Response criteria in AML
| Category . | Definition . | Comment . |
|---|---|---|
| Response | ||
| CR without minimal residual disease (CRMRD−) | If studied pretreatment, CR with negativity for a genetic marker by RT-qPCR, or CR with negativity by MFC | Sensitivities vary by marker tested, and by method used; therefore, test used and sensitivity of the assay should be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
| Complete remission (CR) | Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L (1000/µL); platelet count ≥100 × 109/L (100 000/µL) | MRD+ or unknown |
| CR with incomplete hematologic recovery (CRi) | All CR criteria except for residual neutropenia (<1.0 × 109/L [1000/µL]) or thrombocytopenia (<100 × 109/L [100 000/µL]) | |
| Morphologic leukemia-free state (MLFS) | Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required | Marrow should not merely be “aplastic”; at least 200 cells should be enumerated or cellularity should be at least 10% |
| Partial remission (PR) | All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50% | Especially important in the context of phase 1-2 clinical trials |
| Treatment failure | ||
| Primary refractory disease | No CR or CRi after 2 courses of intensive induction treatment; excluding patients with death in aplasia or death due to indeterminate cause | Regimens containing higher doses of cytarabine (see Table 8) are generally considered as the best option for patients not responding to a first cycle of 7+3; the likelihood of responding to such regimens is lower after failure of a first |
| Death in aplasia | Deaths occurring ≥7 d following completion of initial treatment while cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 d of death, without evidence of persistent leukemia | |
| Death from indeterminate cause | Deaths occurring before completion of therapy, or <7 d following its completion; or deaths occurring ≥7 d following completion of initial therapy with no blasts in the blood, but no bone marrow examination available | |
| Response criteria for clinical trials only | ||
| Stable disease | Absence of CRMRD−, CR, CRi, PR, MLFS; and criteria for PD not met | Period of stable disease should last at least 3 mo |
| Progressive disease (PD)*,† | Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the blood: | Category mainly applies for older patient given low-intensity or single-agent “targeted therapies” in clinical trials |
| • >50% increase in marrow blasts over baseline (a minimum 15% point increase is required in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% over at least 3 mo; without at least a 100% improvement in ANC to an absolute level (>0.5 × 109/L [500/µL], and/or platelet count to >50 × 109/L [50 000/µL] nontransfused); or | In general, at least 2 cycles of a novel agent should be administered | |
| • >50% increase in peripheral blasts (WBC × % blasts) to >25 × 109/L (>25 000/μL) (in the absence of differentiation syndrome)†; or | Some protocols may require blast increase in 2 consecutive marrow assessments at least 4 wk apart; the date of progression should then be defined as of the first observation date | |
| • New extramedullary disease | Some protocols may allow transient addition of hydroxyurea to lower blast counts | |
| “Progressive disease” is usually accompanied by a decline in ANC and platelets and increased transfusion requirement and decline in performance status or increase in symptoms | ||
| Relapse | ||
| Hematologic relapse (after CRMRD−, CR, CRi) | Bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development of extramedullary disease | |
| Molecular relapse (after CRMRD−) | If studied pretreatment, reoccurrence of MRD as assessed by RT-qPCR or by MFC | Test applied, 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 without minimal residual disease (CRMRD−) | If studied pretreatment, CR with negativity for a genetic marker by RT-qPCR, or CR with negativity by MFC | Sensitivities vary by marker tested, and by method used; therefore, test used and sensitivity of the assay should be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
| Complete remission (CR) | Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L (1000/µL); platelet count ≥100 × 109/L (100 000/µL) | MRD+ or unknown |
| CR with incomplete hematologic recovery (CRi) | All CR criteria except for residual neutropenia (<1.0 × 109/L [1000/µL]) or thrombocytopenia (<100 × 109/L [100 000/µL]) | |
| Morphologic leukemia-free state (MLFS) | Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required | Marrow should not merely be “aplastic”; at least 200 cells should be enumerated or cellularity should be at least 10% |
| Partial remission (PR) | All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50% | Especially important in the context of phase 1-2 clinical trials |
| Treatment failure | ||
| Primary refractory disease | No CR or CRi after 2 courses of intensive induction treatment; excluding patients with death in aplasia or death due to indeterminate cause | Regimens containing higher doses of cytarabine (see Table 8) are generally considered as the best option for patients not responding to a first cycle of 7+3; the likelihood of responding to such regimens is lower after failure of a first |
| Death in aplasia | Deaths occurring ≥7 d following completion of initial treatment while cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 d of death, without evidence of persistent leukemia | |
| Death from indeterminate cause | Deaths occurring before completion of therapy, or <7 d following its completion; or deaths occurring ≥7 d following completion of initial therapy with no blasts in the blood, but no bone marrow examination available | |
| Response criteria for clinical trials only | ||
| Stable disease | Absence of CRMRD−, CR, CRi, PR, MLFS; and criteria for PD not met | Period of stable disease should last at least 3 mo |
| Progressive disease (PD)*,† | Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the blood: | Category mainly applies for older patient given low-intensity or single-agent “targeted therapies” in clinical trials |
| • >50% increase in marrow blasts over baseline (a minimum 15% point increase is required in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% over at least 3 mo; without at least a 100% improvement in ANC to an absolute level (>0.5 × 109/L [500/µL], and/or platelet count to >50 × 109/L [50 000/µL] nontransfused); or | In general, at least 2 cycles of a novel agent should be administered | |
| • >50% increase in peripheral blasts (WBC × % blasts) to >25 × 109/L (>25 000/μL) (in the absence of differentiation syndrome)†; or | Some protocols may require blast increase in 2 consecutive marrow assessments at least 4 wk apart; the date of progression should then be defined as of the first observation date | |
| • New extramedullary disease | Some protocols may allow transient addition of hydroxyurea to lower blast counts | |
| “Progressive disease” is usually accompanied by a decline in ANC and platelets and increased transfusion requirement and decline in performance status or increase in symptoms | ||
| Relapse | ||
| Hematologic relapse (after CRMRD−, CR, CRi) | Bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development of extramedullary disease | |
| Molecular relapse (after CRMRD−) | If studied pretreatment, reoccurrence of MRD as assessed by RT-qPCR or by MFC | Test applied, sensitivity of the assay, and cutoff values used must be reported; analyses should be done in experienced laboratories (centralized diagnostics) |
ANC, absolute neutrophil count; IDH, isocitrate dehydrogenase; MLFS, morphologic leukemia-free state; WBC, white blood cell.
The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at harmonizing the various definitions used in different clinical trials.
Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD.