Table 1.
Clinical trials of TFR with second‐generation TKIs
| Registry information | Trial title | Enrolled patients/line of therapy | TFR eligibility | Relapse definition | TFR rate; time after discontinuing | Patients regaining molecular response after reinitiating TKIs | References |
|---|---|---|---|---|---|---|---|
| NCT0185004 | Open‐label study evaluating Dasatinib therapy discontinuation in patients with chronic phase CML with stable complete molecular response (DASFREE) | 84/dasatinib (frontline or subsequent lines) | MR4.5 For ≥1 year | Loss of MMR | 48%; 1 year | 42/42a | Shah et al.38 |
| NCT01627132 | Discontinuation of Dasatinib in patients with chronic myeloid leukemia‐CP who have maintained complete molecular remission for 2 years; Dasatinib stop trial (D‐STOP) | 65/dasatinib (frontline or subsequent line after imatinib) | MR4 for 2 years | 2 positive MR4 readings in 1 month | 63%; 1 year | 20/20 | Kumagai et al.57 |
| NCT02268370 | Treatment‐free remission accomplished with Dasatinib in patients with CML (TRAD) | 118/dasatinib rechallenge and discontinuation after imatinib discontinuation (second‐stop) | MR4.5 For ≥2 years | Loss of MR4 on 2 consecutive occasions or MMR on 1 occasion | 67%; 1 year | 35/40 | Kim et al.59 |
| NCT01761890 | Front‐line treatment of BCR‐ABL+ chronic myeloid leukemia (CML) with Dasatinib (CML1113) | 133/dasatinib (frontline) | CMR | NR | NR | NR | CML111343 |
| UMIN000005130 | Discontinuation of Dasatinib in patients with chronic myeloid leukemia‐CP who have maintained complete molecular remission for 2 years; Dasatinib stop trial (DADI) | 63/dasatinib (frontline or subsequent line after imatinib) |
MR4 for ≥1 year | Loss of MR4 | 44%; 3 years | NR | Okada et al.58
DADI44 |
| UMIN000008999 | Dasatinib discontinuation for CML‐CP with 1 year CMR (IMIDAS) | 50/dasatinib | CMR for ≥1 year | NR | NR | NR | IMIDAS45 |
| UMIN000011099 | DAsatinib DIscontinuation for 1st‐line treatment with CML‐CP with 1 year CMR (1st DADI) | 100/dasatinib (frontline) | CMR for ≥1 year | Loss of CMR | NR | NR | 1st DADI46 |
| NCT01887561 | Dasatinib for patients achieving complete molecular response for cure (D‐NewS) | 100/dasatinib (frontline) | NR | NR | NR | NR | D‐NewS47 |
| UMIN000008583 | Clinical research of safety and efficacy after a stop of dasatinib administration in patients with CML‐CP achieving a CMR on a treatment of TKIs (STDAST) | 60/imatinib, nilotinib + dasatinib, dasatinib | CMR for ≥2 years | NR | NR | NR | STDAST48 |
| UMIN000007221 | Multicenter clinical study evaluating the safety and efficacy of Dasatinib treatment and its discontinuation in patients with CP CML who had reached CMR during Imatinib therapy | 40/dasatinib (after imatinib) | CMR on imatinib | NR | NR | NR | Multicenter clinical study on the safety and efficacy of Dasatinib Discontinuation49 |
| UMIN000022254 | Phase II clinical trial of Dasatinib therapy aiming for TFR in patients with CP‐CML (D‐FREE) | 300/dasatinib (frontline) | MR4.5 For ≥1 year | Loss of MMR once, or loss of MR4 twice | NR | NR | D‐FREE50 |
| UMIN000007141 | Multicenter phase II clinical study of the safety and efficacy of discontinuing Nilotinib treatment in patients with chronic phase chronic myelogenous leukemia who have achieved complete molecular response with Imatinib or Nilotinib (NILSt) | 112/nilotinib (frontline, or after imatinib) | MR4.5 For 2 years | Loss of MR4.5 | 59%; 1 year | 32/34 | Kadowaki et al.39 |
