International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia
1. Complete remission (CR) | i. Complete resolution of disease-related symptoms and signs including palpable hepatosplenomegaly. |
| ii. Peripheral blood count remission defined as hemoglobin level at least 110 g/L, platelet count at least 100 × 109/L, and absolute neutrophil count at least 1.0 × 109/L. In addition, all 3 blood counts should be no higher than the upper normal limit. | |
| iii. Normal leukocyte differential including disappearance of nucleated red blood cells, blasts, and immature myeloid cells in the peripheral smear, in the absence of splenectomy.* | |
| iv. Bone marrow histologic remission defined as the presence of age-adjusted normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis grade no higher than 1.† | |
| 2. Partial remission (PR) | Requires all of the above criteria for CR except the requirement for bone marrow histologic remission. However, a repeat bone marrow biopsy is required in the assessment of PR and may or may not show favorable changes that do not however fulfill criteria for CR. |
| 3. Clinical improvement (CI) | Requires one of the following in the absence of both disease progression (as outlined below) and CR/PR assignment (CI response is validated only if it lasts for no fewer than 8 weeks) |
| i. A minimum 20-g/L increase in hemoglobin level or becoming transfusion independent (applicable only for patients with baseline hemoglobin level of less than 100 g/L).‡ | |
| ii. 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.§ | |
| iii. A minimum 100% increase in platelet count and an absolute platelet count of at least 50 000 × 109/L (applicable only for patients with baseline platelet count below 50 × 109/L). | |
| iv. A minimum 100% increase in ANC and an ANC of at least 0.5 × 109/L (applicable only for patients with baseline absolute neutrophil count below 1 × 109/L). | |
| 4. Progressive disease (PD) | Requires one of the following:|| |
| i. Progressive splenomegaly that is defined by the appearance of a previously absent splenomegaly that is palpable at greater than 5 cm below the left costal margin or a minimum 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a minimum 50% increase in palpable distance for baseline splenomegaly of greater than 10 cm. | |
| ii. Leukemic transformation confirmed by a bone marrow blast count of at least 20%. | |
| iii. An increase in peripheral blood blast percentage of at least 20% that lasts for at least 8 weeks. | |
| 5. Stable disease (SD) | None of the above. |
| 6. Relapse | Loss of CR, PR, or CI. In other words, a patient with CR or PR is considered to have undergone relapse when he or she no longer fulfills the criteria for even CI. However, changes from either CR to PR or CR/PR to CI should be documented and reported. |
1. Complete remission (CR) | i. Complete resolution of disease-related symptoms and signs including palpable hepatosplenomegaly. |
| ii. Peripheral blood count remission defined as hemoglobin level at least 110 g/L, platelet count at least 100 × 109/L, and absolute neutrophil count at least 1.0 × 109/L. In addition, all 3 blood counts should be no higher than the upper normal limit. | |
| iii. Normal leukocyte differential including disappearance of nucleated red blood cells, blasts, and immature myeloid cells in the peripheral smear, in the absence of splenectomy.* | |
| iv. Bone marrow histologic remission defined as the presence of age-adjusted normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis grade no higher than 1.† | |
| 2. Partial remission (PR) | Requires all of the above criteria for CR except the requirement for bone marrow histologic remission. However, a repeat bone marrow biopsy is required in the assessment of PR and may or may not show favorable changes that do not however fulfill criteria for CR. |
| 3. Clinical improvement (CI) | Requires one of the following in the absence of both disease progression (as outlined below) and CR/PR assignment (CI response is validated only if it lasts for no fewer than 8 weeks) |
| i. A minimum 20-g/L increase in hemoglobin level or becoming transfusion independent (applicable only for patients with baseline hemoglobin level of less than 100 g/L).‡ | |
| ii. 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.§ | |
| iii. A minimum 100% increase in platelet count and an absolute platelet count of at least 50 000 × 109/L (applicable only for patients with baseline platelet count below 50 × 109/L). | |
| iv. A minimum 100% increase in ANC and an ANC of at least 0.5 × 109/L (applicable only for patients with baseline absolute neutrophil count below 1 × 109/L). | |
| 4. Progressive disease (PD) | Requires one of the following:|| |
| i. Progressive splenomegaly that is defined by the appearance of a previously absent splenomegaly that is palpable at greater than 5 cm below the left costal margin or a minimum 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a minimum 50% increase in palpable distance for baseline splenomegaly of greater than 10 cm. | |
| ii. Leukemic transformation confirmed by a bone marrow blast count of at least 20%. | |
| iii. An increase in peripheral blood blast percentage of at least 20% that lasts for at least 8 weeks. | |
| 5. Stable disease (SD) | None of the above. |
| 6. Relapse | Loss of CR, PR, or CI. In other words, a patient with CR or PR is considered to have undergone relapse when he or she no longer fulfills the criteria for even CI. However, changes from either CR to PR or CR/PR to CI should be documented and reported. |
Because of subjectivity in peripheral blood smear interpretation, CR does not require absence of morphologic abnormalities of red cells, platelets, and neutrophils
In patients with CR, a complete cytogenetic response is defined as failure to detect a cytogenetic abnormality in cases with a pre-existing abnormality. A partial cytogenetic response is defined as 50% or greater reduction in abnormal metaphases. In both cases, at least 20 bone marrow- or peripheral blood-derived metaphases should be analyzed. A major molecular response is defined as the absence of a specific disease-associated mutation in peripheral blood granulocytes of previously positive cases. In the absence of a cytogenetic/molecular marker, monitoring for treatment-induced inhibition of endogenous myeloid colony formation is encouraged. Finally, baseline and posttreatment bone marrow slides are to be stained at the same time and interpreted at one sitting by a central review process
Transfusion dependency is defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. Similarly, during protocol therapy, transfusions for a hemoglobin level of 85 g/L or more is discouraged unless it is clinically indicated
In splenectomized patients, palpable hepatomegaly is substituted with the same measurements
It is acknowledged that worsening cytopenia might represent progressive disease, but its inclusion as a formal criterion was avoided because of the difficulty distinguishing disease-associated from drug-induced myelosuppression. However, a decrease in hemoglobin level of 20 g/L or more, a 100% increase in transfusion requirement, and new development of transfusion dependency, each lasting for more than 3 months after the discontinuation of protocol therapy, can be considered disease progression