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CHRONIC MYELOID LEUKEMIA, THE TUNISIAN EXPERIENCE IN IMATINIB ERA

CHRONIC MYELOID LEUKEMIA, THE TUNISIAN EXPERIENCE IN IMATINIB ERA. Ben Amor R, Ben Lakhal R, Ghedira H, Belaaj H, Laatiri MA, Ben Youssef Y, Ben Romdhane N, M’sadek F, Menif S, Elloumi M, Khelif A, Meddeb B. IN TUNISIA. - IMATINIB : June 2002

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CHRONIC MYELOID LEUKEMIA, THE TUNISIAN EXPERIENCE IN IMATINIB ERA

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  1. CHRONIC MYELOID LEUKEMIA, THE TUNISIAN EXPERIENCE IN IMATINIB ERA Ben Amor R, Ben Lakhal R, Ghedira H, Belaaj H, Laatiri MA, Ben Youssef Y, Ben Romdhane N, M’sadek F, Menif S, Elloumi M, Khelif A, Meddeb B.

  2. IN TUNISIA - IMATINIB : June 2002 - 1streferential : October 2005 : monitoring of response - 1stretrospectivestudy : April 2007 (La Tunisie médicale 2007)  77 patients : - Median of IM initiation: 9 Months (1-180 M) - CHR : 95%, Partial CyR (12M) : 63 % - 2ndreferential : October 2008 - Definition of responses (ELN) - Dose-Adaptation - Management of resistances (2ndgen TK-i, IM dosing)

  3. OBJECTIVE Retrospective Tunisian multicenter study : - Evaluate the response to IM according to the “ELN criteria”: CCyR - MMR - Analyze the predictives response factors, the event free survival(EFS) and the overall survival(OS)

  4. PATIENTS 160 CML Selected  116 CML Included - July 2002 - Dec 2008 - 6 Hematologic centers - Aziza Othmana Hospital : 51 patients - Sfax : 25 patients - Monastir : 16 patients - Sousse : 12 patients - La Rabta : 8 patients - Military Hospital (Tunis) : 4 patients

  5. PATIENTS - The median age = 44 years (13 – 76 years). - Sex ratio = 1,6 (72M/44F) • Chronic phase (CP) = 104 patients • Accelerated phase (AP)= 12 patients

  6. PATIENTS Cytogenetic : * t(9,22) = 113 patients * Additional : 10 pts - Trisomy 18 = 2 patients - Del 11 = 1 patient - Del 7 ; Del 13 = 1 patient - Complex Translocation = 6 patients

  7. PATIENTS,SOKAL Score

  8. PATIENTS - IM 400mg/day was initiated at least one year after diagnosis - Median of 3 months (1 - 12months) - Response evaluation : “ELN criteria”

  9. MONITORING

  10. METHODS STATISTIC STUDY 1-Predictivesresponsefactors: (Sokal, Time to CCR, TTT Dicontinuation …) ( Chi-square test, p < 0.05 ) 2 -The «event free survival» and the «overallsurvival» : (Kaplan-Meiermethod and Log-Rank test) - Univariatestudy - Multivariatestudy

  11. RESULTS

  12. RESPONSE TO IM ACCORDING TO « ELN Criteria »

  13. RESULTS : CCyR - Complete cytogenetic response (CCyR) = 76% ++ - Median = 12 months (3 - 36 months)

  14. Predictive factors of CCyR Independent Factors : multivariate study

  15. RESULTS : MOLECULAR RESPONSE - Molecular Monitoring : Performed in 80%of cases • 20%: - Pb of monitoring - No CCyR  62 % = MMR ++ • Mediane : 18 months ( 6 – 48 months)

  16. Predictive factors of MMR

  17. PRIMARY RESISTANCE : 25pts - No CHR at 3 months = 5 patients - No CyR at 6 months = 20 patients - IM Dose escalation = 18 pts 5 CCyR(24-36 mo) - Same dose of IM = 7 pts 2 CCyR(24 mo) - Mutation : 5 cases ( = 1 +)

  18. SECONDARY RESISTANCE ( 4 – 44 months) 13 patients Loss of CCyR= 7 Loss of CHR = 6  IM = 7 Death = 2  IM = 4 - 4 suboptimal Response - 2 resistances  1 : Allo, 1 : Death - 1 progression  Allo SCT - 2 Death - 2 Resistances

  19. DOSE ESCALATION = 37 pts - SuboptimalResponse : 10 pts / 53 : 19% - Primary Resistance : 18 pts / 25 : 72% - Secondary Resistance : 9 pts / 13 : 70%

  20. TREATMENT DICONTINUATION 2O Patients ( 7 days – 2 months ) : • 15 pts = Cytopenia • 4 pts = No adherence to treatment - 1 pt = Missed in follow up

  21. MUTATION 7 patients - 5 = Negative - 1 = mutation T 315i + F 359c - 1 = mutation M 244v

  22. RESULTS : EFS EFS at 5 years follow-up = 79%

  23. EFS 20072010

  24. EVENT FREE SURVIVAL, univariate study

  25. RESULTS : EFS • p = 0,0001 EFS : CCyR

  26. RESULTS : EFS P = 0,002 EFS : INITIAL DISEASE STATUE

  27. RESULTS : EFS P = 0,008 EFS : INITIAL RESPONSE

  28. RESULTS : EFS p = 0,2 EFS : MMR

  29. OVERALL SURVIVAL OS at 5 years = 88%

  30. RESULTS : OS p = 0,00001 OS : CCyR

  31. COMMENTS 1 - Hopeful results : EFS : OS :

  32. COMMENTS 2 • Monitoring difficulty: - 160 patients selected : * 116 = included * 44 pts = Not included  Synchronize the follow up : - To All the patients - In All the centers “according the Tunisian referential updated in 2009”

  33. COMMENTS 3 - Management of resistances and suboptimal responses :  Dose escalation benefit to only 42% of patients eligible for IM escalation (38/91) • Primary resistance : maintain and escalation of IM : • CCyR in some cases • No increase of survival in most of cases

  34. CONCLUSION - The management of our patients can be improved by bettermonitoring of response and dose escalation • The newly introduced: * BCR-ABL mutational analysis * Plasma dosing of IM * Use of 2nd generation tyrosine-kinase inhibitors  improve the outcome of resistance

  35. ACKNOWLEGMENT • Ben Lakhal R, Menif S • Ghedira H, Achour M • Belaaj H • Laatiri MA • Ben Youssef Y • Ben Romdhane N • M’Sadek F • Saad A

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