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免疫グロブリン遊離鎖 κ/λ比

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免疫グロブリン遊離鎖 κ/λ比

  1. 1. 免疫グロブリン遊離L鎖κ/λ比 • 免疫グロブリンはリンパ, 形質細胞で合成 – 1つの形質細胞より1種類のH鎖, L鎖が産生され, H鎖はγ(IgG), α(IgA), µ(IgM), δ(IgD), ε(IgE)の5種あり, L鎖はκとλ鎖の2種類ある. – 多発性骨髄腫のような形質細胞が単クローン性に増殖している場合, κ鎖 or λ鎖どちらかが優位に増加するため, κ/λ比は偏る. – また, L鎖はH鎖より40%ほど過剰に産生されるため, H鎖と結合できないL鎖が増加する(free light chain; FLC). モダンメディア 2012;58:278-283 • 従って, κ/γ比やFLCの評価がMMの早期診断や フォローに使用できる可能性がある. – 単クローン性のFLCはBence Jones蛋白のこと. – 健常人におけるκ型FLC 7.3[3.3-19.4], λ型FLC 12.7[5.7-26.3]mg/Lであり, κ/λ比は0.58[0.26-1.65]が正常範囲とされる. Am. J. Hematol. 85:787–790, 2010.
  2. 2. • また, 従来のM蛋白測定法の検出感度は, – 血清蛋白電気泳動法(SPE)で500-2000mg/L, IFE法(Immunofixation; 免疫電気泳動)で150-500mg/Lであるのに対し, • FREELITETMを用いたFLCの測定では5mg/Lとかなり優秀. – 従ってMGUSや多発性骨髄腫の早期診断が可能となる. (ただし, 多クローン性のものの鑑別が必要となる) – 多クローン性のFLCが上昇する疾患は, 腎不全(排出低下), 慢性炎症, 膠原病等. – 末期腎不全でのκ/λ比は1.19[0.37-3.1]となる Am. J. Hematol. 85:787–790, 2010. – ただし, H鎖とL鎖の産生バランスが1:1のMMではFLCは正常 • 単クローン性と多クローン性FLCの鑑別に有用なのがκ/λ比 – κ/λ比が0.26-1.65ならば多クローン性の可能性が高く, <0.26ではλ型の単クローン性, >1.65ならばκ型の単クローン性となる. モダンメディア 2012;58:278-283
  3. 3. 100 000 血清λ型FLC濃度(mg/L) 10 000 + 健常者(n=282) ● BJP-κ型多発性骨髄腫(n=120) 1000 □ 腎機能障害(n=31) ▲ BJP-λ型多発性骨髄腫(n=104) 100 ○ 非分泌型多発性骨髄腫(n=28) 10 1 0.1 0. 1 1 10 0 10 0 00 1 10 00 血清κ型FLC濃度(mg/L) 0 0 10 0 00 図 3 健常者と多発性骨髄腫患者における血清 FLC 値の分布 (文献 7 から引用)  健常者と腎機能障害患者においてはκ/λ比が基準範囲内に分布しているが、 多発性骨髄腫患者におけるκ/λ比は異常値を示す。
  4. 4. • 尿中のκ/λ比の尿中BJP陽性に対する感度, 特異度は, – Cutoffは <0.1, >5.5とした場合, 感度 86.4%[75.0-94.0], 特異度 94.0%[88.6-97.0] Clin Chem Lab Med 2004;42(4):429–434 • Monoclonal gammopahtyの精査をされた833例では, – 最終的に28例がMM, 25例がB-cell NHL, 156例がMGUS – 血清蛋白電気泳動(PE), 血清FLC κ/λ比, 血清, 尿中IFEの 上記疾患群(monoclonal P. Vermeersch et al B-cell disorders)に対する感度, 特異度は, Table I. Comparison of different strategies for the diagnosis of malignant monoclonal B-cell disorders and MGUS. Strategy Sensitivity (%) Specificity (%) Missed monoclonal B-cell disorders and MGUS FLC j/k ratio SPE SPE ± IFE SPE ± IFE + UIFE SPE ± IFE + FLC j/k ratio SIFE SIFE + FLC j/k ratio SIFE + UIFE 36Æ8 80Æ4 78Æ5 81Æ8 82Æ3 91Æ9 93Æ8 92Æ3 96Æ8 77Æ9 100 100 96Æ8 100 96Æ8 100 3 MM, 1 PC, 112 MGUS, 16 B-NHL 1 MM, 1 AL-A, 1 PC, 25 MGUS, 13 B-NHL 1 MM, 1 AL-A, 1 PC, 26 MGUS, 16 B-NHL 24 MGUS, 14 B-NHL 1 PC, 23 MGUS, 13 B-NHL 15 B-NH L, 2MGUS 12 B-NHL, 1 MGUS 14 B-NHL 2 MGUS AL-A, AL amyloidosis; PC, plasmacytoma; MM, multiple myeloma; SIFE, serum immunofixation electrophoresis; UIFE, urine immunofixation British Journal of Haematology 2008;143:496–502 electrophoresis; SPE ± IFE, serum IFE on positive serum PE (SPE) samples.
  5. 5. was 36Æ8% (Table I). Serum FLC j/k ratio was abnormal (i) in 24 of the 28 patients (86%) diagnosed with a malignant plasma cell disorder (including 18 patients with an intact MM, two with a light chain MM, and three with AL amyloidosis), (ii) in nine of the 25 patients with a B-NHL (36%), and (iii) in 44 of the 156 patients (28%) diagnosed with MGUS (Table II). Twenty-three patients had an abnormal j/k ratio but no monoclonal band on serum or urine IFE. Of these 23 patients, three were diagnosed with a B-NHL (Table III, patients 1–3). The results and clinical data of the other 20 patients that were considered false-positive are summarized in Table III (Patients 4–23). The specificity of serum FLC j/k ratio in our study was 96Æ8%. Six of the 20 (30%) false-positive patients had a polyclonal increase of immunoglobulins compared to 99 of the 604 (16%) true-negative patients. Nine of the 20 (45%) falsepositive patients had a glomerular filtration rate (GFR) of <60 ml/min/1Æ73 m2 compared to 243 of the 604 (40%) truenegative patients. Five (20%) false-positive patients had a GFR of <30 ml/min/1Æ73 m2 compared to 97 (16%) true-negative patients. The percentage of false-positive results in patients with a GFR of GFR of ‡60, <60 and <30 ml/min/1Æ73 m2 was 2Æ9%, 3Æ6% and 4Æ9% respectively. • FLC κ/λ比は MM, リンパ腫, AL-Amyloidosisに保険適応があるが, – リンパ腫に対する感度はイマイチ. – MGUSも正常例が多い. Serum FLC j/k ratio in patients with a malignant plasma cell disorder or MGUS British Serum FLC j/k ratio was abnormal in 77 of the 209 patients (36Æ8%) with a malignant plasma cell disorder, B-NHL or MGUS (Tables I and II). Of these 77 patients, 74 had a monoclonal band on serum and/or urine IFE. The change in serum FLC j/k ratio was concordant with serum and/or urine IFE in 73 of the 74 patients. One patient who was diagnosed with a IgGk MGUS (reconfirmed 6 months later) had an increased serum FLC j/k ratio with individual concentrations of j and k within the normal reference range. The sensitivity of serum FLC j/k ratio in patients with a monoclonal gammopathy on serum and/or urine IFE was 38Æ3%. Journal of Haematology 2008;143:496–502 Three patients diagnosed with a B-NHL had an abnormal j/k ratio but no monoclonal band on serum or urine IFE. The Table II. Results of different strategies using serum FLC, serum PE, serum IFE and/or urine IFE. Number of positive patients n j/k ratio SPE* SPE ± IFE* SIFE UIFE Malignant plasma cell disorders Intact MM  18 15 17 (1) 17 (1) 18 Light chain MMà 2 2 2 2 2 Plasmacytoma 1 0 0 0 1 Osteosclerotic myeloma 1 1 1 1 1 Plasma cell leukaemia 1 1 1 1 1 WM 2 2 2 2 2 Primary amyloidosis 3 3 2 2 3 All 28 24 25 25 28 B non-Hodgkin lymphoma (B-NHL) B-CLL 8 3 4 (1) 3 (1) 3 B-NHL (other) 17 6 8 (2) 6 (1) 7 All 25 9 12 (3) 9 (2) 10 Monoclonal gammopathy of unknown significance (MGUS) All§ 156 44 131 (3) 130 (3) 154 Other patients All 624 20 138 (47) 0 0 17 2 1 1 1 2 2 26 2 7 9 71 0 WM, Waldenstrom macroglobulinaemia; B-CLL, B-cell chronic lymphocytic leukaemia; SIFE, serum immunofixation electrophoresis; UIFE, urine immunofixation electrophoresis; SPE ± IFE, serum IFE on positive serum PE (SPE) samples. *Values within parentheses indicate the number of patients in which hypogammaglobulinaemia on CZE was the only abnormality.  Monoclonal component in patients with intact MM on SIFE: 9 IgGj, 3 IgGk, 4 IgAj, 1 IgAk, 1 IgDk. àMonoclonal component in patients with light chain MM on SIFE: 1 j, 1 k. §Monoclonal component in MGUS patients with SIFE: 59 IgGj, 40 IgGk, 1 IgG(k?), 29 IgMj, 8 IgMk, 2 IgM(?), 4 IgAj, 9 IgAk, 2 IgMj+k, 1 IgMj+IgGk, and 1 j (also in urine). Two patients with IgMk were negative with normal SIFE but positive when serum was kept at 37°C. 5 change in serum FLC j/k ratio in these three patients was concordant with the clonality of the malignant B-cell disorder (Table III, patients 1–3).
  6. 6. Table IV. Results of 25 patients newly diagnosed with a B non-Hodgkin lymphoma (including Ann Arbor stage at diagnosis). No Age (years) Sex SPE SIFE j (mg/l) k (mg/l) j/k ratio GFR UIFE Diagnosis/other details 1 2 3 4 5 6 7 8 9 10 11 74 66 66 71 58 58 58 64 64 80 56 F F M M M F M M F F F MP HypoG pMP 0 pMP 0 0 0 MP pMP 0 IgG-j IgG-j IgM-k 0 0 0 0 0 IgM-j IgM-k 0 52Æ7 › 12Æ9 12Æ8 13Æ0 18Æ1 9Æ4 12Æ9 17Æ9 68Æ0 › 28Æ0 › 3Æ57 11Æ3 4Æ6 fl 42Æ5 › 5Æ7 fl 18Æ2 10Æ0 14Æ3 32Æ4 › 39Æ4 › 110 › 21Æ3 4Æ66 2Æ82 0Æ30 2Æ30 0Æ99 0Æ94 0Æ90 0Æ55 1Æ73 0Æ29 0Æ17 12 13 14 15 16 17 18 57 61 59 81 67 47 46 F M M F F M F 0 0 0 GM 0 0 HypoG 0 0 IgM-j 0 0 0 0 12Æ4 30Æ7 › 14Æ2 14Æ3 41Æ5 › 12Æ3 10Æ0 19 20 21 22 23 24 25 77 80 51 59 76 61 65 F F M F M F M 0 MP pMP 0 MP HypoG RP 0 IgG-j IgG-j 0 IgM-j IgM-j 0 17Æ9 144 › 24Æ3 › 8Æ9 34Æ4 › 3Æ6 34Æ4 › › › › fl fl ‡60 ‡60 52 ‡60 ‡60 ‡60 ‡60 ‡60 46 51 51 j 0 k 0 0 0 0 0 j k 0 41Æ8 › 22Æ7 8Æ8 19Æ4 38Æ0 › 15Æ2 5Æ0 fl 0Æ30 1Æ35 1Æ61 0Æ74 1Æ09 0Æ81 2Æ02 › ‡60 ‡60 ‡60 ‡60 ‡60 ‡60 30 k 0 j 0 0 0 0 15Æ8 12Æ3 20Æ7 11Æ2 11Æ7 4Æ5 fl 62Æ8 › 1Æ13 11Æ71 › 1Æ17 0Æ80 2Æ94 › 0Æ79 0Æ55 48 ‡60 ‡60 ‡60 46 ‡60 ‡60 0 j 0 0 j 0 0 › B-CLL (BM: s-j) B-CLL (BM: s-j) B-CLL (BM: cy-k) B-CLL (BM: s-j) (Table III, patient 1) B-CLL (BM: s-k) B-CLL (BM: s-j) B-CLL (BM: s-j) B-CLL (BM: s-j) B-NHL: marginal zone lymphoma? (stage IVa) Mantle cell lymphoma (stage IVb) (BM: s-k) Mantle cell lymphoma (stage IVb) (BM: s-k) (Table III, Patient 2) Mantle cell lymphoma (stage IVb) (BM: s-k) Mantle cell lymphoma (stage IVb) Mantle cell lymphoma (stage IVa) (BM: s-j) MALT-lymphoma (stage IVa) MALT-lymphoma (stage Ia) Follicular lymphoma (stage IIIa) Follicular lymphoma (stage IIa) (lymph node: k) (Table III, patient 3) Follicular lymphoma (stage IIa) Diffuse large B-cell lymphoma (stage IVb) Diffuse large B-cell lymphoma (stage IIIsb) Diffuse large B-cell lymphoma (stage IIea) Diffuse large B-cell lymphoma (stage IIea) Diffuse large B-cell lymphoma (stage Ib) Post-transplant lymphoproliferative disorder (stage IVa) British Journal of Haematology 2008;143:496–502 Results of immunophenotyping are given within parentheses. +, abnormal (cfr. methods); 0, no abnormality detected; s-j, surface IgKappa; cy-k, cytoplasmatic IgLambda; DD, differential diagnosis; SPE, serum protein electrophoresis; SIFE, serum immunofixation electrophoresis; UIFE, urine immunofixation electrophoresis; B-CLL, B-cell chronic lymphocytic leukaemia; MALT-lymphoma, mucosa-associated lymphoid tissue lymphoma.
