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The role of Minimal Residual Disease in the Management of Acute Leukemia

The role of Minimal Residual Disease in the Management of Acute Leukemia. Francesco Lo-Coco Università Tor Vergata, Roma Corso Nazionale di Aggiornamento in Ematologia Clinica Catania, 6-7 Novembre 2008. leukemic cell n. sensitivity. CLINICAL DIAGNOSIS. RELAPSE. 10 12.

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The role of Minimal Residual Disease in the Management of Acute Leukemia

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  1. The role of Minimal Residual Disease in the Management of Acute Leukemia Francesco Lo-Coco Università Tor Vergata, Roma Corso Nazionale di Aggiornamento in Ematologia Clinica Catania, 6-7 Novembre 2008

  2. leukemic cell n. sensitivity CLINICAL DIAGNOSIS RELAPSE 1012 MORPHOLOGIC & CYTOGENETIC REMISSION 1010 102 Flow cytometry 108 104 PCR 106 106 MOLECULAR REMISSION 104 108 INDUCT. CONSOLID. CURE ? THERAPY 10 2 10 0 2 4 6 8 10 12 14 16 18 20 24 36 48 MOS.

  3. Relevant issues in MRD studies • - Disease & therapeutic context • - MRD techniques and targets • Standardization • Timing/source of sampling • clinicians’ compliance

  4. Methods for studying MRD Technique Targets Sensitivity Flow cytometry Antigens 10-3 FISH DNA 10-3/10-4 PCR/Q-PCR DNA/RNA 10-4/10-6

  5. Leukemia-Associated Immunophenotypes (LAIP) in AML

  6. Genetic markers detectable by PCR and useful for MRD detection in acute leukemia • Clono-specific markers -Ig gene rearrangements -TCR gene rearrangements and  • Tumor specific markers -new hybrid genes produced by reciprocal chromosome translocations -gene mutations

  7. Genetic defects useful for MRD detection by PCR DISEASE Chrom. abnormality Molecular Target Frequency% ALL B-lineage t (9:22) BCR/ABL 25-30% t (1;19) E2A/PBX1 5-6% t (4;11) MLL/AF4 5% T- Lineage del 1p32 TAL1/SCL 5% AML t (15;17) PML/RAR 10% t ( 8;21) AML1/ETO 8-10%  inv (16) CBF/MYH11 6-8% t (6;9) DEK/CAN 1% 11q23 MLL/? 5-10%

  8. • • • • • • • • • • • • • • • • • ‘Europe Against Cancer’ Network • Fusion Transcripts (n=9) & RQ PCR • For leukemias • Standardization • Quality Controls • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

  9. Is molecular remission a therapeutic goal in acute leukemia ? • t(15;17) APL yes • inv(16) AML yes • t(8;21) AML ? • t(9;22) ALL yes • t(4;11) ALL yes • Other AML/ALL ?

  10. Real Time PCR in inv(16) AML CBFβ/MYH11 X 104 copies CCR pts. R ABL Relapsed pts. 10000 R R R R R 1000 R 100 10 1 0 2 4 6 8 10 12 14 16 18 20 24 26 28 MONTHS

  11. Distinct kinetics of molecular remission in AML 0 2-3 log 4-5 log 0 3 6 9 12 15 18 21 24 m. AML1-ETO PML-RARa CBFb-MYH11 PCR + ve PCR - ve Jaeger et al, 2003

  12. Int. BFM study for MRD in childhood pre-B ALLs Detection of MRD in patients remaining in CCR PCR + % THERAPY INDUCTION MAINTENANCE END

  13. Bcr-Abl t(9;22) Other 23% 26% MLL t(4;11) t(11;19) Hypodiploidy t(9;11) 1% 10% Hyperdiploidy 7% TEL-AML1 t(12;21) Lyl1 19p13 2% 2% Myc t(8;14), t(2;8), t(8;22) 4% Tal1 1p32 Hox11L2 5p35 Hox11 10q24 12% 1% 8% MLL-ENL E2a-PBX1 t(1;19) 0% 3% Molecular heterogeneity of ALL

