ELN 2021 clinical MRD recommendations based on a Delphi poll
| No. . | Clinical MRD recommendation . | LoE . | GoR . | LoA (%) . |
|---|---|---|---|---|
| D1 | MRD should be assessed to refine relapse risk in patients who achieve morphologic remission, with full or partial hematologic recovery (CR/CRi/CRp/CRh). | I | A | 89 |
| D2 | For patients with mutant NPM1, CBF AML (RUNX1-RUNX1T1 or CBFB-MYH11), or APL (PML-RARA), we recommend molecular MRD assessment by qPCR or dPCR. | II | A | 88 |
| D3 | AML patients who are not included in the molecularly defined subgroups should be monitored for MRD by MFC. | II | A | 84 |
| D4 | NGS-MRD monitoring is useful to refine prognosis in addition to MFC but, to date, there are insufficient data to recommend NGS-MRD as a stand-alone technique. | IV | B | 84 |
| D5 | In NPM1-mutated AML, MRD should be assessed preferentially in PB after 2 cycles of chemotherapy, in BM at the end of consolidation, and in BM every 3 mo for 24 mo after the end of consolidation. Alternatively, MRD may be assessed from PB every 4 to 6 wk during follow-up for 24 mo. | IV | B | 95 |
| D6 | In RUNX1-RUNX1T1, and CBFB-MYH11 mutated AML MRD should be assessed preferentially in PB after 2 cycles of chemotherapy, in BM at the end of consolidation treatment, and in PB every 4 to 6 wk for 24 mo after the end of consolidation. | IV | B | 94 |
| D7 | In APL, the most important MRD end point is PCR negativity for PML-RARA at the end of consolidation. | I | A | 100 |
| D8 | For patients with non–high-risk APL, MRD monitoring is recommended only after completion of consolidation and may be discontinued once BM MRD negativity is achieved. | V | B | 100 |
| D8a* | For high-risk APL MRD should be assessed by qPCR from BM every 3 mo for 24 months starting at the end of treatment. Alternatively, MRD may be assessed from PB every 4 to 6 wk during follow-up. | —* | — | — |
| D9 | Ongoing molecular MRD monitoring beyond 24 mo of follow-up should be based on individual clinical features. | V | C | 95 |
| D10 | Patients who are followed-up with MFC-MRD should have BM assessment after 2 cycles of chemotherapy, at the end of consolidation, and prior to stem cell transplantation, if applicable. | II | A | 100 |
| D11 | MFC-MRD test positivity is defined as ≥0.1% of CD45-expressing cells with the target immunophenotype. | II | A | 80 |
| D12 | MRD test positivity by qPCR is defined as Ct <40 in ≥2 of 3 replicates. | III | B | 73 |
| D13 | MRD test negativity by qPCR is defined as Ct ≥40 in at least 2 of 3 replicates, when ≥10 000 copies (optimally, ≥30 000 copies) of the housekeeping gene were measured. | II | A | 80 |
| D14 | MRD-LL detection using cDNA in NPM1-mutated AML is provisionally defined as <2%, but above the detection limit of the assay (ratio of the target and housekeeping genes).79 MRD-LL is associated with a very low relapse risk in patients with NPM1 mutations when measured at the end of consolidation chemotherapy. | II | A | 67 |
| D15 | The optimal NGS-MRD threshold level that best discriminates subsequent relapse risk has not yet been defined for individual mutations, combinations of mutations, or treatment time points. NGS-MRD test positivity (measured on genomic DNA) is provisionally defined as ≥0.1% VAF. Although NGS-MRD test negativity is defined as <0.1% VAF, results <0.1% may still be associated with adverse outcomes and may be reported as molecular MRD-LL. | IV | B | 93 |
| D16 | MRD relapse is now defined as either (1) conversion of MRD negativity to MRD positivity, independent of the MRD technique, or (2) increase of MRD ≥1 log10 between any 2 positive samples measured in the same tissue (PB or BM) in patients with MRD-LL. | V | A | 86 |
| D17 | Conversion from negative to positive MRD in PB or BM should be confirmed within 4 wk, in a second consecutive sample, preferably with a BM sample. | IV | A | 89 |
| D18 | Available data suggest that patients with 1 positive and 1 negative MRD result from 2 different techniques have a higher relapse risk than patients with 2 negative MRD results, but a lower relapse risk than patients with 2 positive MRD results. | IV | B | 95 |
| D19 | MRD assay parameters are defined in supplemental Table 4 and should be included in results reports. Scientific reports on MRD studies should include the parameters listed in supplemental Table 5. | V | A | 89 |
| D20 | Future MRD studies, including clinical trials, should report data using the thresholds and response definitions given in this article. | V | A | 94 |
