IWG 2023 response criteria for HR-MDS
| Response . | IWG 2006 . | IWG 2023 . |
|---|---|---|
| CR | •BM: ≤5% myeloblasts; dysplasia may persist•PB: Hb ≥11 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0% | •BM: <5% myeloblasts;∗ dysplasia may persist•PB: Hb ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%† |
| CR equivalent∗ | Not included | Patients with <5% BM blasts at baseline•BM: <5% myeloblasts∗; dysplasia may persist•PB: Hb ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%†•Full cytogenetic clearance of baseline abnormalities (complete cytogenetic response) |
| mCR | •BM: ≤5% blasts and decrease by ≥50% over pretreatment•No PB responses required | Eliminated as a response criterion‡ |
| PR | All CR criteria except:•BM blasts decreased by ≥50% over pretreatment but still >5%•Cellularity and morphology not relevant | All CR criteria except:•BM blasts decreased by ≥50% over pretreatment but still ≥5%•Cellularity and morphology not relevant |
| SD | Failure to achieve at least PR, but no evidence of progression for >8 wk | Eliminated as a response criterion‡ |
| CRL§ (CRuni and CRbi) | Not included | •BM: <5% myeloblasts;∗ dysplasia may persist•PB: blasts 0%†•CRuni: PB, not meeting CR but only 1 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L•CRbi: PB, not meeting CR but only 2 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L |
| CRh§ | Not included | •BM: <5% myeloblasts;∗ dysplasia may persist•PB: Not meeting criteria for CR or CRL, no Hb threshold required, platelets ≥50 × 109/L; neutrophils ≥0.5 × 109/L; blasts 0%† |
| HI | HI (responses >8 wk):•Erythroid response (pretreatment, <11 g/dL):Hb increase by ≥1.5 g/dL and 50% reduction of RBC transfusions.•Platelet response (pretreatment, <100 × 109/L):absolute increase of ≥30 × 109/L for patients starting with >20 × 109/L platelets or increase from <20 × 109/L to >20 × 109/L and by at least 100%.•Neutrophil response (pretreatment, <1.0 × 109/L): at least 100% increase and an absolute increase >0.5 × 109/L. | HI defined according to IWG 2018 response criteria:‖•Not meeting criteria for CR (or CR equivalent) or CRuni or CRL•HIerythroid (HI-E)•HIplatelets (HI-P)•HIneutrophils (HI-N) |
| ORR | Not defined | ORR = CR (or CR equivalent)∗ + PR + CRL + CRh + HI |
| No response | Not defined | Not meeting criteria for CR (or CR equivalent)∗, PR, CRL, CRh, or HI‡ |
| Not evaluable | Not included | All registered/randomly assigned patients should be reported in the denominator of response assessment analyses in line with the intention-to-treat principle. This category may include patients yet to have a response assessment, suffering early death, exiting the study early, or those with a technically suboptimal BM sample precluding assessment. |
| Cytogenetic response¶ | •Complete: disappearance of the chromosomal abnormality without appearance of new ones.•Partial: ≥50% reduction of the chromosomal abnormality. | •Complete: disappearance of the chromosomal abnormality without appearance of new ones.•Partial: ≥50% reduction of the chromosomal abnormality. |
| PD | For patients with:•<5% blasts: ≥50% increase in blasts to >5% blasts•5%-10% blasts: ≥50% increase to >10% blasts•10%-20% blasts: ≥50% increase to >20% blasts•20%-30% blasts: ≥50% increase to >30% blastsAny of the following:•At least 50% decrement from maximum remission/response in granulocytes or platelets•Reduction in Hb by ≥2 g/dL•Transfusion dependence | Fulfilling any of the criteria below:#,∗∗,††•Disease progression by blasts: ≥50% relative increase in blasts and absolute increase of blast percentage by at least 5% from pretreatment sample taken before current line of therapy.•Disease progression by worsening cytopenia: new, repeated (more than once and separated by ≥7 days) need for RBC or platelet transfusions within 8 weeks, not related to acute intercurrent illness (eg, sepsis, gastrointestinal tract bleed) or treatment effect, in the absence of HI of at least one other blood lineage as defined above.•Progression to AML: ≥50% increase in blasts from baseline assessment to ≥20% blasts. |
| Disease relapse | Any of the following:•Return to pretreatment BM blast percentage.•Decrement of 50% from maximum remission/response levels in granulocytes or platelets.•Reduction in Hb concentration by 1.5 g/dL or transfusion dependence. | Fulfilling any of the criteria below:#•Disease relapse by blasts: absolute and relative increase in BM blasts by at least 5% and ≥50%, respectively, from prior assessment, or reappearance of blasts in the blood, or development of extramedullary disease (myeloid sarcoma).•Disease relapse by worsening cytopenias: decrement in one or more blood cell lineage counts by ≥50% from maximum remission/response levels for platelets or absolute neutrophil count or a reduction of Hb by 1.5 g/dL combined with an absolute reduction in the same lineage(s) as follows: Hb <10 g/dL, platelets <100 × 109/L, or absolute neutrophils <1.0 × 109/L or repeated (more than once and separated by ≥7 days) need for RBC or platelet transfusions which are not related to acute intercurrent illness (eg, sepsis, gastrointestinal tract bleed) or treatment effect; in the absence of HI of at least one other blood lineage as defined above. |
| Patient reported outcomes (PROs) | Not included | Reporting by means of a validated assessment tool is encouraged‡‡ |
| Response . | IWG 2006 . | IWG 2023 . |
|---|---|---|