  7. 7. Immunochemotherapy Median FLC Kappa J Range Lambda Range Total FLC Range Abnormal FLC ratio Elevated FLC Elevated kappa Elevated lambda 76 1.53 Clin Oncol 2011;29:1620-1626. 0.73-5.57 1.69 0.43-15.2 3.27 1.48-19.1 • リンパ腫におけるFLC ratioの異常は0-36%と様々. – リンパ腫のタイプにより異なり, 100 9 26 23 11 DLBCLでは8%程度, Mantle-cell lymphomaでは36%. CLL/SLLでは24%. 11.8 34.2 30.3 14.5 • DLBCLにおけるFLC ratioの予後予測能 Abbreviations: NCCTG, North Central Cancer Treatment Group; SPORE, Specialized LDH, lactate dehydrogenase; ULN, upper limit of normal; IPI, International Prognosti – North Central Cancer Treatment Group trialよりDLBCL 76例, University of lowa/Mayo Clinic Specialized age, worse performance status, advancedExcellence creatProgram of Research  stage, and elevated Molecular Epidemiology inine, although association with the IPI was modest (Table 2). An increase in serum Resource(MER)より219例を解析 FLC was univariately associated with EFS and OS in both cohorts for ␭ (all P Ͻ .05), ␬ (all P Ͻ .02), and total FLC (all P Ͻ .002) measurements (Appendix Table A1, Appendix Figs – FLC ratioの異常は全体の14%で認められた. Lambda mg/dL 100 MER N0489 10 i T F ␬ 1 1 0.1 A i a E O s . ( w ( 1 10 100 Kappa mg/dL Fig 1. Pretreatment serum free light chain values (mg/dL) from North Central Cancer Treatment Group N0489 and Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) cohorts. Dashed box indicates normal range. n e h e 2 a
  8. 8. Table 1. Clinical Characteristics of the Patients With New, Untreated Diffuse Large B-Cell Lymphoma Enrolled Onto This Study NCCTG N0489 (n ϭ 76) Characteristic Median age, years Range Male sex Age Ͼ 60 years Performance status 2ϩ Ann Arbor stage III/IV Two or more extranodal sites LDH Ͼ ULN IPI 0-1 2 3 4-5 B symptoms Bulky disease Bone marrow involvement Creatinine Ͼ ULN Immunochemotherapy Median FLC Kappa Range Lambda Range Total FLC Range Abnormal FLC ratio Elevated FLC Elevated kappa Elevated lambda No. % SPORE MER (n ϭ 219) No. 62 21-82 % All Patients (N ϭ 295) No. 64 21-93 % 62 21-93 43 43 11 61 25 52 56.6 56.6 14.5 80.3 32.9 68.4 117 131 42 126 46 103 53.4 59.8 19.2 58.1 21.4 48.4 160 174 53 187 71 155 54.2 59.0 18.0 63.8 24.4 53.6 18 17 28 13 29 13 9 12 76 23.7 22.4 36.8 17.1 38.2 17.1 11.8 15.8 100 79 59 49 32 46 26 29 28 186 36.1 26.9 22.4 14.6 21.0 11.9 14.3 13.4 85.3 97 76 77 45 75 39 38 40 262 23.9 25.8 26.1 15.3 25.4 13.3 13.6 14.0 89.1 1.53 0.73-5.57 1.69 0.43-15.2 3.27 1.48-19.1 9 26 23 11 1.48 0.02-45.7 1.44 0.20-11.8 2.93 0.37-51.1 11.8 34.2 30.3 14.5 32 68 63 29 1.50 0.02-45.7 1.51 0.20-15.2 3.08 0.37-51.1 14.8 31.1 28.8 13.2 41 94 86 40 14.0 31.9 29.2 13.6 Abbreviations: NCCTG, North Central Cancer Treatment Group; SPORE, Specialized Program of Research Excellence; MER, Molecular Epidemiology Resource; LDH, lactate dehydrogenase; ULN, upper limit of normal; IPI, International Prognostic Index; FLC, free light chain. J Clin Oncol 2011;29:1620-1626.
  9. 9. Table 2. Association of Clinical Characteristics With FLC Abnormalities Characteristic No. % Elevated FLC OR All patients Sex Female Male Age, years Ͻ 60 60ϩ Performance status 0-1 2ϩ Ann Arbor stage I-II III-IV Extranodal sites, No. 0-1 2ϩ LDH Ͻ ULN Ͼ ULN B symptoms Absent Present Bulky disease Absent Present Bone marrow involvement No Yes Creatinine Ͻ ULN Ͼ ULN Treatment Immunochemotherapy Other IPI 0-1 2 3 4-5 0-2 3-5 295 31.9 135 160 28.2 35.0 1.00 1.37 121 174 20.7 39.7 1.00 2.52 242 53 26.9 54.7 1.00 3.29 106 187 24.5 35.8 1.00 1.72 220 71 32.3 28.2 1.00 0.82 134 155 33.6 31.0 1.00 0.89 220 75 30.0 37.3 1.00 1.39 255 39 31.0 38.5 1.00 1.39 241 38 29.5 36.8 1.00 1.40 245 40 28.6 57.5 1.00 3.38 262 32 30.5 40.6 0.62 1.00 97 76 77 45 173 122 22.7 34.2 37.7 37.8 27.8 37.7 1.00 1.77 2.06 2.07 1.00 1.58 95% CI P % Abnormal ␬:␭ Ratio OR 95% CI P .21 11.9 15.7 1.00 1.39 0.71 to 2.72 .34 Ͻ .001 11.7 15.6 1.00 1.40 0.70 to 2.80 .34 Ͻ .001 13.3 17.3 1.00 1.37 0.61 to 3.07 .45 .05 10.4 16.2 1.00 1.67 0.80 to 3.49 .17 .52 16.5 7.0 1.00 0.38 0.14 to 1.02 .05 .64 15.7 13.1 1.00 0.81 0.42 to 1.57 .53 .24 12.3 18.9 1.00 1.66 0.82 to 3.67 .16 .35 14.6 10.3 1.00 0.67 0.22 to 1.99 .47 .36 12.5 24.3 1.00 2.25 0.67 to 5.23 .06 1.70 to 6.71 .005 12.4 25.0 1.00 2.37 1.05 to 5.33 .04 0.30 to 1.36 .25 13.9 15.6 0.87 1.00 0.31 to 2.40 .78 10.3 19.7 16.0 8.9 14.5 13.3 1.00 2.14 1.66 0.85 1.00 0.91 0.90 to 5.08 0.67 to 4.08 0.25 to 2.87 .08 .27 .79 0.46 to 1.79 .79 14.0 0.83 to 2.25 1.48 to 4.37 1.79 to 6.06 1.01 to 2.93 0.46 to 1.48 0.54 to 1.46 0.80 to 2.41 0.69 to 2.80 0.68 to 2.86 0.91 to 3.47 1.06 to 3.99 0.96 to 4.46 .09 .03 .06 0.96 to 2.59 .07 Abbreviations: FLC, free light chain; OR, odds ratio; LDH, lactate dehydrogenase; ULN, upper limit of normal; IPI, International Prognostic Index.
