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APML

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APML

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  1. Under representation of bcr1 subtype of PML-RARα fusion gene in APML in Indian patientsSudha Sazawal, Syed k Hasan, Bijender Kumar, Pankhi Dutta, Rajat Kumar, Lalit Kumar*, VP Choudhry, Renu Saxena Departments of Hematology and *Medical Oncology,All India Institute of Medical Sciences, New Delhi- 29

  2. APML AML subtype: good response to ATRA Problems/ dilemma associated with APML: • Diagnosis (morphologic M2/M4 may be confused) • Response to ATRA: variable. percent

  3. Pathogenesis of APML Molecular defects • PML-RARα- t(15;17): good prognosis (99%) • (NPM) -t(5;17) – 5q35 : good prognosis • (PLZF) -t(11;17) – 11q23 • (NUMA) -t(11;17) – 11q13 Bad prognosis

  4. 10 -8 Techniques to detect t(15;17)/ PML-RARα

  5. RARa PML bcr2 bcr1 bcr bcr3 3 4 5 6 7 2 3 4 3’ 3’ 5’ 5’ A = Normal PML and RARa 3 4 5 6 3 4 3’ 5’ B = 3’ PML breakpoint (L) 3 3 4 3’ 5’ C = 5’ PML breakpoint (S) Isoforms of APML • Ambiguity exists regarding the Potential independent prognostic implications of these isoforms • bcr 1: (Long isoform) good response to ATRA • bcr 3: (short isoform) poor response to ATRA

  6. AIMS • Evaluation of role of PML-RARα in diagnosis of APML • Determination of the occurrence of breakpoint regions/ isoforms in APML in our population • Correlation with response to ATRA

  7. Material Subjects: AML patients • Inclusion criteria • Increased blasts/promyelocytes • MPO, SB, NSE/ NASDC positive • No prior chemotherapy • Exclusion criteria • Pts. received prior chemotherapy • MDS • Cytochemistry revealed MPO -ve, SB -ve Controls: ALL patients

  8. Molecular studies • RT-PCR: • RNA Extraction • Reverse transcription • Integrity assessed by β2 microglobulin • Well documented primers used (Grimwade et al 1996) • RQ/RT-PCR: for detection of PML-RARα isoforms (Cassinat et al 2000) • bcr3 • bcr1

  9. APML Management • Induction • ATRA – 45 mg/m2/ day (max. 90 days) • Inj Daunorubicin – 60mg/m2 (day 3 onwards) • Consolidation – 3 cycles • Inj Daunorubicin – 60mg/m2 • Maintenance – 2 years • ATRA – 45 mg/m2/ day x 15d (every 3 months) • 6MP – 60mg/m2/ day • MTX – 20mg/m2/ weekly

  10. AML M2 AML M3 AML M4 AML M5 AML M6

  11. RESULTS β2 microglobulin of cDNA Marker 1 2 3 4 5 6 7 8 135 bp

  12. RESULTS t(15;17)/PML-RARα PJD2A1 P1 P2 P3 P4 Marker -ve Ctrl 355 bp

  13. RESULTSPresence of PML-RARα in AML Subtypes Number of cases : 54 percent

  14. RESULTS Frequency of PML-RARα Isoforms bcr1 vs bcr3 (p=0.03)

  15. Distribution of PML-RAR Isoforms percent (p=0.004)

  16. PML-RAR Isoforms and Age

  17. PML-RARα Isoforms and median TLC Gallagher et al Blood 1997,90:1656-63 Gonzalez et al BJH 2001,114:99-03

  18. RESULTS PCR results of PML-RARα fusion transcript

  19. Conclusion • Detection of PML-RARa by RT-PCR is essential in diagnosis of AML M3 . • BCR3 Isoform is more common than BCR1 • Median WBC at presentation in Indian APMLis much higher than that in the West. • No correlation was found between WBC and Isoforms of PML-RARA

  20. Conclusion (Contd..) • No conclusive comment can be made regarding relation of bcr isoform and treatment response in this study due to small number of cases. • However, poorer response in India Vs West may be due to high WBC or bcr 3

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