| NCT01784068 | Nilotinib treatment‐free remission study in CML patients (ENESTfreedom) | 215/nilotinib (frontline) | MR4.5 | Loss of MMR | 49%; 96 weeks | 87/88b | Hochhaus et al.60
Ross et al.61 |
| NCT01744665 | Safety and efficacy of CML patients who switch to Nilotinib and stop treatment after achieving and sustaining MR4.5 (ENESTGoal) | 59/nilotinib (after imatinib) | MR4.5 | Loss of MMR | 41%; NR | NR | Ritchie et al.62 |
| NCT01698905 | Treatment‐free remission after achieving sustained MR4.5 On Nilotinib (ENESTop) | 163/nilotinib (after imatinib) | MR4.5 For ≥2 years on nilotinib | Loss of MMR or confirmed loss of MR4 | 53%; 96 weeks | 54/56 | Mahon et al.25 |
| UMIN000005904 | Multicenter clinical study on the safety and efficacy of Nilotinib discontinuation in patients with chronic myelogenous leukemia‐chronic phase and complete molecular response (STAT2) | 96/nilotinib (after imatinib) | MR4.5 for 2 years | Loss of MR4.5 | 68%; 1 year | NR | Takahashi et al.63
Stop Tasigna Trial51 |
| NCT01743989 | A randomized phase III study to assess the effect of a longer duration of consolidation treatment with Nilotinib on TFR in CP CML (ENESTPath) | 619/nilotinib (after imatinib) | Stable MR4 for ≥1 year | Loss of MR4 | NR | NR | ENESTPath52 |
| NCT01657604 | Tasigna and interferon alpha evaluation initiated by the German CML study group (TIGER) | 652/nilotinib, nilotinib+IFN (frontline) | Confirmed MMR for ≥2 years | Loss of MMR | NR | NR | TIGER53 |
| NCT02917720 | Stop second generation TKI study (STOP‐2G TKI) | 100/dasatinib or nilotinib (frontline or subsequent line) | MR4.5 For ≥2 years | Loss of MMR | 63%; 1 year | 26/26 | Rea et al.20 |
| NCT01596114 | European stop tyrosine kinase inhibitory study (EURO‐SKI) | 821/imatinib, dasatinib, or nilotinib (frontline or second line due to intolerance) | MR4 for ≥1 year | Loss of MMR | 52%; 2 years | 86% | Mahon et al.65 |
| NCT02269267 | The life after stopping tyrosine kinase inhibitors study (the LAST study) | 173/imatinib, dasatinib, nilotinib, or bosutinib | MR4 for ≥2 years | Molecular recurrence | 66%; 12.3 months | 48 | LAST54
Atallah et al.65 |
| NCT01804985 | De‐escalation and stopping treatment of Imatinib, Nilotinib or sprYcel in chronic myeloid leukemia (DESTINY) | 174/frontline imatinib, dasatinib, or nilotinib (second line if due to intolerance allowed) | MMR for 1 year | Loss of MMR in 2 consecutive samples | 93%; 1 year | 12/12 | Clark et al.55 |
| UMIN000007944 | Stop imatinib or dasatinib study in CP‐CML patients maintaining CMR for 2 years (TWMU‐TKI‐STOP) | 40/imatinib or dasatinib | CMR for 2 years | NR | NR | NR | TWMU‐TKI‐STOP (2012)56 |
Abbreviations: CCyR, complete cytogenetic response; CML‐CP, chronic myeloid leukemia in chronic phase (also called CP CML in some trials); CMR, complete molecular response; IFN, interferon; MMR, major molecular response; MR4, molecular response of 4‐log reduction of BCR‐ABL1 transcripts; MR4.5, molecular response of 4.5‐log reduction of BCR‐ABL1 transcripts; MRFS, molecular recurrence‐free survival; TFR, treatment‐free remission; TKI, tyrosine kinase inhibitor.
a
One patient lost MMR and restarted treatment. The patient was not evaluable because he/she discontinued the study after only one PCR assessment.
b
One patient who did not regain MMR after restarting nilotinib withdrew consent and discontinued after 7.1 weeks of treatment, and was not eligible for evaluation.