  10. 10. Event-Free Survival (%) FLC ratioの異常は予後不良因子の1つとなる. A 100 80 60 40 20 0 Nonelevated FLC - N0489 Nonelevated FLC - MER Elevated FLC - N0489 Elevated FLC - MER 12 24 36 48 60 48 60 Time (months) B Overall Survival (%) J Clin Oncol 2011;29:1620-1626. 100 80 60 40 20 0 Nonelevated FLC - N0489 Nonelevated FLC - MER Elevated FLC - N0489 Elevated FLC - MER 12 24 36 Time (months) Fig 2. (A) Event-free survival and (B) overall survival Kaplan-Meier survival curves by serum free light chain (FLC) in two cohorts (North Central Cancer Treatment Group trial N0489 and the Specialized Program of Research Excellence Molecular Epidemiology Resource [MER]) of patients with untreated diffuse large B-cell lymphoma.
  11. 11. • 1020例でFLC κ/λ比を評価 879 Clinical Chemistry 51, No. 5, 2005 – 899名のPlasma cell disorderを含む Clinical Chemistry 51:5 878 – 881 (2005) routine clinical laboratory practice, we reviewed the diagnoses and FLC results for these 1020 patients. Materials and Methods We queried the Laboratory Information System for the FLC results of all Mayo Clinic patients who were tested for serum ␬ and ␭ FLCs from January 1, 2003, to December 31, 2003. The list of 1020 patients was merged with data from the Dysproteinemia database, which contained each patient’s diagnosis, date of diagnosis, and serum and urine IFE results. Individual patient histories were reviewed for any patients not contained in the database. If a patient had more than one sample tested, only the initial 2003 sample was included in this study. The samples were obtained at the patient’s initial presentation, during disease monitoring, or depending on the diagnosis, post treatment. The treatment status of the AL and NSMM patients was determined from the patient history. All queries to the Laboratory Information System, Dysproteinemia database, or patient histories followed a protocol approved by the Mayo Institutional Review Board. The serum FLC assay was performed on the same day as the venipuncture and was reported to the patient’s medical record. The FLC assay (FREELITETM; The Binding Site Ltd.) (6 ) was performed on a Dade Behring BNII automated nephelometer. This assay consists of two sep- Table 1. Distribution of PCDs (n ‫.)998 ؍‬ Diagnosis No. of cases Multiple myeloma NSMM Osteosclerotic myeloma SMM Indolent/evolving myeloma Plasmacytoma (solitary) Extramedullary myeloma Multiple solitary plasmacytoma Macroglobulinemia IgM lymphoproliferative disease IgM lymphoma Smoldering macroglobulinemia Primary systemic amyloidosis LCDD MGUS Idiopathic Bence Jones proteinuria Heavy chain disease Cryoglobulinemia Acquired Fanconi syndrome Scleromyxedema Plasma cell leukemia 330 20 15 72 8 22 5 3 9 2 5 2 269 7 114 4 2 4 3 2 1 abnormal FLC ␬/␭ ratio. The 6 NSMM patients with normal FLC ␬/␭ ratios had all received a stem cell
  12. 12. FLC results. (It should be remembered, however, that in ALTable 2. FLC results. requires histopathologically confirmed the diagnosis CurrentAL amyloid.) With these Retrospective published data study 2 caveats in mind, we are Diagnosis n Abnormal FLC ratio, %regarding the diagnostic use of the FLC assay as n Abnormal FLC ratio, % Reference reassured Normal 282 0 Katzmann et al. (1 a tool that is complementary to other laboratory tests. ) Polyclonal 25 0 Katzmann et al. (1 ) The current gold standard for detection of a monocloNonmonoclonal gammopathy 121 0 NSMM, untreated 5 28 68 nal100 FLC is IFE. IFE assays are qualitative, Drayson although and et al. (2 ) NSMM, treated 15 60 their sensitivities may vary98among laboratoriesal. and AL, untreated 110 91 262 Lachmann et (3 ) among antiserum lots, nonlaboratorians tend to et al. (4 ) of 34 88 Abraham think LCDD 7 100 89 them as black or 19 white with no ambiguity Katzmann et al. (1 ) in results. The MGUS 114 44 97 43 Rajkumar et al. (7 ) use 88 a quantitative assay with defined normal cutoffs of SMM 72 relies on low assay variability and long-term reagent stability standard. Although we are reassured as new reagents formed by the clinical laboratory as samples were re-that will yield consistent results by the performance • ALとLCDD(light chain deposition disease)ではthis 1-year produced by a ceived, and during this 1-year time frame, are used 2 we prepared. TheFLC assay during currently study period, a of the FLC assay is different reagent lots. Earlier, we chose to single the define manufacturer, and there is no developed.international verifiable standard needs to be defined FLC ratioの感度は良好. reference