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A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis

Giovanni Palladini, Ute Hegenbart, Paolo Milani, Christoph Kimmich, Andrea Foli, Anthony D. Ho, Marta Vidus Rosin, Riccardo Albertini, Remigio Moratti, Giampaolo Merlini and Stefan Schönland

Data supplements

  • Supplemental materials for: Palladini et al

    Files in this Data Supplement:

    • Supplemental Figure 1 (PDF, 362 KB) - Progression to dialysis in the overall population according to the novel criterion of renal progression. Six-month landmark analysis by renal stage.

Article Figures & Data

Figures

  • Figure 1

    Patients’ survival and time to dialysis. (A) Patients’ survival. Median survival was 47 months in the Pavia cohort and 54 months in the Heidelberg cohort (P = .230). (B) Renal survival (P < .001). (C) Survival from dialysis initiation. Median survival was 39 months in the Pavia cohort and 24 months in the Heidelberg cohort (P = .102).

  • Figure 2

    Progression to dialysis according to renal stage. (A) Testing cohort (461 patients; P < .001). (B) Validation cohort (271 patients; P < .001). Renal stage I: both proteinuria ≤5 g/24 h and eGFR ≥50 mL/min per 1.73 m2. Renal stage II: either proteinuria >5 g/24 h or eGFR <50 mL/min per 1.73 m2. Renal stage III: both proteinuria >5 g/24 h and eGFR <50 mL/min per 1.73 m2.

  • Figure 3

    Progression to dialysis in the testing and validation cohorts according to the novel response and progression criteria (6-month landmark analysis). (A) Renal progression in the testing cohort (P < .001). (B) Renal progression in the validation cohort (P < .001). (C) Renal response in the testing cohort (P < .001). (D) Renal response in the validation cohort (P = .039). (E) Hematologic response in the testing cohort (P = .014). (F) Hematologic response in the validation cohort (P < .001). Renal progression is defined as a decrease in eGFR ≥25%. Renal response is defined as a decrease in proteinuria ≥30% or a drop of proteinuria below 0.5 g/24 h in the absence of renal progression. VGPR is defined as dFLC <40 mg/L.

  • Figure 4

    Progression to dialysis in the overall population according to the novel response and progression criteria (3-month landmark analysis). (A) Renal progression (P = .002). (B) Renal response (P < .001). (C) Hematologic response (P = .013). Renal progression is defined as a decrease in eGFR ≥25%. Renal response is defined as a decrease in proteinuria ≥30% or a drop of proteinuria below 0.5 g/24 h in the absence of renal progression. VGPR is defined as dFLC <40 mg/L.

Tables

  • Table 1

    Patients’ characteristics

    VariablePavia cohort (n = 461)Heidelberg cohort (n = 271)P
    n (%) or median (IQR)n (%) or median (IQR)
    Age, y64 (56-61)61 (54-68)<.001
    Gender, male264 (57)159 (59).710
    Organ involvement
     Heart322 (70)190 (70).940
     Liver75 (16)72 (27).001
     Peripheral nervous system55 (12)39 (14).337
     Soft tissues49 (11)91 (33)<.001
    Cardiac stage I/II/III105 (23)/196 (42)/160 (35)59 (27)/89 (41)/70 (32)*.504
    NT-proBNP > 8500 ng/L85 (18)43 (16).377
    Proteinuria, g/24 h5.1 (2.3-9.4)6.0 (3.3-9.0).046
    Serum creatinine, mg/dL1.11 (0.87-1.70)1.1 (0.83-1.63).184
    eGFR, mL/min per 1.73 m262 (38-84)64 (42-88).204
    CKD stage 1/2/3/4/594 (21)/148 (32)/139 (30)/53 (11)/27 (6)65 (24)/92 (34)/73 (27)/34 (12)/7 (3).154
    dFLC, mg/L160 (62-402)126 (54-306).219
    Type of first-line treatment
     Melphalan + dexamethasone214 (46.4)87 (32.1)<.001
     Bortezomib based128 (27.8)55 (20.3).024
     Thalidomide based57 (12.4)1 (0.4)<.001
     Dexamethasone alone34 (7.4)8 (2.9)<.001
     Autologous stem cell transplant19 (4.1)80 (29.5)<.001
     Treatment of IgM clones9 (1.9)1 (0.4)
     Melphalan + prednisone0 (0.0)16 (5.9)
     Anthracycline based0 (0.0)9 (3.3)
     Bendamustine0 (0.0)1 (0.4)
     Untreated0 (0.0)13 (4.8)
    Type of second-line treatment
     Bortezomib based79 (42.5)62 (60.2).004
     Thalidomide based39 (21.0)6 (5.8)<.001
     Lenalidomide based19 (10.2)13 (12.6).532
     Melphalan + dexamethasone19 (10.2)14 (13.6).387
     Autologous stem cell transplant18 (9.7)0 (0.0).001
     Pomalidomide-dexamethasone5 (2.7)0 (0.0)
     Treatment of IgM clones4 (2.1)2 (1.9)
     Dexamethasone alone3 (1.6)0 (0.0)
     Bendamustine0 (0.0)3 (2.9)
     Ixazomib0 (0.0)2 (1.9)
     Melphalan + prednisone0 (0.0)1 (1.0)
    • The differences in treatment reflected different strategies over time. Chronic kidney disease stages are defined according to eGFR as follows: stage I, ≥90 mL/min per 1.73 m2; stage II, 60 to 89 mL/min per 1.73 m2; stage III, 30 to 59 mL/min per 1.73 m2; stage IV, 15-29 mL/min per 1.73 m2; and stage V, <15 mL/min per 1.73 m2.

