Suggested modified IWG 2018 HI-E criteria for response evaluation
| Item . | Suggested IWG 2018 criteria . | IWG 2006 criteria . |
|---|---|---|
| Baseline criteria | ||
| Definition of transfusion-burden categories | 3 groups: NTD (0 RBCs in 16 wk)* LTB (3-7 RBCs in 16 wk in at least 2 transfusion episodes, maximum 3 in 8 wk)* HTB (≥8 RBCs in 16 wk, ≥4 in 8 wk) | 2 groups: TD (at least 4 U of RBC with 8 wk for Hb < 9 g/dL) TID (<4 U of RBC with 8 wk for Hb < 9 g/dL) |
| Pretreatment RBC transfusion policy | Transfusion policy for the individual patient prior to therapy should be maintained on treatment† | Transfusion threshold of 9 g/dL, no exception for clinical indication |
| Response evaluation criteria: HI-E | ||
| NTD (0 RBCs in 16 wk)* | At least 2 consecutive Hb measurements ≥1.5 g/dL for a period of minimum 8 wk in an observation period of 16 to 24 wk compared with the lowest mean of 2 Hb measurements (apart from any transfusion) within 16 wk before treatment onset‡; only a response duration of at least 16 wk, however, is considered clinically meaningful | Hb increase by 1.5 g/dL and/or relevant reduction of U of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk; only RBC transfusions given for an Hb of ≤9.0 g/dL pretreatment will count in the RBC transfusion response evaluation |
| LTB (3-7 RBCs in 16 wk in at least 2 transfusion episodes, maximum 3 in 8 wk)* | HI-E in LTB patients corresponds to transfusion independence, defined by the absence of any transfusions for at least 8 wk in an observation period of 16-24 wk with the same transfusion policy (defined below) compared with 16 wk prior to treatment; only a response duration of at least 16 wk, however, is considered clinically meaningful | |
| HTB (≥8 RBCs in 16 wk, ≥4 in 8 wk) | Major response: Major HI-E response in HTB patients corresponds to transfusion independence, defined by the absence of any transfusions over a period of minimum 8 wk in an observation period of 16-24 wk with the same transfusion policy (defined below) compared with 16 wk prior to treatment; only a response duration of at least 16 wk, however, is considered clinically meaningful | |
| Minor response: Minor HI-E response in HTB patients is defined as a reduction by at least 50% of RBCs over a minimum of 16 wk with the same transfusion policy (defined below) compared with 16 wk prior to treatment | ||
| On-treatment RBC transfusion policy§ | Transfusion policy for the individual patient prior to therapy should be maintained on treatment if not otherwise clinically indicated (documentation by the treating physician required); we suggest a maximum variation between pre- and on-study practice of 1 g/dL (or 0.6 mmol/L) in terms of transfusion threshold | Transfusion threshold of 9 g/dL, no exception for clinical indication |
| Dose adjustment thresholds for high Hb levels | If the drug under investigation is stopped or its dose reduced in a responding patient for protocol-defined reasons leading to a loss of response, this should not be counted as such if reintroduction at the same or lower dose of the drug induces a new response; if reintroduction of the drug at a lower dose does not reinduce a response, this should be documented as such | NA |
| Item . | Suggested IWG 2018 criteria . | IWG 2006 criteria . |
|---|---|---|
| Baseline criteria | ||
| Definition of transfusion-burden categories | 3 groups: NTD (0 RBCs in 16 wk)* LTB (3-7 RBCs in 16 wk in at least 2 transfusion episodes, maximum 3 in 8 wk)* HTB (≥8 RBCs in 16 wk, ≥4 in 8 wk) | 2 groups: TD (at least 4 U of RBC with 8 wk for Hb < 9 g/dL) TID (<4 U of RBC with 8 wk for Hb < 9 g/dL) |
| Pretreatment RBC transfusion policy | Transfusion policy for the individual patient prior to therapy should be maintained on treatment† | Transfusion threshold of 9 g/dL, no exception for clinical indication |
| Response evaluation criteria: HI-E | ||
| NTD (0 RBCs in 16 wk)* | At least 2 consecutive Hb measurements ≥1.5 g/dL for a period of minimum 8 wk in an observation period of 16 to 24 wk compared with the lowest mean of 2 Hb measurements (apart from any transfusion) within 16 wk before treatment onset‡; only a response duration of at least 16 wk, however, is considered clinically meaningful | Hb increase by 1.5 g/dL and/or relevant reduction of U of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk; only RBC transfusions given for an Hb of ≤9.0 g/dL pretreatment will count in the RBC transfusion response evaluation |
| LTB (3-7 RBCs in 16 wk in at least 2 transfusion episodes, maximum 3 in 8 wk)* | HI-E in LTB patients corresponds to transfusion independence, defined by the absence of any transfusions for at least 8 wk in an observation period of 16-24 wk with the same transfusion policy (defined below) compared with 16 wk prior to treatment; only a response duration of at least 16 wk, however, is considered clinically meaningful | |
| HTB (≥8 RBCs in 16 wk, ≥4 in 8 wk) | Major response: Major HI-E response in HTB patients corresponds to transfusion independence, defined by the absence of any transfusions over a period of minimum 8 wk in an observation period of 16-24 wk with the same transfusion policy (defined below) compared with 16 wk prior to treatment; only a response duration of at least 16 wk, however, is considered clinically meaningful | |
| Minor response: Minor HI-E response in HTB patients is defined as a reduction by at least 50% of RBCs over a minimum of 16 wk with the same transfusion policy (defined below) compared with 16 wk prior to treatment | ||
| On-treatment RBC transfusion policy§ | Transfusion policy for the individual patient prior to therapy should be maintained on treatment if not otherwise clinically indicated (documentation by the treating physician required); we suggest a maximum variation between pre- and on-study practice of 1 g/dL (or 0.6 mmol/L) in terms of transfusion threshold | Transfusion threshold of 9 g/dL, no exception for clinical indication |
| Dose adjustment thresholds for high Hb levels | If the drug under investigation is stopped or its dose reduced in a responding patient for protocol-defined reasons leading to a loss of response, this should not be counted as such if reintroduction at the same or lower dose of the drug induces a new response; if reintroduction of the drug at a lower dose does not reinduce a response, this should be documented as such | NA |
Abbreviations are explained in Table 1.
The coauthors did not fully agree on whether patients who received only 1 or 2 RBC concentrates during the 16-wk screening period should be categorized in the NTB or LTB group. If such patients are included in clinical trials evaluating HI-E, it is recommended that HI-E achievement requires not only transfusion independence but also an increase of Hb by at least 1.5 g/dL (= 0.9 mmol/L).
As in IWG 2006 criteria, only RBC transfusions administered for an Hb level below 9 g/dL are taken into account. Exceptions to this rule may be accepted in cases of well-documented moderate or severe angina pectoris, cardiac or pulmonary insufficiency, or ischemic neurologic diseases. In these cases, a higher transfusion trigger level may be established for an individual patient. These patients may require special attention when analyzing responses within clinical trials. Transfusions for intercurrent diseases (bleeding, surgical procedure, etc) are not considered.
Oscillations (eg, natural or due to drug intervals) within this period are accepted as long as the patient remains off any transfusions and the same transfusion policy has been maintained. We suggest accepting 1 drop to an increase of between 1.0 and 1.5 g/dL over a period of 8 wk. We recommend that intervals between blood counts do not exceed 2 wk.
Exceptions to this rule may be accepted in cases of well-documented moderate or severe angina pectoris, cardiac or pulmonary insufficiency, or ischemic neurologic diseases. In these cases, a higher transfusion trigger level may be established for an individual patient. These patients may require special attention when analyzing responses within clinical trials. Transfusions for intercurrent diseases (bleeding, surgical procedure, etc) should not be taken into account.