interval for the FLC ␬/␭ ratio as the interval that In addition to the absence of false-positive results, this included all of the reference population to ensure high study has also Clinical Chemistry the FLC – 881 ratio as a validated use of 51:5 878 ␬/␭ (2005) specificity (1 ). The absence of abnormal results in the 121 diagnostic tool in the light chain diseases. The identificaTable tion of abnormal results in various AL (n ‫)011 ؍‬ patients with no monoclonal gammopathy in this study, 3. Diagnostic performance indisease groups closely however, was unexpected. We assume that 2 factors may Assay % diagnostic matches the published retrospective data. The Positive (CI)a have contributed to the absence of false-positive results. FLC ␬/␭ ratio results in AL are similar to those in 2 published studies 91 (84–96) The first is that most of the requests were from the (3, 4 ). In this study and in our previous retrospective Serum IFE 69 (60–78) Division of Hematology and not from general medical study (4 ), the sensitivity of the FLC assay in AL was lower Urine IFE 83 (74–89) practice. As the assay becomes more widely requested, we than the sensitivity of 98% reported by Lachmann et al. expect to see false-positive FLC results. The second, and ϩ urineThat study used a 95% reference interval95 (90–99) Serum IFE (3 ). IFE for the FLC perhaps more important, factor is that in this study some ␬ ␭ ratio (0.3–1.2) vs our use of a range that encompassed FLC ␬/␭ ratio ϩ/urine IFE 91 (84–96) of the clinical diagnoses may have been influenced by the 100% of the reference population (0.26 –1.65). None of the ratio ϩ serum IFE 99 (95–100) FLC ␬/␭ in FLC results. (It should be remembered, however, that 110 AL patients, however, had borderline FLC ␬/␭ ratios AL the diagnosis requires histopathologically confirmed All 3 assays that would have been categorized differently by the 2 99 (95–100) AL amyloid.) With these 2 caveats in mind, we are a criteria. determined by the exact diagnostic sensitivity CI, confidence intervalAny differences in thebinomial distribution. reassured regarding the diagnostic use of the FLC assay as therefore cannot be explained by the different criteria a tool that is complementary to other laboratory tests.
  13. 13. Log lambda FLC (mg/ L ) Log kappa/la FLC concentrations, but had an abnormal κ/λ FLC ratio. 0 The other case had elevated κ and λ FLC concentrations and, consequently, had Ann Hematol (2005) 84: 588–593 a normal κ/λ FLC ratio. There were 12 cases where M protein was not detected in -1 61例のMM, 45例の非MM例*, 120例のContorl群において, • serum PEP, although they were MM patients (Table 2). M protein was detected in three of these cases (37.5%, 3/8) by 蛋白電気泳動(PEP), 免疫固定電気泳動(IFE),12 cases had abnormal concentrations of IFE. However, all FLCを評価. -2 κ or λ FLC or abnormal κ/λ FLC ratios. Case 1 had normal Kappa type Lambda type Other disease Control concentrations of both – MM 非MM症例は腎疾患, DM, 悪性リンパ腫, CTD, 悪性腫瘍, FLC types and case 2 showed a group group MM normal κ/λ FLC ratio due to increases in both κ and λ FLC 高血圧, 慢性B型肝炎, BPH, and 塞, IDA, クローン病, 骨髄炎. Fig. 1 Distribution of κ and λ FLC concentrations (a)脳 κ/λ FLC concentrations. Table 2 shows that they were mostly light ratios (b) in the multiple myeloma group, other diseases group, and 590 chain type MM, and the detected M protein at the time of control group – FLC κ/λ比は, Adiagnosis was mainly in the β region. Cases 6 and 7 had 6 high κ FLC concentrations (>4,000 mg/l), but they were nine λ light chain types. Control群と MMと非MM, In urine, the monoclonal im- not detected by PEP. 5 FLC concentrations in the MM urine samples were munoglobulin and light chains were composed of five 明らかに異なる. IgG-κ types, one IgA-κ type, two IgA-λ types, three κ light similar to those in the serum samples. Twelve of 14 cases 4 had abnormal FLC concentrations according to their chain types, and three λ light chain types. – PEPとFLCのMMに対する abnormal κ/λ Fifty-nine out of 61 MM patients (97%) had elevated κ specific light chain type and all cases hadKappa type MM 3 Lambda type MM or λ FLC concentrations according to their specific light FLC ratios. Although the FLC concentrations in the urine 感度, 特異度は Otherdis, group chain type and simultaneously showed abnormal κ/λ FLC samples were all abnormal, M protein was not detected by 2 Control group ratios. One of the other two patients had normal κ and λ PEP in six of these samples (Table 3). Sensitivity (%) Specificity (%) PPV (%) NPV (%) PEP 76.3 100 100 71.4 Cutoff