Detection methods of minimal residual disease and their prognostic value in patients with malignant hematological diseases はじめに (m

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1 Detection methods of minimal residual disease and their prognostic value in patients with malignant hematological diseases はじめに (minimal residual disease: MRD) MRD MRD ( 1) MRD PCR MRD 測定法 (1) マルチパラメーターフローサイトメトリー (multiparameter flow cytometry: MFC) 法 4 MRD MFC MRD 2 MFC MRD 10-4 ( ) PCR MFC 1 (minimal residual disease: MRD) MRD MFC (i) 白血病での臨床的意義 Inaba (AML)203 MRD MFC MFC MRD (>=0.1%) event-free survival (P<0.001) 1) Araki AML 359 MRD MFC MRD MRD 3 (OS) MRD OS (P<0.001) MRD 2) Sanchez-Garcia (ALL) 102 MRD MFC MRD (<0.01%, 72 ) MRD ( %, 12 ) MRD (>0.1%, 18 ) 3 OS ) (ii) 多発性骨髄腫での臨床的意義 International Myeloma Working Group (IMWG) criteria stringent complete response (scr) MFC MRD immunophenotypic CR (icr) Rawstron MRC Myeloma IX MRD MFC MRD (PFS)( : 28.6 vs 15.5 P<0.001) OS ( : 80.6 vs 59.0 P=0.0183) 4) (2) Polymerase chain reaction (PCR) 法 PCR DNA MRD mrna cdna DNA mrna RT-PCR (reverse transcriptase -PCR)

93 DNA RNA RT-PCR 10-6 (10 6 1 ) MRD 5) PCR PCR MRD PCR PCR MRD PCR PCR PCR ( ) (i) キメラ遺伝子を用いる方法 (APL) PML-RARα MRD Santamaría 145 APL MRD PML-RARα PCR 10 PML-RARα (n=7) 1 (n=62) 6) AML core binding

2 93 DNA RNA RT-PCR 10-6 ( ) MRD 5) PCR PCR MRD PCR PCR MRD PCR PCR PCR ( ) (i) キメラ遺伝子を用いる方法 (APL) PML-RARα MRD Santamaría 145 APL MRD PML-RARα PCR 10 PML-RARα (n=7) 1 (n=62) 6) AML core binding factor (CBF) (t(8; 21) inv (16)) MRD RT-PCR MRD 26 2 MRD ) BCR-ABL1 (CML) PCR MRD Etienne Complete Cytogenetic Response (CCyR) Major Molecular Response (MMR) (CCyR+MMR-) MMR /MR 4.5 (CCyR+MMR+MR 4.5 -) MMR /MR 4.5 (CCyR+MMR+MR 4.5 +) event-free survival (EFS) MMR (157 ) MR 4.5 (65 ) EFS 8) MR 4.5 International Scale (IS)-PCR % (ii) WT1 遺伝子を用いる方法 Wilm s tumor gene (WT1) 80% AML PCR MRD AML46 WT-1 WT-1 (P=0.002) (P=0.02) 5 OS WT % 9) AML WT-1 OS EFS 44 WT ) WT-1 WT-1 (iii) 免疫グロブリン /T 細胞受容体遺伝子再構成を用いる方法 (Ig) T (TCR) PCR MRD ( 2) MRD B Ig T B TCR (ALL) Bassan NILG-ALL 09/00 ALL 112 MRD MRD OS 75% 33% (P=0.001) MRD 11) (MM) molecular CR (mcr) mcr Ladetto CR VGPR MM mcr 1 (3%) 6 (19%) mcr PFS 100 ( 42 ) 2 (allele-specific oligonucleotide-polymerase chain reaction (ASO) ) PCR (MRD)

3 94 mcr 1 mcr ) MM DNA IgH PCR (50 64 ) MRD MRD MRD 8 MRD 14 PFS (P=0.012) mcr PFS ) PCR IgH-based MRD 14) (3) 次世代シークエンサー法 (next-generation sequencing: NGS) NGS PCR MRD DNA (IgH-VJ/DJ, IgK ) PCR PCR PCR PCR 10 6 ( 3 15) 1 ) PCR MRD )-18) Ladetto 3 B MRD NGS PCR ALL (77%) PCR clonal evolution NGS 16) Martinez- Lopez CR MM 62 MRD NGS MRD 26 MRD 36 time to progression (TTP) ( 131 vs 35 months; P=0.0009) NGS MRD MFC ASO-PCR NGS MRD (MRD NGS (-)) MFC MRD NGS MRD (MRD MFC (-)MRD NGS (+)) TTP ( not reached vs 50 months; P=0.05) MRD MFC (+)MRD NGS (-) 5 1 MFC NGS MRD 3 (MRD) (i) DNA (IgH-VJ/DJ, IgK ) PCR (ii) PCR PCR (iii) PCR 10 6 MRD 4 (MRD) (A) allele-specific oligonucleotide-polymerase chain reaction (ASO)-PCR (NGS) MRD (B) NGS MRD progression-free survival (PFS), (C) overall survival (OS) (D) NGS ASO-PCR MRD (MRD NGS (-)MRD ASO (-)) (n=7) NGS MRD ASO-PCR MRD (MRD NGS (+) MRD ASO (-)) (n=12) PFS (E)NGS MRD PFS (F) NGS ASO-PCR MRD (MRD NGS (-)MRD ASO (-)) (n=12) NGS MRD ASO-PCR MRD (MRD NGS (+) MRD ASO (-)) (n=5) PFS

