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Established Prognostic Factors Associated With Inferior Survival

Established Prognostic Factors Associated With Inferior Survival. Advanced stage at diagnosis Short lymphocyte doubling time Diffuse pattern of bone marrow infiltration Advanced age/males Abnormal karyotype High serum levels of ß 2 -microglobulin. Summary: Prognostic Factors in CLL.

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Established Prognostic Factors Associated With Inferior Survival

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  1. Established Prognostic Factors Associated With Inferior Survival • Advanced stage at diagnosis • Short lymphocyte doubling time • Diffuse pattern of bone marrow infiltration • Advanced age/males • Abnormal karyotype • High serum levels of ß2-microglobulin

  2. Summary: Prognostic Factors in CLL • Various prognostic markers predict for disease progression and survival in CLL: • -2 microglobulin • IgVH gene mutation • CD38 • ZAP-70 • Current challenges • Defining and validating prognostic significance of markers • Identifying which are readily available and reliable • Addressing use in clinical management of patients

  3. Problems with Current Studies • “Uni-factorial” • Do not take into account the impact of other prognostic factors • Small patient numbers • Retrospective design • Selection bias • Survival from date of initial diagnosis, not date of test • Not uniformly treated

  4. Clonal Evolution by VH Mutation Status 100 % clonal evolution 80 Unmutated CLL 60 40 Mutated CLL 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Time since initial genetic study (months)

  5. The MD Anderson Studies • CLL Database - prospective record of all patients assessed at MD Anderson. • Determinants of Survival • Progression to First Therapy • Complete Remission • Remission Duration } Untreated Patients N=594, 2003 - 2007 } FCR Study N=300, 1999 - 2003

  6. IgVH - Time to First TherapyInteraction with ß2m Unmutated IgVH Mutated IgVH ß2m < 3mg/L (n=160) p=NS ß2m ≥ 3mg/L (n=19) p=0.0005 ß2m < 3mg/L (n=89) ß2m ≥ 3mg/L (n=35)

  7. IgVH - Time to First TherapyInteraction with Genetic Status Deletion 13q / Negative FISH Trisomy 12 Mutated (n=152) Mutated (n=27) Unmutated (n=95) Unmutated (n=30) p<0.0001 p=NS

  8. Zeta-Associated Protein 70 (ZAP-70) Crespo et al 2003 348:1764 Rassenti et al 2004 351:893

  9. ZAP-70 by Immunohistochemistry Positive in CLL Infiltrate Negative in CLL Infiltrate Ellen Schlette, MD Hematopathology

  10. M, ZAP- (n=98) } p=NS M, ZAP+ (n=23) U, ZAP+ (n=74) } p=0.03 U, ZAP- (n=23) ZAP-70: Additional Value to IgVH? Time to First Therapy

  11. 100 80 60 40 20 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 Chromosome 17p Deletion (FISH) Dohner et al N Engl J Med. 343:1910-1916,2000 17p deletion 11q deletion 12q trisomy Normal 13q deletion as sole abnormality Patients Surviving (%) Months

  12. De Novo 17p- CLL : The MD Anderson Experience Not All Patients Progress…. Depending on Rai Stage & IgVH Status Rai 0, any IgVH (n=14) Rai 1-2, mutated (n=5) Rai 1-2, unmutated (n=11) p<0.0001 Lost 17p- clone on repeat FISH

  13. Determinants of Survival I : Biological Risk II : Symptoms Low Risk (23) Asymptomatic High Risk (13) High Risk (33) Symptomatic High Risk (20) p = 0.003 p = 0.04 Low Risk = Rai 0/1and <50% Deletion

  14. Deletion 17p CLL - Published Studies

  15. 100 <5% 75 Percent >20% 50 5-20% 25 2P < 0·00001 0 0 12 24 36 48 60 Months De Novo 17p- CLL: Survival GCLLSG-CLL4: F vs FC LRF-CLL4: Chl vs F vs FC (15) (18) (15) Stilgenbauer ASH 2005 Eichorst Blood 2006, 107: 885 Catovsky ASH 2004 Catovsky Lancet 2007, 370: 230

  16. The MD Anderson Experience (Dec 2003 - July 2007) Survival from FISH Date Survival from First Therapy N=56 N=38 80% at 24 months 75% at 24 months Follow-up 19 mth (5 - 47) Reasons : Early Stage Patients FISH Techniques Rituximab

  17. Fallacies in 17p- CLL Therapy 17p- ≥50% or DT <6M : 83% vs 26% Major Response (p=0.003)

  18. Frontline FCR in CLL: NCI Response (%) } Complete Response* 72 Nodular Partial Response 10 Partial Response 12 Stable / Progressive Disease 4 Early Death (3 months) <1 95 * 78% flow cytometry negative

  19. The FCR Study: IgVH Status Pre-treatment 79 patients Stored BM Clot Sections 98 patients Known : 177 of 300 pts Lin K, ASH 2007, Updated Feb 12th 2008

  20. Baseline Characteristics UM= Unmutated; M=Mutated; ND= Not determined *p=0.04

  21. The FCR Study : Response Rate *n=164

  22. The FCR Study : CR Duration & Survival Complete Remission Duration Overall Survival p<0.0001 p=0.05 Mutated (n=60) Mutated (n=72) Unmutated (n=77) Unmutated (n=105)

  23. ZAP-70: Additional Value to IgVH? CR Rate Following FCR FCR Remission Duration M, ZAP- (n=21) } p=NS ZAP+ ZAP- ZAP- ZAP+ M, ZAP+ (n=19) Unmutated Mutated U, ZAP+ (n=48) } p=0.26 U, ZAP- (n=13)

  24. Progression free Survival of FR and FCR by Mutation Status Mutation PFS Rx Status Pts Median (mo) %5 yr FR Unmutated 50 31 19 FR Mutated 38 46 40 FCR Unmutated 96 48 40 FCR Mutated 62 NR 75

  25. Frontline FCR in CLL: CR Duration p-value

  26. Multivariate Analysis of CR Duration p-value

  27. Conclusion III - 17p- / p53 *assumes that 17p- and p53 overexpression identifies the same group of patients

  28. Final Thoughts • CLL prognosis is multi-factorial: • Avoid interpretation of individual prognostic factors in isolation. • Therapeutic dissection: • Let the treatment outcome tell you what factors are truly important. • Only possible when patients are treated homogenously, with the best available therapy.

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