values of upper limit in diagnostic ranges of κ/λ FLC ratioa >1.2 96.1 84.2 73.7 97.9 >1.5 93.4 95.8 91.0 96.9 >2.0 89.5 100 100 95.3 PPV positive predictive value, NPV negative predictive value The lower limit in each diagnostic range is 0.3 a 0 Other diseases group -1 The other diseases group was divided into three subgroups 3 5 by -1 serum PEP1 results: A, no abnormal findings (n=19, 42%); B, polyclonal FLC (mg/ L ) Log kappa gammopathy with an increased γ globulin fraction (n=17, 38%); and C, minor abnormalities Bother than polyclonal gammopathy such as increased α and/or β globulin fractions (n=9, 20%) (Table 4). The subgroup with no abnormal findings 13 14 cases with had 2 normal κ/λ FLC ratios (11 normal and three elevated FLC concentrations) and five cases with abnormal κ/λ FLC C ratio Table 1 Comparison of diagnostic characteristics for the PEP and cutoff values of κ/λ FLC ratio 1 1 Ta PE Ca 1 2 3 4 5 6 7 8 9 10 11 12 IF n a T [4 m κ
  14. 14. test of the month Am. J. Hematol. 85:787–790, 2010. Figure 1. A diagnostic algorithm for the evaluation of a patient with a suspected monoclonal gammopathy. The screening panel includes quantitative immunoglobulins/serum protein electrophoresis (Igs/SPEP) and immunofixation electrophoresis (IFE) if necessary, along with quantitative serum free light chains (sFLC) with Kappa/Lambda ratio (j/k). Occasionally 24 hour urine for evidence of monoclonal FLC or Bence-Jones protein (BJP) by electrophoretic assays is required. The presence of a monoclonal band warrants an IFE and sFLC with j/k ratio (if not already sent), so as to characterize the monoclonal gammopathy. A normal SPEP/IFE and/or unexplained hypogammaglobulinemia warrants the performance of sFLC with j/k ratio so as to exclude light chain myeloma (LCM), light chain deposition disease (LCDD), or primary AL amyloidosis. *If the work up for monoclonal gammopathy (including sFLC with j/k ratio and urine BJP) is negative but the clinical suspicion of AL amyloid is high, appropriate tissue biopsy 14 with special staining for amyloid must be performed. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
  15. 15. • FLCはフォローにも有用. – FLCの半減期はκで2-4h, λで3-6h, 一方, ImmunoglobulinはIgGで20-25d(IgG3で8d),  IgAで6d, IgDで3d, IgEで2dであり, 治療への反応はよりFLCで迅速. – 治療の強度やレジメ変更への判断基準となる可能性が示唆される. 15
  16. 16. tudy cohort was derived from persons who resided in the 11 counties outheastern Minnesota who met previously established diagnostic Blood. 2005; 106:812-817 ia for MGUS at the Mayo Clinic from January 1, 1960, through mber 31, 1994.5 Of 1384 patients with MGUS diagnosed during this d, a cohort whose baseline characteristics, methods of detection, w-up, and risk of progression have been well described by us earlier,5 – 1148例のMGUSのフォロー. patients who had cryopreserved serum samples collected within 30 of the MGUS diagnosis were studied. Follow-up was through the 15年間フォローし, 悪性化したのは87例(7.6%)であった. w of each patient’s complete medical records at the Mayo Clinic. The AUGUST 2005 ⅐ VOLUME 106, NUMBER 3 BLOOD, 1 was approved by the Mayo Institutional Review Board. – FLC κ/λ比の異常(<0.26, >1.65)はMMへの移行HR 2.6[1.7-4.2] he FLC level in serum collected at the time MGUS was first nized was determined on all 1148 patient samples using the FLC assay Table 3. Multivariate analysis of prognostic factors for progression lite; The Binding Site, Birmingham, United Kingdom) performed on a of monoclonal gammopathy of undetermined significance -Behring Nephelometer (Deerfield, IL).12-14 It consists of 2 separate Hazard ratio (95% urements, one to detect free-kappa (normal range, 3.3-19.4 mg/L) and Prognostic factor confidence interval)* other to detect free-lambda (normal range, 5.7-26.3 mg/L) light s.16 In addition to measuring the absolute levels of FLC, the test also Abnormal FLC ratio 2.6 (1.7-4.2) s the assessment of clonality based on the ratio of kappa-lambda light • FLC比はMGUS→MMのリスク因子となる Serum M protein size 2.4 (1.7-3.5) IgA, IgM, or biclonal IgA plus IgM 2.6 (1.7-4.0) *P Ͻ .001 for each variable. confidence interval [CI], 2.3-5.5; P Ͻ .001). The risk of progression to myeloma or related malignancy at 10 years was 17% with an abnormal ratio compared with 5% with a normal ratio; corresponding rates at 20 years were 35% and 13%, respectively (Figure 1B). There was a good correlation between increasingly abnormal FLC ratio and the relative risk of progression (Figure 2A). The 16 absolute risk of progression at 5, 10, 15, and 20 years for varying FLC ratios is given in Table 2.