  14. CIR according to MRD status in Ph’+ve ALL MRD at transplant MRD at day +100 Spinelli, Haematologica 2007

  15. DFS and OS by Early MRD Response to Imatinib Imatinib 100 early MRD neg.: 15/29 90 OS earlyCRmol OS 80 70 60 % p=0.0002 50 40 persisting MRD+: 14/29 DFS 30 OS OS - persistent MRD+ p=0.0001 20 DFS DFS - persistent MRD+ 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Months since Imatinib start Wassmann et al, Blood 2005

  16. Randomized Study of Pre-emptive versus MRD- Triggered Imatinib after SCT for Ph+ALL (EBMT) MRD MRD monitoring Dasatinib* Imatinib Randomisation (<6 wks. post SCT) Mutation analysis Pre- registr. DLI (optional) SCT R MRD+ MRD MRD monitoring Dasatinib* Imatinib Mutation analysis * If MRD by >2log or BCR-ABL transcripts >10-3 or BCR-ABL Mutation

  17. Molecular heterogeneity of NK-AML Döhner et al, ASH 2007

  18. NPM1-mutA NPM1-w/t ASO-RT-PCR to detect NPM1 type A mutation NPM1-mutA 320 bp ABL 258 bp 10-1 10-2 10-3M 10-1 10-2 10-3 10-4 10-510-6 Mctrl+ ctrl- M ASO-RT-PCR semi-nested-ASO-PCR Ottone et al, J Mol Diag 2008

  19. Early assessment of MRD by optimized RQ-PCR of WT1 provides an independent predictor of DFS IN AML (Cilloni et al, EHA 2008) Background: WT1 overexpressed in >90% AMLs Suitable “universal” MRD marker for AML Methods: Comparison of sensitivity & specifitiy of 9 different R-Q-PCR assays 729 diagnostic & 106 f-up samples 11 European labs (LeukemiaNet) 20

  20. Results: Failure to normalize WT1 transcripts post-induction correlates with relapse in 100% of cases (independent predictive factor) Decreased levels post-treatment not fully informative on outcome Comments: Important early information, most relevant (if confirmed) to adjust post-induction therapy Early assessment of MRD by optimized RQ-PCR of WT1 provides an independent predictor of DFS IN AML (Cilloni et al, EHA 2008) 21

  21. MRD negative FLT3 negative (80%) MRD positive FLT3 negative (29%) FLT3 positive (10%) RFS analysis in 80 adult patients with NK-AML 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 4015 4380 4745 Time (Days) Buccisano et al, unpublished

  22. MRD negative (75%) MRD negative NPM positive (60%) MRD positive NPM positive (24%) MRD positive (23%) RFS analysis in 80 adult patients with NK-AML 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 4015 4380 4745 Time (Days) Buccisano et al, unpublished

  23. Clinical relevance of PCR monitoring in APL • Assessment of response to therapy (molecular remission) at the end of consolidation as an early surrogate of improved survival • Identification of molecular relapse. Benefit in early salvage • Provides sensitive surveillance of disease status in experimental clinical trials

  24. J Clin Oncol 2003

  25. Suggested timing of marrow sampling for RT-PCR in patients receiving ATRA and chemotherapy Induction Consolidation Follow-up 3 6 9 12 15 18 21 24 27 30 Mos. from dx

  26. Kinetics of molecular/frank relapse in APL revealed by RQ-PCR: Implications for optimal frequency of MRD monitoring Grimwade et al. (submitted)

  27. Evaluation of MRD monitoring & pre-emptive ATO therapy to reduce rates of frank relapse in PML-RARA+ APL in MRC AML15 trial Burnett AK (unpublished)

  28. Summary • Well standardised PCR-based MRD evaluation drives therapy in APL and Ph’ ALL • MRD assessment using “universal” markers (LAIP, WT1) appears promising and may provide early prognostic information (WT1) • Need of better standardization of flow cytometry • and of its comparison/integration with PCR data • Need of reference labs and standardised MRD • evaluation in prospective large trials *

  29. *

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