4 95 17) DNA MRD 10-5 NGS 10-6 MRD (PR) MM 119 / NGS (93%) ASO-PCR (72%) NGS (71%) MRD ASO-PCR (41 ) MRD MRD 10-5 ASO-PCR NGS DNA NGS MRD 10-6 PCR 10-5 ( 4A) 45 MRD PFS ( 4B) OS ( 4C) NGS ASO-PCR MRD (MRD NGS (-)MRD ASO (-))7 (group 1) NGS MRD ASO-PCR MRD (MRD NGS (+)MRD ASO (-))12 (group 2) PFS group 1 group 2 PFS (P=0.087) ASO-PCR NGS ( 4D) MRD NGS % PFS MRD ( ) ( 4E) NGS ASO-PCR MRD (MRD NGS (-)MRD ASO (-))12 (group 3) NGS MRD ASO-PCR MRD (MRD NGS (+)MRD ASO (-))5 (group 4) group 3 group 4 PFS ( 4F) ASO-PCR MRD NGS MRD ( ) 19) NGS MRD MRD Roschewski 6 B 101 MRD NGS 5 EFS MRD (45.9% vs 83.0%, P<0.0001) 20) MRD 検出法の比較 ( 表 1) MFC 90 PCR 4 MFC MFC PCR CDRIII 30-80% PCR MRD DNA MRD PET CT MRI おわりに CR MRD 使用可能患者 (%) 感度再現性初診時検体の必要性 MRD 検体症例特異的試薬の必要性 Clonal evolution 時の MRD 検出検査時間検査可能施設標準化コスト 1 (MRD) MFC ASO-PCR ( 4-color) ~ 100% 10-4 ~ 10-5 高い重要であるが必須ではない細胞無可能 2-3 時間中等度進行中 (EuroFlow/IMF) 安価 ~ 80% 10-4 ~ 10-6 高い必須細胞 DNA 有不可能 5 日間 (follow-up), 3-4 週間 (ASO-PCR プライマー設計 ) 中等度有 (EuroMRD) 高額 NGS 90% ~ 10-6 ~ 未報告必須細胞,DNA 無可能 7 日間極めて限定未報告現在高額だが, 今後安価になる可能性あり MFC, multiparameter flow cytometry; ASO-PCR, allele-specific oligonucleotide-polymerase chain reaction; NGS, Next-generation sequencing; MRD, minimal residual disease; IMF, International Myeloma Foundation

5 96 MRD MRD 謝 LSI Adaptive Biotechnologies Malek Faham ( ) 辞参考文献 1 ) Inaba H, Coustan-Smith E, Cao X, et al: Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol 30: , ) Araki D, Wood BL, Othus M, et al: Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission? J Clin Oncol, ) Sanchez-Garcia J, Serrano J, Serrano-Lopez J, et al: Quantification of minimal residual disease levels by flow cytometry at time of transplant predicts outcome after myeloablative allogeneic transplantation in ALL. Bone Marrow Transplant 48: , ) Rawstron AC, Child JA, de Tute RM, et al: Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol 31:2540-7, ) Voena C, Ladetto M, Astolfi M, et al: A novel nested-pcr strategy for the detection of rearranged immunoglobulin heavychain genes in B cell tumors. Leukemia 11:1793-8, ) Santamaria C, Chillon MC, Fernandez C, et al: Using quantification of the PML-RARalpha transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia. Haematologica 92:315-22, ) Krauter J, Gorlich K, Ottmann O, et al: Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol 21: , ) Etienne G, Dulucq S, Nicolini FE, et al: Achieving deeper molecular response is associated with a better clinical outcome in chronic myeloid leukemia patients on imatinib front-line therapy. Haematologica 99:458-64, ) Lapillonne H, Renneville A, Auvrignon A, et al: High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 24: , ) Weisser M, Kern W, Rauhut S, et al: Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 19: , ) Bassan R, Spinelli O, Oldani E, et al: Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 113: , ) Ferrero S, Ladetto M, Drandi D, et al: Long-term results of the GIMEMA VEL trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics impact on survival. Leukemia 29:689-95, ) Takamatsu H, Ogawa Y, Kobayashi N, et al: Detection of minimal residual disease in patients with multiple myeloma using clonotype-specific PCR primers designed from DNA extracted from archival bone marrow slides. Exp Hematol 41: , ) Wee R, Takamatsu H, Murata R, et al: A Comparison of Minimal Residual Disease Detection Among ASO-PCR, Dd-PCR and Deep-Sequencing in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation. Blood (ASH Annual Meeting Abstract #1782), ) Faham M, Zheng J, Moorhead M, et al: Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 120: , ) Ladetto M, Bruggemann M, Monitillo L, et al: Nextgeneration sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia 28: , ) Martinez-Lopez J, Lahuerta JJ, Pepin F, et al: Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 123:3073-9, ) Logan AC, Vashi N, Faham M, et al: Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant 20: , ) Takamatsu H, Murata R, Zheng J, et al: Prognostic Value of Sequencing-Based Minimal Residual Disease Detection in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation. Blood (ASH Annual Meeting Abstract #1788), ) Roschewski M, Dunleavy K, Pittaluga S, et al: Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 16:541-9, 2015

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