| CR | •BM: ≤5% myeloblasts; dysplasia may persist•PB: Hb ≥11 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0% | •BM: <5% myeloblasts;∗ dysplasia may persist•PB: Hb ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%† |
| CR equivalent∗ | Not included | Patients with <5% BM blasts at baseline•BM: <5% myeloblasts∗; dysplasia may persist•PB: Hb ≥10 g/dL, platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L; blasts 0%†•Full cytogenetic clearance of baseline abnormalities (complete cytogenetic response) |
| mCR | •BM: ≤5% blasts and decrease by ≥50% over pretreatment•No PB responses required | Eliminated as a response criterion‡ |
| PR | All CR criteria except:•BM blasts decreased by ≥50% over pretreatment but still >5%•Cellularity and morphology not relevant | All CR criteria except:•BM blasts decreased by ≥50% over pretreatment but still ≥5%•Cellularity and morphology not relevant |
| SD | Failure to achieve at least PR, but no evidence of progression for >8 wk | Eliminated as a response criterion‡ |
| CRL§ (CRuni and CRbi) | Not included | •BM: <5% myeloblasts;∗ dysplasia may persist•PB: blasts 0%†•CRuni: PB, not meeting CR but only 1 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L•CRbi: PB, not meeting CR but only 2 of the following: Hb ≥10 g/dL; platelets ≥100 × 109/L; neutrophils ≥1.0 × 109/L |
| CRh§ | Not included | •BM: <5% myeloblasts;∗ dysplasia may persist•PB: Not meeting criteria for CR or CRL, no Hb threshold required, platelets ≥50 × 109/L; neutrophils ≥0.5 × 109/L; blasts 0%† |
| HI | HI (responses >8 wk):•Erythroid response (pretreatment, <11 g/dL):Hb increase by ≥1.5 g/dL and 50% reduction of RBC transfusions.•Platelet response (pretreatment, <100 × 109/L):absolute increase of ≥30 × 109/L for patients starting with >20 × 109/L platelets or increase from <20 × 109/L to >20 × 109/L and by at least 100%.•Neutrophil response (pretreatment, <1.0 × 109/L): at least 100% increase and an absolute increase >0.5 × 109/L. | HI defined according to IWG 2018 response criteria:‖•Not meeting criteria for CR (or CR equivalent) or CRuni or CRL•HIerythroid (HI-E)•HIplatelets (HI-P)•HIneutrophils (HI-N) |
| ORR | Not defined | ORR = CR (or CR equivalent)∗ + PR + CRL + CRh + HI |
| No response | Not defined | Not meeting criteria for CR (or CR equivalent)∗, PR, CRL, CRh, or HI‡ |
| Not evaluable | Not included | All registered/randomly assigned patients should be reported in the denominator of response assessment analyses in line with the intention-to-treat principle. This category may include patients yet to have a response assessment, suffering early death, exiting the study early, or those with a technically suboptimal BM sample precluding assessment. |
| Cytogenetic response¶ | •Complete: disappearance of the chromosomal abnormality without appearance of new ones.•Partial: ≥50% reduction of the chromosomal abnormality. | •Complete: disappearance of the chromosomal abnormality without appearance of new ones.•Partial: ≥50% reduction of the chromosomal abnormality. |
| PD | For patients with:•<5% blasts: ≥50% increase in blasts to >5% blasts•5%-10% blasts: ≥50% increase to >10% blasts•10%-20% blasts: ≥50% increase to >20% blasts•20%-30% blasts: ≥50% increase to >30% blastsAny of the following:•At least 50% decrement from maximum remission/response in granulocytes or platelets•Reduction in Hb by ≥2 g/dL•Transfusion dependence | Fulfilling any of the criteria below:#,∗∗,††•Disease progression by blasts: ≥50% relative increase in blasts and absolute increase of blast percentage by at least 5% from pretreatment sample taken before current line of therapy.•Disease progression by worsening cytopenia: new, repeated (more than once and separated by ≥7 days) need for RBC or platelet transfusions within 8 weeks, not related to acute intercurrent illness (eg, sepsis, gastrointestinal tract bleed) or treatment effect, in the absence of HI of at least one other blood lineage as defined above.•Progression to AML: ≥50% increase in blasts from baseline assessment to ≥20% blasts. |
| Disease relapse | Any of the following:•Return to pretreatment BM blast percentage.•Decrement of 50% from maximum remission/response levels in granulocytes or platelets.•Reduction in Hb concentration by 1.5 g/dL or transfusion dependence. | Fulfilling any of the criteria below:#•Disease relapse by blasts: absolute and relative increase in BM blasts by at least 5% and ≥50%, respectively, from prior assessment, or reappearance of blasts in the blood, or development of extramedullary disease (myeloid sarcoma).•Disease relapse by worsening cytopenias: decrement in one or more blood cell lineage counts by ≥50% from maximum remission/response levels for platelets or absolute neutrophil count or a reduction of Hb by 1.5 g/dL combined with an absolute reduction in the same lineage(s) as follows: Hb <10 g/dL, platelets <100 × 109/L, or absolute neutrophils <1.0 × 109/L or repeated (more than once and separated by ≥7 days) need for RBC or platelet transfusions which are not related to acute intercurrent illness (eg, sepsis, gastrointestinal tract bleed) or treatment effect; in the absence of HI of at least one other blood lineage as defined above. |
| Patient reported outcomes (PROs) | Not included | Reporting by means of a validated assessment tool is encouraged‡‡ |
CRbi, CR bilineage; CRuni, CR unilineage; CRL, CR with limited count recovery; CRh, CR with partial hematologic recovery; wk, weeks.
