fludarabine and Cyclophosphamide • Down regulates Bcl-2 protein Fludarabine • Prevents DNA repair of alkylating agent cross links • Down Regulates CD46, CD55, CD59 (Complement Defense Proteins)

  5. FC + Rituximab Schedule In CLL (Allopurinol 300mg/day)

  6. Response to FC + Rituximab(NCI-WG: 300 Patients) Response # Pts. ( % ) CR 217 (72%) Nodular PR 31 (10%) 95% PR 37 (12%) No Response 13 ( 4%) Early Death2 ( 1%)

  7. Survival FCR by Response Proportion Alive } p=ns } p<.001 } p<.002

  8. Conclusions from Randomized Clinical Trials Each Confirmed the superiority of the new therapy 5-7 years after MDACC single institution studies

  9. Why not treat all patients with FCR?

  10. Response to FCR (Front-Line) by Age, Stage, 2M Characteristic Value Pts. %CR p-value Age (years) <55 112 76 55-69 147 69 .002 >70 41 46 Rai Stage 0-II 199 73* .002 III-IV 101 59 2Microglobulin <3 91 86 3-4 78 76 <.001 >4 122 53

  11. Survival FCR by Rai Stage Proportion Alive

  12. Survival FCR by b2-Microglobulin Proportion Alive p<.001

  13. Survival FCR by Age and b2M Proportion Alive } p<.01 } p=.03 } }

  14. Time to Fail FCR by Age and b2M Proportion } p<.001 } p= ns } }

  15. Survival by TreatmentFC/FM vs. FCR/FCR3 Age > 70 Proportion

  16. Present Front Line Priorities for Advanced/Progressive CLL

  17. Response Rituxan + GM-CSF Untreated CLL Age > 70 Total patients: 32 CR 2 ( 6%) nPR 2 ( 6%) PR 18 (56%) Fail 10 (32%)

  18. Survival vs. Time to Fail Rituxan + GM-CSF Untreated CLL Age > 70 Proportion

  19. Time to Fail Patients Age > 70 by Treatment FCR vs Ritux+GMCSF Proportion

  20. Survival Patients Age > 70 by Treatment: FCR vs Ritux+GMCSF Proportion p = .ns

  21. Time to Treatment Failure by b2-MFCR Age > 70 years Proportion

  22. Clinical and Flow Cytometry Response (<70 years & b2m <4mg/l) Time to Treatment Failure identical

  23. CFAR (N=26) FCR (N=119) Response %Pts %Pts CR 69 60 nPR -- 17 PR cytopenia 19 6 PR disease 8 11 Overall 96 93 Flow negative84 59 Clinical and Flow Cytometry Response(<70 years & b2m >4mg/l)

  24. Newer Prognostic Markers in CLL Characteristic Value Unfavorable IgVh Mutation Status <2% Mutated ZAP 70 (Tyrosine Kinase) >20% of cells CD 38 (Activation Marker) >30%, or 20%, or 7% FISH (Cytogenetics) 11q-, 17p-

  25. Background OFAR in RS & rCLL Platinum compounds: • Activate excision DNA repair mechanisms • Synergistic with ara-C and fludarabine Fludarabine & ara-C: inhibit the resynthesis step of excision repair Fludarabine: ↑ ara-CTPaccumulation in leukemic cells Oxaliplatin: • Synergistic with fludarabine in vitro • Minimal renal/auditory toxicity

  26. Course 1 OFAR Treatment Design Oxaliplatin 17.5/20/25 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

  27. OFAR in Relapsed/Refractory CLL and Richter’s SyndromePhase 2 (20 evaluable patients) Characteristics: Relapsed CLL 5 Refractory CLL 12 Richter’s 3 Prior Rx: Median(Range) 3 ( 0 – 9 ) b2 Micro: Median(Range) 4.3 mg/L (2.4-14.4) FISH 17p 6

  28. OFAR in Relapsed/Refractory CLL and Richter’s Syndrome20 evaluable patients

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