| D21 | Failure to achieve MRD− remission by MFC, molecular MRD positivity after completion of consolidation chemotherapy, and/or MRD relapse (either molecular or MFC, as defined herein) are associated with disease relapse and inferior outcomes. However, select patients with NPM1 mutations and CBF AML may have prolonged survival, despite MRD-LL (<2%). | III | B | 93 |
| D22 | For patients who are (1) MRD positive by MFC after 2 cycles of intensive chemotherapy, after consolidation chemotherapy, prior to stem cell transplantation, and/or after stem cell transplantation83,84; (2) MRD+ by ≥2% NPM1 mutant copies per ABL1 copies measured in BM or transcript levels of NPM1 or CBF fusions failed to reach a 3- to 4-log reduction in the same tissue after completion of consolidation chemotherapy (the ratio of target copies/ABL1 copies between the sample at diagnosis and the sample after completion of consolidation chemotherapy, measured in the same tissue, preferably BM)37,71,80,85,86; and/or (3) demonstrated to have MRD relapse (either molecular or MFC), individualized treatment83 and/or conditioning regimen strategies should be considered, preferably as part of clinical trials, in an effort to reduce disease relapse. | V | C | 100 |
| D23 | Patients with NPM1 or CBF AML who have stable molecular MRD-LL do not necessarily require a change in treatment (at end of treatment or during follow-up). | III | B | 89 |
| D24 | Stable or declining levels of PML-RARA by PCR during active treatment of APL should not trigger a change in treatment plan. | V | B | 94 |
| D25 | Conversion of PML-RARA by PCR from undetectable to detectable, and/or a ≥1 log10 increase in high-risk patients with previously stable PML/RARA levels should be regarded as imminent disease relapse in APL, when confirmed in a second sample. | IV | B | 88 |
| D26 | Pretransplant MRD positivity should not be viewed as a contraindication to stem cell transplantation. | IV | A | 100 |
| D27 | The panel recommends that patients with detectable MRD before allo-HCT myeloablative conditioning be considered. | II | A | 95 |
| D28 | All AML clinical trials should monitor molecular and/or MFC-MRD assessments whenever response is assessed in BM. | V | B | 100 |
| No. . | Clinical MRD recommendation . | LoE . | GoR . | LoA (%) . |
|---|---|---|---|---|
| D1 | MRD should be assessed to refine relapse risk in patients who achieve morphologic remission, with full or partial hematologic recovery (CR/CRi/CRp/CRh). | I | A | 89 |
| D2 | For patients with mutant NPM1, CBF AML (RUNX1-RUNX1T1 or CBFB-MYH11), or APL (PML-RARA), we recommend molecular MRD assessment by qPCR or dPCR. | II | A | 88 |
| D3 | AML patients who are not included in the molecularly defined subgroups should be monitored for MRD by MFC. | II | A | 84 |
| D4 | NGS-MRD monitoring is useful to refine prognosis in addition to MFC but, to date, there are insufficient data to recommend NGS-MRD as a stand-alone technique. | IV | B | 84 |
| D5 | In NPM1-mutated AML, MRD should be assessed preferentially in PB after 2 cycles of chemotherapy, in BM at the end of consolidation, and in BM every 3 mo for 24 mo after the end of consolidation. Alternatively, MRD may be assessed from PB every 4 to 6 wk during follow-up for 24 mo. | IV | B | 95 |
| D6 | In RUNX1-RUNX1T1, and CBFB-MYH11 mutated AML MRD should be assessed preferentially in PB after 2 cycles of chemotherapy, in BM at the end of consolidation treatment, and in PB every 4 to 6 wk for 24 mo after the end of consolidation. | IV | B | 94 |
| D7 | In APL, the most important MRD end point is PCR negativity for PML-RARA at the end of consolidation. | I | A | 100 |
| D8 | For patients with non–high-risk APL, MRD monitoring is recommended only after completion of consolidation and may be discontinued once BM MRD negativity is achieved. | V | B | 100 |
| D8a* | For high-risk APL MRD should be assessed by qPCR from BM every 3 mo for 24 months starting at the end of treatment. Alternatively, MRD may be assessed from PB every 4 to 6 wk during follow-up. | —* | — | — |
| D9 | Ongoing molecular MRD monitoring beyond 24 mo of follow-up should be based on individual clinical features. | V | C | 95 |
| D10 | Patients who are followed-up with MFC-MRD should have BM assessment after 2 cycles of chemotherapy, at the end of consolidation, and prior to stem cell transplantation, if applicable. | II | A | 100 |
| D11 | MFC-MRD test positivity is defined as ≥0.1% of CD45-expressing cells with the target immunophenotype. | II | A | 80 |
| D12 | MRD test positivity by qPCR is defined as Ct <40 in ≥2 of 3 replicates. | III | B | 73 |
