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Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission

Roland B. Walter, Sarah A. Buckley, John M. Pagel, Brent L. Wood, Barry E. Storer, Brenda M. Sandmaier, Min Fang, Boglarka Gyurkocza, Colleen Delaney, Jerald P. Radich, Elihu H. Estey and Frederick R. Appelbaum

Article Figures & Data

Figures

  • Figure 1

    Association between pre-HCT MRD, as determined by multiparameter flow cytometry, and post-HCT outcome for AML patients in CR1 and CR2. Estimates of OS (A), DFS (B), cumulative incidence of relapse (C), and cumulative incidence of NRM (D) after myeloablative allogeneic HCT for AML in complete morphologic remission, shown individually for MRDneg (n = 147; black solid line) and MRDpos (n = 36; gray solid line) CR1 patients, as well as MRDneg (n = 52; black dashed line) and MRDpos (n = 18; gray dashed line) CR2 patients.

  • Figure 2

    Relationship between pre-HCT MRD levels, as determined by multiparameter flow cytometry, and post-HCT outcome for AML patients in morphologic remission. Estimates of OS (A), DFS (B), cumulative incidence of relapse (C), and cumulative incidence of NRM (D) after myeloablative allogeneic HCT for AML in complete morphologic remission, shown individually for patients without flow cytometric evidence of MRD (MRDneg; n = 199; black solid line), low-level MRD (≤0.1%; n = 14; gray solid line), intermediate-level MRD (>0.1%-1%; n = 24; gray long-dashed line), or high-level MRD (>1%; n = 16; gray short-dashed line).

Tables

  • Table 1

    Pretransplantation demographic and clinical characteristics of study cohort, stratified by CR status

    All (n = 253)CR1 (n = 183)CR2 (n =70)P*
    Median age at HCT (range), y43.1
    (0.6-72.6)
    44.7
    (0.6-69.5)
    42.3
    (2.1-72.6)
    NS
    Male gender, n (%)131 (51.8%)92 (50.3%)39 (55.7%)NS
    Median WBC at diagnosis, ×103/µL9.6 (0.2-326)8.6 (0.2-280)14.9 (1.2-326)NS
    Cytogenetics, n (%)<.001
     Favorable22 (8.7%)6 (3.3%)16 (22.9%)
     Intermediate168 (66.4%)124 (67.8%)44 (62.9%)
     Adverse56 (22.1%)48 (26.2%)8 (11.4%)
     Missing7 (2.8%)5 (2.7%)2 (2.9%)
    Secondary AML, n (%)69 (27.3%)63 (34.4%)6 (8.6%)<.001
    No. of induction courses, n (%).014
     1167 (66.0%)109 (59.6%)58 (82.9%)
     275 (29.6%)64 (35.0%)11 (15.7%)
     ≥311 (4.3%)10 (5.5%)1 (1.4%)
    Consolidation after initial induction, n (%).006
     No40 (15.8%)36 (19.7%)4 (5.7%)
     Yes213 (84.2%)147 (80.3%)66 (94.3%)
     No. of consolidation courses<.001
      1111 (43.9%)93 (50.8%)18 (25.7%)
      ≥2102 (40.3%)54 (29.5%)48 (68.6%)
    No. of re-induction courses, n (%)NA
     1NA57 (81.4%)
     2NA10 (14.3%)
     ≥3NA3 (4.3%)
    Consolidation after re-induction, n (%)NA
     NoNA46 (65.7%)
     YesNA24 (34.3%)
     No. of consolidation courses
      1NA22 (31.4%)
      ≥2NA2 (2.9%)
    Median remission duration before HCT (range), days121 (16-465)59.5 (17-231)<.001
    Peripheral blood counts before HCT.001
     ANC ≥1 000/µL and platelets ≥100 000/µL216 (85.4%)164 (89.6%)52 (74.3%)
     ANC <1 000/µL and/or platelets <100 000/µL36 (14.2%)18 (9.8%)18 (25.7%)
     Missing1 (0.4%)1 (0.6%)0 (0%)
    Routine cytogenetics before HCTNS
     Normal karyotype222 (87.8%)159 (86.9%)63 (90.0%)
     Abnormal karyotype24 (9.5%)20 (10.9%)4 (5.7%)
     Missing/inadequate data7 (2.8%)4 (2.2%)3 (4.3%)
    MRD status at HCTNS
     Positive, n (%)54 (21.3%)36 (19.7%)18 (25.7%)
     <0.1%14 (5.5%)12 (6.6%)2 (2.9%)
     0.1%-1%24 (9.5%)14 (7.7%)10 (14.3%)
     >1%16 (6.3%)10 (5.5%)6 (8.6%)
     Median % abnormal blasts, range0.30
    (0.007-7.8)
    0.29
    (0.007-7.8)
    0.41
    (0.05-3.5)
     Negative, n (%)199 (78.7%)147 (80.3%)52 (74.3%)
    • ANC, absolute neutrophil count; NA, not applicable; NS, not significant; WBC, white blood cell count.

