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MRD in ALL, technique and predictive value

MRD in ALL, technique and predictive value. 울산대학교 의과대학 서울아산병원 혈액내과 이 규 형. Utilization of disease markers. Goal. Survival prolongation Disease free survival prolongation Toxicity reduction Improved QOL Improved cost- effectiveness of care. Screening Differential Dx

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MRD in ALL, technique and predictive value

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  1. MRD in ALL, technique and predictive value 울산대학교 의과대학 서울아산병원 혈액내과 이 규 형

  2. Utilization of disease markers Goal • Survival prolongation • Disease free survival prolongation • Toxicity reduction • Improved QOL • Improved cost- effectiveness of care • Screening • Differential Dx • Prognostic factor • Disease follow-up

  3. (1) Level I : 가장 확실한 증거로 잘 수행된 meta-analysis 또는 많은 수의 환자를 대상으로한 동시대조군을 동반한 전향적 연구로 연구의 주 목적이 tumor marker 이용에 대한 평가이어야 한다. (2) Level II : 전향적 연구의 결과이나 연구의 주목적은 치료에 관한 가설을 검증하는 것이고 tumor marker의 평가는 부차적인 목적인 경우이다. 단 이 경우에도 tumor marker의 평가는 전향적으로 그 목적이 기술되어 있어야 한다. (3) Level III : 대규모 후향적 연구의 결과로 대개는 다변량 분석을 포함하는 연구이다. (4) Level IV : 후향적 연구의 결과로 환자의 숫자가 작거나 다변량 분석을 하지 않아 level III evidence의 연구보다 신뢰성이 떨어지는 경우이다. (5) Level V : 작은 규모의 후향적 연구로 연구의 design이 tumor marker 결과와 환자의 임상적 경과와의 상관관계를 알아보는 데에 적절하지 못한 경우이다.  Levels of evidence

  4. Adult ALL • Leukemic cell burden of up to 1012 cells at Dx • Morphologic CR: 1010 cells • Combination chemotherapy induce CR in 90% of patients • MRD: Post-remission persistence of leukemia that cannot be detected by histomorphologic assessment

  5. Adult ALL, AMC experience P=0.03 III II I Days from DX

  6. Chromosomal abnormalities in ALL

  7. Molecular pathogenesis of CML • 1960 - Shortening of chromosome 22 (Philadelphia chromosome) • 1973 – Translocation of long arm of chromosome 9 to 22 • 1970 - Abelson leukemia virus (v-ABL) • Normal cellular homology (c-ABL)을 chromosome 9의 장완에서 발견 • 그러나 CML 세포의 경우 22번염색체에서 발견 • BCR-ABL chimeric protein 발견 (P210)

  8. Ph-ALL • Ph-ALL is a subset of B-precursor ALL with very poor prognosis. - CR rate of 60-90%; Median CR duration of 6-11 months - rare long term survivor; unless allo-transplanted in CR1. • Imatinib (Glivec): BCR-ABL tyrosine kinase inhibitor- anti-leukemic effect in advanced Ph-ALL - non-overlapping toxicities with cytotoxic chemotherapy • Imatinib alone for newly diagnosed Ph-ALL? - Maximum leukemia reduction of 2.9 log in CML by imatinib alone, which is not likely produce long-term disease control in Ph-ALL. - Additional chromosomal abnormalities in over half cases at Dx. • Anti-leukemic effect and toxicities of combined treatment of imatinib & conventioanl chemotherapy is not known.

  9. A1 : 5' TGA TTA TAG CCT AAG ACC CGG A 3' A2 : 5' ATC TCC ACT GGC CAC AAA ATC ATA CG 3' B1 : 5' GAA GTG TTT CAG AAG CTT CTC C 3' B2 : 5' TGG AGC TGC AGA TGC TGA CCA ACT CG 3' B3 : 5' ACC ATC GTG GGC GTC CGC AAG A 3' B4 : 5' AGA TCT GGC CCA ACG ATG GCG AGG GC 3' Primers used for nested rt-PCR analysis of Bcr-Abl transcripts and their locations on Bcr-Abl fusion cDNA

  10. Bcr-Abl as disease predictor • Positivity correlated with relapse after HCT(10/23+ vs. 2/13- relapses, P=0.025, or=5.7) (Radich J et al. Blood , 1997) • Quantitative real-time PCR at 4 weeks of treatment with imatinib correlated with patient survival • (Scheuring U, et al. Blood, 2003)

  11. Results: Patient characteristics

  12. Results: Complete Remission Proportion achieving CR Imatinib+ chemotherapy Chemotherapy alone P=0.11 Days * Started imatinib D1 to D8 of chemo

  13. Results: Clinical courses (5 relapses; 7 deaths) Median follow up of 584 days (range, 45-800) 20 1 early death due to sepsis (D14) 19 CR 3 Relapse (D 89,95, 341) 14 with Allogeneic BMT 2 alive in CR (D 45, 94) 9 alive and NED 1 died with leukemia (D 137) 1 died with leuk post uBMT (D478) 3 died TRM 2 GVHD, 1 int pneu 2 relapsed (post HCT D 279,318) (one died) 1 alive in 2nd CR after haplo-BMT (D69)

  14. Results: Relapse • Five patients relapsed with 2-year projected relapse rate of 38% (vs. 84% in chemo only group). Chemo only (n=15) P=0.031 Chemo+imatinib (n=19)

  15. Overall survival • Seven died (1 sepsis during induction tx, 3 relapsed leukemia, 3 TRM after allo HCT) with 2-year projected survival rate of 48% (vs. 22% in chemo only group). Chemo+imatinib (n=20) P=0.05 Chemo only (n=18)

  16. Serial quantitative rt-PCR for Bcr-Abl transcripts (I)

  17. Serial quantitative rt-PCR for Bcr-Abl transcripts (II)

  18. Serial plotting of the amount of Bcr-Abl transcripts as expressed by Bcr-Abl/G6PDH ratio. Assuming negative results are 4.5 log reduction from the base line, the median (range) log-reductions from the baseline are 2.13 (0.63-4.5) at CR, 3.60 (1.0-4.5) after 1st consolidation, 4.36 (3.41-4.73) after 2nd consolidation and 3.81 (1.52-4.5) at HCT.

  19. PCR for Ig H gene rearrangement • Ig H gene (variable, diversity, and joining segments) • Unique clonal complementarity-determining region 3 (CDR3), detected by fingerprint, sensitivity 1/103 • CDR3 further analyzed for DNA sequence and allele specific oligonucleotide with sensitivity 1/104 (Mortuza F et al, J Clin Oncol 2002)

  20. MRD detection using Ig H rearrangement in adult ALL • 85/110 diagnostic bone marrow samples (77%) showed rearrangement of VH-(DH)-JH. • 50 cases (59%) had1clone, 18 cases(21%) had 2clones, and17 cases(20%) had 3 or moreclones. • All clones needed to be followed for MRD detection. • 21 of 85 cases showed positive finerprinting while clinically in CR. 18 of 21 subsequently relapsed • Among 64 cases with negative fingerprinting, test with allele specific primer (ASO) were feasible in 32 cases. 9 cases were positive with 6 cases relapsing subsequently. • Among 23 cases where bothfingerprinting andASO tests were negative, 6 relapsed. • Among 32 cases where ASO test was not feasible, 7 cases relapsed. (Mortuza F et al, J Clin Oncol 2002)

  21. MRD detected by Ig H showed significant correlation with disease free survival • Only 77% had suitable fingerprinting marker • Tedious with need for sequencing in significant number of patients

  22. Options for MRD in ALL

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