| D13 | MRD test negativity by qPCR is defined as Ct ≥40 in at least 2 of 3 replicates, when ≥10 000 copies (optimally, ≥30 000 copies) of the housekeeping gene were measured. | II | A | 80 |
| D14 | MRD-LL detection using cDNA in NPM1-mutated AML is provisionally defined as <2%, but above the detection limit of the assay (ratio of the target and housekeeping genes).79 MRD-LL is associated with a very low relapse risk in patients with NPM1 mutations when measured at the end of consolidation chemotherapy. | II | A | 67 |
| D15 | The optimal NGS-MRD threshold level that best discriminates subsequent relapse risk has not yet been defined for individual mutations, combinations of mutations, or treatment time points. NGS-MRD test positivity (measured on genomic DNA) is provisionally defined as ≥0.1% VAF. Although NGS-MRD test negativity is defined as <0.1% VAF, results <0.1% may still be associated with adverse outcomes and may be reported as molecular MRD-LL. | IV | B | 93 |
| D16 | MRD relapse is now defined as either (1) conversion of MRD negativity to MRD positivity, independent of the MRD technique, or (2) increase of MRD ≥1 log10 between any 2 positive samples measured in the same tissue (PB or BM) in patients with MRD-LL. | V | A | 86 |
| D17 | Conversion from negative to positive MRD in PB or BM should be confirmed within 4 wk, in a second consecutive sample, preferably with a BM sample. | IV | A | 89 |
| D18 | Available data suggest that patients with 1 positive and 1 negative MRD result from 2 different techniques have a higher relapse risk than patients with 2 negative MRD results, but a lower relapse risk than patients with 2 positive MRD results. | IV | B | 95 |
| D19 | MRD assay parameters are defined in supplemental Table 4 and should be included in results reports. Scientific reports on MRD studies should include the parameters listed in supplemental Table 5. | V | A | 89 |
| D20 | Future MRD studies, including clinical trials, should report data using the thresholds and response definitions given in this article. | V | A | 94 |
| D21 | Failure to achieve MRD− remission by MFC, molecular MRD positivity after completion of consolidation chemotherapy, and/or MRD relapse (either molecular or MFC, as defined herein) are associated with disease relapse and inferior outcomes. However, select patients with NPM1 mutations and CBF AML may have prolonged survival, despite MRD-LL (<2%). | III | B | 93 |
| D22 | For patients who are (1) MRD positive by MFC after 2 cycles of intensive chemotherapy, after consolidation chemotherapy, prior to stem cell transplantation, and/or after stem cell transplantation83,84; (2) MRD+ by ≥2% NPM1 mutant copies per ABL1 copies measured in BM or transcript levels of NPM1 or CBF fusions failed to reach a 3- to 4-log reduction in the same tissue after completion of consolidation chemotherapy (the ratio of target copies/ABL1 copies between the sample at diagnosis and the sample after completion of consolidation chemotherapy, measured in the same tissue, preferably BM)37,71,80,85,86; and/or (3) demonstrated to have MRD relapse (either molecular or MFC), individualized treatment83 and/or conditioning regimen strategies should be considered, preferably as part of clinical trials, in an effort to reduce disease relapse. | V | C | 100 |
| D23 | Patients with NPM1 or CBF AML who have stable molecular MRD-LL do not necessarily require a change in treatment (at end of treatment or during follow-up). | III | B | 89 |
| D24 | Stable or declining levels of PML-RARA by PCR during active treatment of APL should not trigger a change in treatment plan. | V | B | 94 |
| D25 | Conversion of PML-RARA by PCR from undetectable to detectable, and/or a ≥1 log10 increase in high-risk patients with previously stable PML/RARA levels should be regarded as imminent disease relapse in APL, when confirmed in a second sample. | IV | B | 88 |
| D26 | Pretransplant MRD positivity should not be viewed as a contraindication to stem cell transplantation. | IV | A | 100 |
| D27 | The panel recommends that patients with detectable MRD before allo-HCT myeloablative conditioning be considered. | II | A | 95 |
| D28 | All AML clinical trials should monitor molecular and/or MFC-MRD assessments whenever response is assessed in BM. | V | B | 100 |
Ct, cycling threshold; GoR, grade of recommendation; LoE, level of evidence; LoA, level of agreement. See supplemental Table 6 for definitions of GoR and LoE.
No Delphi score available. The recommendation was reached after discussions among experts.