Patients require ≥5% blasts before treatment initiation to be considered evaluable for CR, PR, CRh, or CRL. For time window of response assessment by PB counts, refer to Table 5. For patients with <5% blasts who have HR-MDS owing to adverse cytogenetics and/or severe cytopenias, full cytogenetic clearance (complete cytogenetic response) and blood counts that meet CR criteria are considered CR equivalent but should be reported separately. Full trilineage count recovery is defined as Hb ≥10 g/dL, platelets ≥100 × 109/L, and ANC ≥1.0 × 109/L independent of baseline PB. Given that molecular clearance has not been validated prospectively, it was not used for CR definition.
For discrepancy between BM and PB blast percentage, refer to Table 5.
A few panelists felt that mCR could still have a value, especially in bridging patients to allo-HSCT, and should therefore, still be reported. If mCR is reported, it should not be included in the ORR. Prolonged SD (≥16 weeks) might have limited benefit in patients with HR-MDS who are not candidates for allo-HSCT. However, SD is a function of time of stability, and in single-arm studies without a control arm, it is challenging to assess whether SD reflects more indolent MDS biology in some patients vs the impact of therapy. Furthermore, disease stability is included as part of the PFS definition. Therefore, SD should not be included in the ORR.
CRL and CRh are provisional entities that require additional prospective validation. Both CRL and CRh are included to allow prospective validation of their value in MDS. Similar to CR and PR, both are defined by blood counts at or around the time of response assessment and independently of the baseline blood counts. To be eligible for CRL, patients need to have achieved PB count levels at or around the time of assessment in 1 or 2 lineages, but not in all 3 lineages, that are at or above the CR threshold for the specific lineage(s). In patients with MDS/AML or MDS with increased blasts as defined by the 2022 International Consensus Classification and the 5th edition of WHO classification, respectively, reporting CRh defined as <5% blasts in the BM, 0% PB blasts, and partial recovery of PB counts (platelets ≥50 × 109/L and ANC ≥0.5 × 109/L) can be considered to achieve consistency with ELN 2022 AML response criteria. Similar to CRL, CRh is considered a provisional response category in MDS and requires additional prospective validation. If patients meet criteria for both CRL and CRh, they should be reported as having achieved CRL for the ORR as it represents a higher threshold for hematologic improvement.
For screening period and time window for assessment of transfusion dependency/independence, refer to Table 5.
If cytogenetic analyses fail, repeating cytogenetics during a subsequent response assessment is recommended. MRD assessment in MDS is insufficiently validated at this time as a surrogate for OS. MRD-negative response can be reported as a provisional response category, and clinical trial protocols should predefine what techniques are used to detect MRD and what cutoffs are considered to define an MRD response.
BM biopsy to assess for disease progression is recommended. In patients with disease progression/relapse defined by the need for transfusion support, the date of the first unit of RBC and platelet transfusion will be the date of disease progression.
Clonal progression (defined as the acquisition of new cytogenetic or molecular abnormalities) can be reported as a provisional progression criterion. This does not necessarily constitute clinical progression unless otherwise specified by the protocol.
For patients with <5% BM blasts from pretreatment sample before current line of therapy, the definition of PD might be applied to patients with ≥50% relative BM blast count increase who do not have an absolute increase of ≥5% blasts in the right clinical context (eg, worsening disease-related cytopenias). Similarly, for patients with an absolute BM blast increase to ≥20% but who have <50% relative BM blast count increase from pretreatment before current line of therapy, this could denote progression in the right clinical context where additional therapeutic options may be available with a new diagnosis of AML.
The panel recognizes that improvements in PROs (including health-related quality of life or symptoms) can be a meaningful, patient-centered goal of treatment. However, there is not yet sufficient evidence in HR-MDS to support specific recommendations at this point. In any case, rigorous assessment of PROs in clinical trials is recommended.