  17. 17. 0 • IgG4-RSDではκ/λ比は上昇する傾向. – 16例においてκ/λ比を評価; Control IgG4 IgG4 RD RD NA 0 Control IgG4 IgG4 RD RD NA Figure 1: Kappa/lambda serum FLC in patients with IgG4-RD. Comparison of serum-free 𝜅 and 𝜆 light chains in controls, IgG4RD patients with active disease (IgG4-RD) and nonactive disease (IgG4-RD NA). Median and interquartile ranges are shown. κ/λ比は1.63[1.06-3.2]と健常人よりも上昇する傾向にある. 4 International Journal of Rheumatology P = 0.0035 2700 1200 550 P = 0.02 P = 0.0003 P < 0.0001 550 450 500 350 450 No correlation was evidenced in our cohort between FLC levels and demographicP = clinical features of patients. 𝜅 and or 0.0049 7 𝜆 FLC levels were higher in patients with more than 3 organ involvement than in those with 3 or less (𝜅 49.8 mg/L (29.0– 6 799.2) versus 20.9 mg/L (20.1–61.85), 𝑃 = 0.2; 𝑙 29.63 mg/L (18.42–195.7) versus 18.4 mg/L (13.0–33.24), 𝑃 = 0.2) but the 5 difference was not statistically significant. P = 0.029 𝜆 sFLC (mg/L) 𝜅 sFLC (mg/L) 350 P = 0.029 𝜅/𝜆 ratio 3.3. 𝜅 : 𝜆 Ratio Is Increased in a Significant Proportion of IgG44 RD Patients. Normal 𝜅 : 𝜆 ratio according to the manufac300 turer is comprised between 0.26 and 1.65. In patients with 3 250 renal insufficiency the ratio can be higher and comprised between 0.37 and 3.01 [1]. 200 2 IgG4-RD patients with active disease had a significantly 150 higher 𝜅 : 𝜆 FLC ratio than controls (Figure 2) with a median 100 1.63 (1.06–3.2) versus 1.00 (0.91–1.1) (𝑃 = 0.0049). The 𝜅 : 𝜆 1 FLC ratio was higher than the upper range of 3.01 in 2 out 50 of 4 IgG4-RD patients with renal insufficiency (range 1.25– 0 0 5.11). It was higher than the upper range of IgG4-RD (41.6%) 1.65 in 5/12 Control IgG4-RD Control IgG4 IgG4 Control IgG4 IgG4 IgG4-RD patients without renal AD insufficiency (range 2.09– NA RD RD NA RD RD NA 6.6). Thus 7 out of 16 (43.7%) IgG4-RD patient presented Figure increased abnormal 𝜅 FLC ratio in patients with IgG4Figure 1: Kappa/lambda serum FLC in patients with IgG4-RD. with an 2: Kappa/lambda serum: 𝜆 FLC ratio at diagnosis. The RD. FLC ratio was serum free 𝜅 and 𝜆 light chains ratio in controls, Comparison of serum-free 𝜅 and 𝜆 light chains in controls, IgG4𝜅 : 𝜆 Comparison of also statistically different when comparing IgG4-RD patients with inactive disease and controls (𝑃 = RD patients with active disease (IgG4-RD) and nonactive disease IgG4-RD patients with active disease (IgG4-RD AD) and nonactive disease (IgG4-RD NA). Median and active disease, 𝑃 = shown. (IgG4-RD NA). Median and interquartile ranges are shown. 0.029) but not with patients with interquartile ranges are 0.39. Serum Immunoglobulin Free Light Chain Assessment in IgG4-Related Disease. In both controls and IgG4-RD patients with inactive disease, International Journal of Rheumatology 2013; online all 𝜅 : 𝜆 FLC ratios were in the normal range. 400 250 120 110 100 90 80 70 60 50 40 30 20 10 0 5 I 6 w 𝜅 I 0 I a 7 b d s 3 a p 3 t 4 A i r p l t a s o a 𝜅
  18. 18. • FLC, κ/λ ratioの使用のまとめ – FLCはLight-chain only MM, AL amyloidosis, non-secretory MM, Oligo-secretory MMの早期発見に有用な検査と言える. Ligh-chain only MMでは尿FLCが疾患モニタリングとしても有用. – FLCはMMやAL amyloidosisの治療反応性評価に有用である. – FLCはMGUS, smouldering MM, solitary plasmacytomaにおける 悪性化のリスク評価に使用できる – MM診断時のFLCや治療による低下速度は予後評価に使用できる. – FLCはMM治療効果の早期判断に使用できる. 臨床的な利点については調査が必要. – FLCはリンパ増殖性疾患の診断にも有用. 特にWM, CLL, mantle cell lymphomaでの感度は良好 – スクリーニングとして, FLCは尿中Bence Jones protein評価に 代わる検査となる. ただし蛋白尿評価としては使用できない. 18 British Journal of Haematology 2008;141:413–422

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