Proposed criteria for measurement of treatment response in adult MDS/MPN
| CR (presence of all of the following improvements)* |
| Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal maturation of all cell lines and return to normal cellularity* |
| Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤grade 1 fibrosis)† |
| Peripheral blood‡ |
| WBC ≤10 × 109 cells/L |
| Hgb ≥11 g/dL |
| Platelets ≥100 × 109/L; ≤450 × 109/L |
| Neutrophils ≥1.0 × 109/L |
| Blasts 0% |
| Neutrophil precursors reduced to ≤ 2% |
| Monocytes ≤1 × 109/L |
| Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, cutaneous disease, disease-related serous effusions), including palpable hepatosplenomegaly |
| Provisional category of CR with resolution of symptoms:‡ CR as described above, and complete resolution of disease-related symptoms as noted by the MPN-SAF TSS |
| Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia* |
| Complete cytogenetic remission |
| Resolution of previously present chromosomal abnormality (known to be associated with myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping with minimal of 20 metaphases or FISH§ |
| Partial remission |
| Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast equivalents) reduced by 50%, but remaining >5% of cellularity except in cases of MDS/MPN with ≤5% bone marrow blasts at baseline |
| Marrow response |
| Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices as presented above. |
| Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining >5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow evaluations spaced at least 2 mo apart |
| Clinical benefit |
| Requires 1 of the following in the absence of progression or CR/partial response and independent of marrow response (cord blood response must be verified at ≥8 wk) to be considered a clinical benefit |
| Erythroid response |
| Hgb increase by ≥2.0 g/dL |
| TI for ≥ 8 wk for patients requiring at least 4 packed red blood cell transfusions in the previous 8 wk |
| Only red blood cell transfusions given based on physician’s judgment for a pretreatment Hgb of ≤8.5 g/dL will count in the red blood cell TI response evaluation|| |
| Platelet response |
| Transfusion independence when previously requiring platelet transfusions of at least a rate of 4 platelet transfusions in the previous 8 wk |
| Pretreatment ≤20 × 109/L: increase from <20 × 109/L to >20 × 109/L and by at least 100% |
| Pretreatment >20 × 109/L but ≤ 100 × 109/L: absolute increase of ≥30 × 109/L|| |
| Neutrophil response |
| Pretreatment ≤0.5 × 109/L at least 100% increase and an absolute increase ≥0.5 × 109/L |
| Pretreatment, >0.5 × 109/L and ≤1.0 × 109/L At least 50% increase and an absolute increase ≥0.5 × 109/L|| |
| Spleen response |
| Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable |
| Symptom response |
| Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring <20 were not considered eligible for measuring clinical benefit.¶ |
| CR (presence of all of the following improvements)* |
| Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal maturation of all cell lines and return to normal cellularity* |
| Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤grade 1 fibrosis)† |
| Peripheral blood‡ |
| WBC ≤10 × 109 cells/L |
| Hgb ≥11 g/dL |
| Platelets ≥100 × 109/L; ≤450 × 109/L |
| Neutrophils ≥1.0 × 109/L |
| Blasts 0% |
| Neutrophil precursors reduced to ≤ 2% |
| Monocytes ≤1 × 109/L |
| Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, cutaneous disease, disease-related serous effusions), including palpable hepatosplenomegaly |
| Provisional category of CR with resolution of symptoms:‡ CR as described above, and complete resolution of disease-related symptoms as noted by the MPN-SAF TSS |
| Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia* |
| Complete cytogenetic remission |
| Resolution of previously present chromosomal abnormality (known to be associated with myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping with minimal of 20 metaphases or FISH§ |
| Partial remission |
| Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast equivalents) reduced by 50%, but remaining >5% of cellularity except in cases of MDS/MPN with ≤5% bone marrow blasts at baseline |
| Marrow response |
| Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of peripheral blood indices as presented above. |
| Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining >5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow evaluations spaced at least 2 mo apart |
| Clinical benefit |
| Requires 1 of the following in the absence of progression or CR/partial response and independent of marrow response (cord blood response must be verified at ≥8 wk) to be considered a clinical benefit |
| Erythroid response |
| Hgb increase by ≥2.0 g/dL |
| TI for ≥ 8 wk for patients requiring at least 4 packed red blood cell transfusions in the previous 8 wk |
| Only red blood cell transfusions given based on physician’s judgment for a pretreatment Hgb of ≤8.5 g/dL will count in the red blood cell TI response evaluation|| |
| Platelet response |
| Transfusion independence when previously requiring platelet transfusions of at least a rate of 4 platelet transfusions in the previous 8 wk |
| Pretreatment ≤20 × 109/L: increase from <20 × 109/L to >20 × 109/L and by at least 100% |
| Pretreatment >20 × 109/L but ≤ 100 × 109/L: absolute increase of ≥30 × 109/L|| |
| Neutrophil response |
| Pretreatment ≤0.5 × 109/L at least 100% increase and an absolute increase ≥0.5 × 109/L |
| Pretreatment, >0.5 × 109/L and ≤1.0 × 109/L At least 50% increase and an absolute increase ≥0.5 × 109/L|| |
| Spleen response |
| Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable |
| Symptom response |
| Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring <20 were not considered eligible for measuring clinical benefit.¶ |
Presence of dysplastic changes, which may be interpreted within the scope of normal range of dysplastic changes, may still exist in the presence of CR as allowed in MDS IWG. Marrow should exhibit age-adjusted normocellularity in CR.
If there is no significant fibrosis present on the initial bone marrow biopsy, a second biopsy is not required to prove resolution of fibrosis. Grading of fibrosis in measurement of treatment response should be according to the European Consensus System.67
Given the current lack of a validated tool to assess complete resolution of symptoms in MDS/MPN, “CR with resolution of symptoms” (a complete resolution of disease-related symptoms as noted by the MPN-SAF TSS in presence of CR) will be a provisional category of disease response.
Loss of cytogenetic burden of disease by (via FISH or classic karyotyping) known to adversely affect prognosis is required to reach complete cytogenetic remission. Decrease in the cytogenetic burden of disease must be by ≥50% (via FISH or classic karyotyping) to be indicative of a partial cytogenetic response. Given variability of fluorescent probes used in FISH, cytogenetic normalization via FISH will depend on the performance characteristics of the specific probes used.
Resolution of abnormal peripheral blood counts must persist for at least 2 separate analyses over at least 8 wk. In the case of proliferative MDS/MPN, CR will include resolution of thrombocytosis to a normal platelet count (150-450 × 109/L) and resolution of leukocytosis to WBC ≤10 × 109 cells/L but ≥1.5 × 109/L. Hgb should be maintained >11 g/dL and platelets ≥100 × 109/L without the support of transfusions. Clinical benefit may occur when these changes occur in absence of other changes required for CR or marrow response. Platelet and packed red blood cell TI would be considered for clinical benefit, and duration of TI should be monitored. Reduction in myeloid precursors (promyelocytes, myelocytes, metamyelocytes, nucleated red blood cells) to less than appreciable levels (≤2-3%) and/or 1 × 109/L monocytosis in the absence of infection, cytokine treatment, or other reactive causes.
MPN-SAF TSS validation among patients with MDS/MPN is currently under way (R.A. Mesa, personal communication, 2014).