    • CKD, chronic kidney disease; dFLC, difference between involved (amyloidogenic) and uninvolved free light chain; IgM, immunoglobulin M; IQR, interquartile range; NT-proBNP, N-terminal pro–natriuretic peptide type B.

    • * Available in 218 patients.

    • The 8500 ng/L NT-proBNP cutoff identifies patients with advanced cardiac involvement.8

  • Table 2

    Cox analysis of variables predicting progression to dialysis in the testing cohort (Italian cohort, n = 461)

    VariableHR (95% CI)P
    Univariate analysis
     Age, y1.00 (0.98-1.03).879
     Male gender0.73 (0.46-1.16).190
     Heart involvement1.07 (0.65-1.73).779
     Cardiac stage III1.21 (0.69-2.15).505
     Liver involvement1.11 (0.60-2.07).737
     Proteinuria, g/24 h1.11 (1.07-1.15)<.001
     Proteinuria >5 g/24 h3.67 (2.05-6.57)<.001
     eGFR, mL/min per 1.73m20.96 (0.95-0.97)<.001
     eGFR <50 mL/min per 1.73 m26.96 (4.15-11.68)<.001
     Serum albumin, g/L0.44 (0.29-0.79).025
     Serum albumin <30 g/L4.20 (0.91-19.29).067
     dFLC1.00 (0.99-1.01).846
     dFLC >160 ng/L1.00 (0.62-1.62).999
    Multivariate model including continuous variables
     Proteinuria, g/24 h1.08 (1.03-1.12)<.001
     eGFR, mL/min per 1.73 m20.96 (0.95-0.97)<.001
     Serum albumin, g/L1.52 (0.64-6.85).186
    Multivariate model including dichotomous variables
     Proteinuria >5 g/24 h3.91 (2.18-7.00)<.001
     eGFR <50 mL/min per 1.73 m27.24 (4.31-12.15)<.001
     Serum albumin <30 g/L1.37 (0.74-8.56).214
    • dFLC, difference between involved (amyloidogenic) and uninvolved free light chain.

  • Table 3

    Cox analysis of the impact of proposed response and progression criteria on renal survival (6-month landmark analysis)

    CriteriaDefinitionTesting cohort (n = 301)Validation cohort (n = 171)
    HR (95% CI)PHR (95% CI)P
    Renal progression≥25% decrease in eGFR4.56 (2.44-8.52)<.0014.74 (2.64-8.50)<.001
    Renal response≥30% decrease in proteinuria or drop of proteinuria below 0.5 g/24 h in the absence of renal progression0.15 (0.05-0.49)<.0010.25 (0.06-0.98).039
    Target hematologic responseVGPR (dFLC <40 mg/L in patients with baseline dFLC ≥50 mg/L) or CR (negative serum and urine immunofixation and normal FLC ratio)0.47 (0.25-0.87).0140.24 (0.13-0.48)<.001
    • CR, complete response; dFLC, difference between involved (amyloidogenic) and uninvolved free light chain.