Response criteria in AML
| Category . | Definition . | Comment . |
|---|---|---|
| Response | ||
| CR*,†,‡ | Bone marrow blasts < 5%; absence of circulating blasts; absence of extramedullary disease; ANC ≥ 1.0 × 109/L (1,000/µL); platelet count ≥ 100 × 109/L (100 000/µL) | |
| CRh*,†,‡ | ANC ≥ 0.5 × 109/L (500/µL) and platelet count ≥ 50 × 109/L (50 000/µL), otherwise all other CR criteria met | If CRh used, CRi should only include patients not meeting the definition of CRh |
| CRi*,†,‡ | All CR criteria except for residual neutropenia < 1.0 × 109/L (1,000/µL) or thrombocytopenia < 100 × 109/L (100 000/µL) | |
| MLFS | Bone marrow blasts < 5%; absence of circulating blasts; absence of extramedullary disease; no hematologic recovery required | Marrow should not merely be “aplastic”; bone marrow spicules should be present; at least 200 cells should be enumerated in the aspirate or cellularity should be at least 10% in the biopsy. Mainly used in the context of phase 1-2 clinical trials |
| PR | All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50% | Mainly used in the context of phase 1-2 clinical trials |
| No response | Patients evaluable for response but not meeting the criteria for CR, CRh, CRi, MLFS or PR are categorized as having no response prior to the response landmark. Patients failing to achieve response by the designated landmark are designated as having refractory disease | |
| Nonevaluable for response | Non-evaluable for response will include patients lacking an adequate bone marrow response evaluation. This category will include patients with early death, withdrawal prior to response assessment, or a technically suboptimal bone marrow sample precluding assessment | |
| Response (if including assessment of MRD)§ | ||
| CR, CRh, or CRi without MRD‡ (CRMRD-, CRhMRD- or CRiMRD-) | CR, CRh or CRi with MRD below a defined threshold for a genetic marker by qPCR, or by MFC. Response without MRD should be confirmed with a subsequent assessment at least 4 wk apart. The date of response without MRD is the first date in which the MRD was below the defined threshold Response with MRD detection at low-level (CRMRD-LL) is included in this category of CR, CRh or CRi without MRD. CRMRD-LL is currently only defined for NPM1-mutant and CBF-AML | Sensitivities vary by marker tested, and by method used; therefore, test used, tissue source and minimum assay sensitivity for evaluability should be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
| Treatment failure | ||
| Refractory disease | No CR, CRh or CRi at the response landmark, ie, after 2 courses of intensive induction treatment or a defined landmark, eg, 180 d after commencing less-intensive therapy | Patients not responding to a first cycle of 7 + 3 should be considered for a regimen containing higher doses of cytarabine |
| Relapsed disease (after CR, CRh or CRi) | Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood in at least 2 peripheral blood samples at least one week apart; or development of extramedullary disease | |
| Treatment failure (if including assessment of MRD)§ | ||
| MRD relapse (after CR, CRh or CRi without MRD) | 1. Conversion from MRD negativity to MRD positivity, independent of method, or 2. Increase of MRD copy numbers ≥ 1 log10 between any two positive samples in patients with CRMRD-LL, CRhMRD-LL or CRiMRD-LL by qPCR The result of 1. or 2. should be rapidly confirmed in a second consecutive sample from the same tissue source | Test methodology, sensitivity of the assay, and cutoff values used must be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
| Category . | Definition . | Comment . |
|---|---|---|
| Response | ||
| CR*,†,‡ | Bone marrow blasts < 5%; absence of circulating blasts; absence of extramedullary disease; ANC ≥ 1.0 × 109/L (1,000/µL); platelet count ≥ 100 × 109/L (100 000/µL) | |
| CRh*,†,‡ | ANC ≥ 0.5 × 109/L (500/µL) and platelet count ≥ 50 × 109/L (50 000/µL), otherwise all other CR criteria met | If CRh used, CRi should only include patients not meeting the definition of CRh |
| CRi*,†,‡ | All CR criteria except for residual neutropenia < 1.0 × 109/L (1,000/µL) or thrombocytopenia < 100 × 109/L (100 000/µL) | |