    • * For the comparison CR1 vs CR2.

  • Table 2

    Donor and transplant recipient demographic and clinical characteristics

    All (n = 253)CR1 (n = 183)CR2 (n = 70)P*
    Donor type, n (%)NS
     Related83 (32.8%)62 (33.9%)21 (30.0%)
     Unrelated170 (67.2%)121 (66.1%)49 (70.0%)
    Median donor age (range), y38.7 (5.7-77.8)39.1 (5.7-67.4)37.6 (10.6-77.8)NS
    Donor gender, n (%)NS
     Male125 (49.4%)96 (52.5%)29 (41.4%)
     Female109 (43.1%)72 (39.3%)37 (52.9%)
     Missing19 (7.5%)15 (8.2%)4 (5.7%)
    Patient/donor gender, n (%)NS
     Male/male66 (26.1%)49 (26.8%)17 (24.3%)
     Female/female56 (22.1%)40 (21.9%)16 (22.9%)
     Male/female53 (21.0%)32 (17.5%)21 (30.0%)
     Female/male59 (23.3%)47 (25.7%)12 (17.1%)
     Missing19 (7.5%)15 (8.2%)4 (5.7%)
    Conditioning regimen, n (%).001
     Bu/Cy ± ATG or CAMP65 (25.7%)57 (31.2%)8 (11.4%)
     Bu/Flu ± ATG34 (13.4%)24 (13.1%)10 (14.3%)
     H-TBI/Cy or H-TBI/TEPA/Flu72 (28.6%)48 (26.2%)24 (34.3%)
     Treo/Flu ± L-TBI68 (26.9%)49 (26.8%)19 (27.1%)
     Flu/radiolabeled Ab/L-TBI14 (5.5%)5 (2.7%)9 (12.9%)
    Source of stem cells, n (%)NS
     PBSC136 (53.8%)99 (54.1%)37 (52.9%)
     BM75 (29.6%)56 (30.6%)19 (27.1%)
     Cord Blood42 (16.6%)28 (15.3%)14 (20.0%)
    GVHD prophylaxisNS
     Calcineurin inhibitor + methotrexate170 (67.2%)129 (70.5%)41 (58.6%)
     Calcineurin inhibitor + MMF56 (22.1%)33 (18.0%)23 (32.9%)
     Cytoxan23 (9.1%)17 (9.3%)6 (8.6%)
     Other4 (1.6%)4 (2.2%)0 (0%)
    • Ab, antibody; ATG, antithymocyte globulin; BM, bone marrow; Bu, busulfan; CAMP, campath; Cy, cytoxan; Flu, fludarabine; H-TBI, high-dose TBI; L-TBI, low-dose TBI; MMF, mycophenolate mofetil; NS, not significant; PBSC, peripheral blood stem cells; TEPA, thiotepa.

    • * For the comparison CR1 vs CR2.

