Molecular biology criteria in TFR studies
| Study . | Evaluation to determine eligibility for attempting TFR . | Molecular monitoring during TFR . | Molecular relapse definition . |
|---|---|---|---|
| STIM127,28 | Undetectable for ≥2 y (≥50 000 ABL copies; >4.5-log sensitivity) | Monthly for the first year, every 2 mo in year 2, and every 3 mo thereafter | Confirmed BCR-ABL1 positivity (≥1-log increase) or any loss of MMR |
| TWISTER29 | Undetectable for ≥2 y (≥4.5-log sensitivity) | Monthly for the first year, every 2 mo in year 2, and every 3 mo thereafter | Confirmed BCR-ABL1 positivity or any loss of MMR |
| A-STIM30 | Undetectable for ≥2 y but occasional detectable BCR- ABL1 IS <0.1% (≥40 000 ABL copies; >4.5-log sensitivity) | Monthly for the first 12 mo, every 2 mo in year 2, and every 3 mo thereafter | Loss of MMR (BCR-ABL1 IS ≥0.1%) |
| KIDS31 | Undetectable for ≥2 y, with duplicate analyses at >6 time points and a screening assessment performed in a central laboratory with ≥4.5-log sensitivity with nested RT-PCR and duplicate RQ-PCR assessments | Monthly for the first 6 mo, every 2 mo through month 12, and every 3 mo thereafter | Loss of MMR 2 consecutive assessments |
| ISAV45 | Undetectable for ≥2 y (≥10 000 ABL copies; >4- log sensitivity) with ≥3 RQ‐PCR tests performed locally | Monthly for the first 6 mo, then every 2 mo for 36 mo | Loss of MMR 2 consecutive assessments |
| EURO‐SKI33 | MR4 in 3 consecutive assessments over the course of > 12 mo, with final confirmation of MR4 performed in a standardized laboratory | Every 4 to 6 wk for the first year and every 3 mo in year 2 and 3 | Loss of MMR |
| STOP 2G‐TKI34 | undetectable MR4.5 for ≥24 mo | Monthly for the first 12 mo, every 2-3 mo in year 2, and every 3-6 mo thereafter | Loss of MMR |
| DADI35 | Deep molecular response sustained for ≥1 y, with assessments every 3 mo at a central standardized laboratory (assay sensitivity, 10 copies in 200 ng total RNA; corresponding to BCR‐ ABL1 IS 0.0069% or MR4 [BCR‐ ABL1 IS ≤0.01% or undetectable disease in cDNA with>10 000 ABL1 transcripts]) | Monthly for the first 12 mo, every 3 mo in year 2, and every 6 mo in year 3 | Loss of MR4 |
| ENESTFreedom36 | MR4.5 ≥1 y, nilotinib ≥2 y | Monthly for the first year, every 1.5 mo in year 2, and every 3 mo thereafter | Loss of MMR |
| ENESTop37 | MR4.5 ≥1 y, imatinib + nilotinib ≥3 y | Monthly for the first year, every 1.5 mo in year 2, and every 3 mo thereafter | Loss of MR4 |
| Study . | Evaluation to determine eligibility for attempting TFR . | Molecular monitoring during TFR . | Molecular relapse definition . |
|---|---|---|---|
| STIM127,28 | Undetectable for ≥2 y (≥50 000 ABL copies; >4.5-log sensitivity) | Monthly for the first year, every 2 mo in year 2, and every 3 mo thereafter | Confirmed BCR-ABL1 positivity (≥1-log increase) or any loss of MMR |
| TWISTER29 | Undetectable for ≥2 y (≥4.5-log sensitivity) | Monthly for the first year, every 2 mo in year 2, and every 3 mo thereafter | Confirmed BCR-ABL1 positivity or any loss of MMR |
| A-STIM30 | Undetectable for ≥2 y but occasional detectable BCR- ABL1 IS <0.1% (≥40 000 ABL copies; >4.5-log sensitivity) | Monthly for the first 12 mo, every 2 mo in year 2, and every 3 mo thereafter | Loss of MMR (BCR-ABL1 IS ≥0.1%) |
| KIDS31 | Undetectable for ≥2 y, with duplicate analyses at >6 time points and a screening assessment performed in a central laboratory with ≥4.5-log sensitivity with nested RT-PCR and duplicate RQ-PCR assessments | Monthly for the first 6 mo, every 2 mo through month 12, and every 3 mo thereafter | Loss of MMR 2 consecutive assessments |
| ISAV45 | Undetectable for ≥2 y (≥10 000 ABL copies; >4- log sensitivity) with ≥3 RQ‐PCR tests performed locally | Monthly for the first 6 mo, then every 2 mo for 36 mo | Loss of MMR 2 consecutive assessments |
| EURO‐SKI33 | MR4 in 3 consecutive assessments over the course of > 12 mo, with final confirmation of MR4 performed in a standardized laboratory | Every 4 to 6 wk for the first year and every 3 mo in year 2 and 3 | Loss of MMR |
| STOP 2G‐TKI34 | undetectable MR4.5 for ≥24 mo | Monthly for the first 12 mo, every 2-3 mo in year 2, and every 3-6 mo thereafter | Loss of MMR |
| DADI35 | Deep molecular response sustained for ≥1 y, with assessments every 3 mo at a central standardized laboratory (assay sensitivity, 10 copies in 200 ng total RNA; corresponding to BCR‐ ABL1 IS 0.0069% or MR4 [BCR‐ ABL1 IS ≤0.01% or undetectable disease in cDNA with>10 000 ABL1 transcripts]) | Monthly for the first 12 mo, every 3 mo in year 2, and every 6 mo in year 3 | Loss of MR4 |
| ENESTFreedom36 | MR4.5 ≥1 y, nilotinib ≥2 y | Monthly for the first year, every 1.5 mo in year 2, and every 3 mo thereafter | Loss of MMR |
| ENESTop37 | MR4.5 ≥1 y, imatinib + nilotinib ≥3 y | Monthly for the first year, every 1.5 mo in year 2, and every 3 mo thereafter | Loss of MR4 |
A‐STIM, According to Stop Imatinib; CMR, complete molecular response; cDNA, complementary DNA; DADI, Dasatinib Discontinuation; ENESTFreedom, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients; ENESTop, Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib; EURO‐SKI, European Stop Tyrosine Kinase Inhibitor; ISAV, Imatinib Suspension and Validation; IS, International Scale; KIDS, Korean Imatinib Discontinuation Study; MMR, major molecular response (BCR‐ABL1 IS ≤0.1%); MR4BCR‐ABL1 IS ≤0.01%; MR4.5BCR‐ABL1 IS ≤0.0032%; RQ‐PCR, real‐time quantitative polymerase chain reaction; RT‐PCR, reverse transcriptase polymerase chain reaction; STOP 2G‐TKI, Stop Second-Generation Tyrosine Kinase Inhibitor; TFR, treatment-free remission; TWISTER, Two Weeks of Low Molecular Weight Heparin for Distal Vein Thrombosis.