| MLFS | Bone marrow blasts < 5%; absence of circulating blasts; absence of extramedullary disease; no hematologic recovery required | Marrow should not merely be “aplastic”; bone marrow spicules should be present; at least 200 cells should be enumerated in the aspirate or cellularity should be at least 10% in the biopsy. Mainly used in the context of phase 1-2 clinical trials |
| PR | All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50% | Mainly used in the context of phase 1-2 clinical trials |
| No response | Patients evaluable for response but not meeting the criteria for CR, CRh, CRi, MLFS or PR are categorized as having no response prior to the response landmark. Patients failing to achieve response by the designated landmark are designated as having refractory disease | |
| Nonevaluable for response | Non-evaluable for response will include patients lacking an adequate bone marrow response evaluation. This category will include patients with early death, withdrawal prior to response assessment, or a technically suboptimal bone marrow sample precluding assessment | |
| Response (if including assessment of MRD)§ | ||
| CR, CRh, or CRi without MRD‡ (CRMRD-, CRhMRD- or CRiMRD-) | CR, CRh or CRi with MRD below a defined threshold for a genetic marker by qPCR, or by MFC. Response without MRD should be confirmed with a subsequent assessment at least 4 wk apart. The date of response without MRD is the first date in which the MRD was below the defined threshold Response with MRD detection at low-level (CRMRD-LL) is included in this category of CR, CRh or CRi without MRD. CRMRD-LL is currently only defined for NPM1-mutant and CBF-AML | Sensitivities vary by marker tested, and by method used; therefore, test used, tissue source and minimum assay sensitivity for evaluability should be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
| Treatment failure | ||
| Refractory disease | No CR, CRh or CRi at the response landmark, ie, after 2 courses of intensive induction treatment or a defined landmark, eg, 180 d after commencing less-intensive therapy | Patients not responding to a first cycle of 7 + 3 should be considered for a regimen containing higher doses of cytarabine |
| Relapsed disease (after CR, CRh or CRi) | Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood in at least 2 peripheral blood samples at least one week apart; or development of extramedullary disease | |
| Treatment failure (if including assessment of MRD)§ | ||
| MRD relapse (after CR, CRh or CRi without MRD) | 1. Conversion from MRD negativity to MRD positivity, independent of method, or 2. Increase of MRD copy numbers ≥ 1 log10 between any two positive samples in patients with CRMRD-LL, CRhMRD-LL or CRiMRD-LL by qPCR The result of 1. or 2. should be rapidly confirmed in a second consecutive sample from the same tissue source | Test methodology, sensitivity of the assay, and cutoff values used must be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
ANC, absolute neutrophil count; CBF, core-binding factor; VAF, variant allele frequency.
To recognize the potential for continuing improvements in blood counts after myelosuppressive therapy, response definitions for patients with marrow blast clearance (< 5%) may be adjusted to reflect the best hematologic response achieved prior to commencement of the next treatment cycle. Aspirate reports that include MLFS, CRh, or CRi should note the potential for post-marrow blood counts to alter the final response designation. Patients should not have received G-CSF, nor platelet transfusions within 7 d prior to hematologic response determination.
For patients with CR, CRh, or CRi, the presence of a low percentage of circulating blasts in the blood may represent a regenerating marrow and should not be interpreted as persistent disease. In such cases the blasts generally disappear within a week.
A response landmark for CR, CRh, or CRi should be stated, eg, after 2 cycles of intensive therapy; this landmark may be longer for nonintensive based treatment options, eg, 180 days.
MFC-MRD positivity is defined as ≥ 0.1% of CD45 expressing cells with the target immunophenotype. MRD test positivity by qPCR is defined as cycling threshold (Ct) < 40 and is negative if Ct ≥ 40 in ≥ 2 of 3 replicates. In NPM1-mutated and CBF-AML, CR with molecular MRD detectable at low-level (CRMRD-LL) defined as < 2% is designated as negative for MRD, because when measured at the end of consolidation treatment, is associated with a very low relapse rate.