  • Table 3

    Comparison of pretransplantation characteristics between MRDneg and MRDpos patients

    MRDneg (n = 199)MRDpos (n = 54)P*
    Median age at HCT (range), y42.5 (0.6-71.6)47.6 (2.2-72.6)NS
    Male gender, n (%)95 (47.7%)36 (66.7%).014
    Median WBC at diagnosis, ×103/µL11.6 (0.2-297)5.3 (0.3-326)NS
    Cytogenetics, n (%)*.040
     Favorable20 (10.1%)2 (3.7%)
     Intermediate137 (68.8%)31 (57.4%)
     Adverse37 (18.6%)19 (35.2%)
     Missing5 (2.5%)2 (3.7%)
    Secondary AML, n (%)46 (23.1%)23 (42.6%)0.004
    No. of induction courses, n (%)NS
     1136 (68.3%)31 (57.4%)
     256 (28.1%)19 (35.2%)
     ≥37 (3.5%)4 (7.4%)
    Consolidation therapy after initial induction, n (%)<.001
     No23 (11.6%)17 (31.5%)
     Yes176 (88.4%)37 (68.5%)
    No. of consolidation courses.009
     192 (46.2%)19 (35.2%)
     ≥284 (42.2%)18 (33.3%)
    No. of re-induction courses, n (%)NS
     141 (20.1%)16 (29.6%)
     28 (4.0%)2 (3.7%)
     ≥33 (1.5%)0 (0%)
    Consolidation therapy after re-induction, n (%)NS
     No32 (16.1%)14 (25.9%)
     Yes20 (10.1%)4 (7.4%)
    No. of consolidation coursesNS
     118 (9.1%)4 (7.4%)
     ≥22 (1.0%)0 (0%)
    Median remission duration before HCT (range), d
     For CR1 patients127 (18-465)93 (16-383).015
     For CR2 patients59.5 (17-231)54 (17-203)NS
    Peripheral blood counts before HCT.006
     ANC ≥1000/µL and platelets ≥100 000/µL176 (88.4%)40 (74.1%)
     ANC <1000/µL and/or platelets <100 000/µL22 (11.1%)14 (25.9%)
     Missing1 (0.5%)0 (0%)
    Routine cytogenetics before HCT, n (%)<.001
     Normal karyotype183 (92.0%)39 (72.2%)
     Abnormal karyotype11 (5.5%)13 (24.1%)
     Missing/inadequate data5 (2.5%)2 (3.7%)
    CR status, n (%)NS
     CR1147 (73.9%)36 (66.7%)
     CR252 (26.1%)18 (33.3%)
    • ANC, absolute neutrophil count; NS, not significant; WBC, white blood cell count.

    • * For the comparison MRDneg vs MRDpos.

  • Table 4

    Univariate Cox regression models for impact of MRDpos status, entire study cohort (n = 253)

    CR1 (n = 183)CR2 (n = 70)All (n = 253)
    OS
     MRDneg1 (reference)1 (reference)1 (reference)
     MRDpos3.35 (2.02-5.55), P < .0012.68 (1.25-5.74), P = .0113.13 (2.06-4.76); P < .001
     MRD <0.1%2.91 (1.44-5.89);P = .003
     MRD 0.1%-1%2.79 (1.58-4.92); P < .001
     MRD >1%3.98 (2.13-7.46); P < .001
    DFS
     MRDneg1 (reference)1 (reference)1 (reference)
     MRDpos4.76 (2.97-7.65); P < .0013.34 (1.65-6.77); P = .0014.15 (2.81-6.13); P < .001
     MRD <0.1%3.93 (2.06-7.48); P < .001
     MRD 0.1%-1%3.22 (1.89-5.50); P < .001
     MRD >1%6.83 (3.84-12.13); P < .001
    Relapse
     MRDneg1 (reference)1 (reference)1 (reference)
     MRDpos5.60 (3.16-9.94); P < .0014.84 (2.11-11.06); P < .0015.19 (3.26-8.27); P < .001
     MRD <0.1%5.22 (2.52-10.81); P < .001
     MRD 0.1%-1%4.03 (2.16-7.53); P < .001
     MRD >1%8.13 (4.11-16.07); P < .001
    NRM
     MRDneg1 (reference)1 (reference)1 (reference)
     MRDpos3.41 (1.46-7.99); P = .0051.14 (0.23-5.53); P = NS2.48 (1.18-5.21); P = .017
     MRD <0.1%1.85 (0.43-7.86); P = NS
     MRD 0.1%-1%1.93 (0.67-5.57), P=NS
     MRD >1%4.69 (1.59-13.84), P = .005
    • Values are given as hazard ratio (95% confidence interval [CI]), P value.

