Table 8.
Revised (2013) IWG-MRT and European LeukaemiaNet response criteria for myelofibrosis
| Response categories | Required criteria (for all response categories, benefit must last for ≥ 12 weeks to qualify as a response) |
|---|---|
| CR | Bone marrowa: Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MFb and Peripheral blood: Hemoglobin ≥ 10.0 g/dL and < UNL; neutrophil count ≥ 1 × 109/L and < UNL; Platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cellsc and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH |
| PR | Peripheral blood: Hemoglobin ≥10.0 g/dL and < UNL; neutrophil count ≥ 1 × 109/L and <UNL; platelet count > 100 × 109/L and < UNL; < 2% immature myeloid cellsc and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or Bone marrowa: Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MFb, and Peripheral blood: Hemoglobin ≥ 8.5 but < 10.0 g/dL and < UNL; neutrophil count ≥ 1 × 109/L and < UNL; platelet count ≥ 50, but < 100 × 109/L and < UNL; < 2% immature myeloid cellsc and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH |
| Clinical improvement (CI) | The achievement of anemia, spleen or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropeniad |
| Anemia response | Transfusion-independent patients: a ≥ 2.0 g/dL increase in hemoglobin levele Transfusion-dependent patients: becoming transfusion-independentf |
| Spleen responseg | A baseline splenomegaly that is palpable at 5–10 cm, below the LCM, becomes not palpableh or A baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥ 50%h A baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for spleen response A spleen response requires confirmation by MRI or CT showing ≥ 35% spleen volume reduction |
| Symptoms response | A ≥ 50% reduction in the MPN-SAF TSSi |
| Progressive diseasej | Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5–10 cm or A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or A peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1 × 10(9)/L that lasts for at least 2 weeks |
| Stable disease | Belonging to none of the above listed response categories |
| Relapse | No longer meeting criteria for at least CI after achieving CR, PR, or CI, or Loss of anemia response persisting for at least 1 month or Loss of spleen response persisting for at least 1 month Recommendations for assessing treatment-induced cytogenetic and molecular changes |
| Cytogenetic remission | At least 10 metaphases must be analyzed for cytogenetic response evaluation and requires confirmation by repeat testing within 6 months window CR: eradication of a preexisting abnormality PR: ≥ 50% reduction in abnormal metaphases (partial response applies only to patients with at least 10 abnormal metaphases at baseline) |
| Molecular remission | Molecular response evaluation must be analyzed in peripheral blood granulocytes and requires confirmation by repeat testing within 6 months window CR: Eradication of a pre-existing abnormality PR: ≥ 50% decrease in allele burden (partial response applies only to patients with at least 20% mutant allele burden at baseline) |
| Cytogenetic/molecular relapse | Re-emergence of a pre-existing cytogenetic or molecular abnormality that is confirmed by repeat testing |
IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; CR, complete response; MF, myelofibrosis; UNL, upper normal limit; EMH, extramedullary hematopoiesis; PR, partial response; LCM, left costal margin; MRI, magnetic resonance imaging; CT, computed tomography; MPN-SAF TSS, MPN Symptom Assessment Form Total Symptom Score.
Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process. Cytogenetic and molecular responses are not required for CR assignment.
Grading of MF is according to the European classification. It is underscored that the consensus definition of a CR bone marrow is to be used only in those patients in which all other criteria are met, including resolution of leukoerythroblastosis. It should also be noted that it was a particularly difficult task for the working group to reach a consensus regarding what represents a complete histologic remission.
Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells. In splenectomized patients, < 5% immature myeloid cells is allowed.
See above for definitions of anemia response, spleen response, and progressive disease. Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 2.0 g/dL decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to CI requires a minimum platelet count of ≥ 25,000 × 109/L and absolute neutrophil count of ≥ 0.5 × 109/L.
Applicable only to patients with baseline hemoglobin of < 10.0 g/dL. In patients not meeting the strict criteria for transfusion dependency at the time of study enrollment (see as follows), but have received transfusions within the previous month, the pretransfusion hemoglobin level should be used as the baseline.
Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days prior to study enrollment. Response in transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive “rolling” 12-week interval during the treatment phase, capped by a hemoglobin level of ≥ 8.5 g/dL.
In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy.
Spleen or liver responses must be confirmed by imaging studies where a ≥ 35% reduction in spleen volume, as assessed by MRI or CT, is required. Furthermore, a ≥ 35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response regardless of what is reported with physical examination.
Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS is the summation of all the individual scores (0–100 scale). Symptoms response requires ≥ 50% reduction in the MPN-SAF TSS.
Progressive disease assignment for splenomegaly requires confirmation my MRI or computed tomography showing a ≥ 25% increase in spleen volume from baseline. Baseline values for both physical examination and imaging studies refer to pretreatment baseline and not to posttreatment measurements.