    • NS, not significant.

  • Table 5

    Multivariate Cox regression models, entire study cohort (n = 253)

    Overall mortalityFailure for DFSRelapse
    MRD status
     Negative (n = 199)1 (reference)1 (reference)1 (Reference)
     Positive (n = 54)2.61 (1.62-4.20); P < .0013.74 (2.38-5.87); P < .0014.90 (2.87-8.37); P < .001
    Age (per 10 y)1.05 (0.90-1.22); P = NS1.07 (0.94-1.23); P = NS1.02 (0.87-1.21); P = NS
    CR status
     CR1 (n = 183)1 (reference)1 (reference)1 (reference)
     CR2 (n = 70)1.01 (0.54-1.92); P = NS1.22 (0.69-2.17); P = NS1.15 (0.58-2.31); P = NS
    Cytogenetic risk group
     Intermediate/favorable (n = 190)1 (reference)1 (reference)1 (reference)
     Adverse (n = 56)1.41 (0.78-2.54); P = NS1.50 (0.88-2.57); P = NS1.61 (0.83-3.13); P = NS
    Type of AML
     Primary AML (n = 184)1 (reference)1 (reference)1 (reference)
     Secondary AML (n = 69)1.24 (0.74-2.09); P = NS1.29 (0.80-2.07); P = NS1.06 (0.59-1.92); P = NS
    Number of induction/re-induction courses before HCT*1.21 (0.83-1.77); P = NS1.45 (1.04-2.01); P = .031.53 (1.03-2.27); P = .04
    Consolidation before HCT
     No (n = 82)1 (reference)1 (reference)1 (reference)
     Yes, with HiDAC (n = 132)0.74 (0.40-1.37); P = NS0.89 (0.49-1.61); P = NS0.89 (0.43-1.86); P = NS
     Yes, without HiDAC (n = 39)0.96 (0.48-1.91); P = NS1.08 (0.56-2.07),;P = NS0.97 (0.43-2.16); P = NS
    CR Duration before HCT (per mo)1.00 (0.96-1.04); P = NS1.01 (0.97-1.05); P = NS1.00 (0.95-1.05); P = NS
    Pre-HCT karyotype
     Normalized (n = 120)1 (reference)1 (reference)1 (reference)
     Not normalized (n = 24)1.52 (0.75-3.08); P = NS1.25 (0.65-2.40) P = NS1.07 (0.47-2.42); P = NS
    Pre-HCT blood counts
     Recovered (n = 216)1 (reference)1 (reference)1 (reference)
     Not recovered (n = 36)0.69 (0.37-1.30); P = NS0.77 (0.43-1.36); P = NS0.71 (0.36-1.42); P = NS
    Conditioning regimen
     Without high-dose TBI (n = 181)1 (reference)1 (reference)1 (reference)
     With high-dose TBI (n = 72)0.79 (0.42-1.48); P = NS0.81 (0.46-1.43); P = NS0.77 (0.38-1.54); P = NS
    • Values are given as hazard ratio (95% CI), P value.

    • NS, not significant.

    • * Number of induction courses for CR1 patients and number of re-induction courses for CR2 patients.

    • Recovered: absolute neutrophil count (ANC) ≥1000/µL and platelets ≥100 000/µL; not recovered: ANC <1000/µL and/or platelets <100 000/µL.