Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients.

Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation. We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML. A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1-64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%-59%] at 6 months, and 50% (95% CI, 43%-57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415-0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360-0.858), respectively. We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML.See related commentary by Yan et al., p. 6561.

Nicolini FE ，Dulucq S ，Boureau L ，Cony-Makhoul P ，Charbonnier A ，Escoffre-Barbe M ，Rigal-Huguet F ，Coiteux V ，Varet B ，Dubruille V ，Lenain P ，Rousselot P ，Rea D ，Guerci-Bresler A ，Legros L ，Liu J ，Gardembas M ，Ianotto JC ，Turlure P ，Johnson-Ansah H ，Martiniuc J ，Jardel H ，Joly B ，Zunic P ，Henni T ，Villemagne B ，Berger MG ，Cayssials E ，Guilhot F ，Larosa F ，Guilhot J ，Etienne G ，Mahon FX ... -  《-》

Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.

Shiseki M ，Yoshida C ，Takezako N ，Ohwada A ，Kumagai T ，Nishiwaki K ，Horikoshi A ，Fukuda T ，Takano H ，Kouzai Y ，Tanaka J ，Morita S ，Sakamoto J ，Sakamaki H ，Inokuchi K ... -  《-》

Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study.

Takahashi N ，Tauchi T ，Kitamura K ，Miyamura K ，Saburi Y ，Hatta Y ，Miyata Y ，Kobayashi S ，Usuki K ，Matsumura I ，Minami Y ，Usui N ，Fukuda T ，Takada S ，Ishikawa M ，Fujimaki K ，Gomyo H ，Sasaki O ，Ohishi K ，Miyake T ，Imai K ，Suzushima H ，Mitsui H ，Togitani K ，Kiguchi T ，Atsuta Y ，Ohtake S ，Ohnishi K ，Kobayashi Y ，Kiyoi H ，Miyazaki Y ，Naoe T ，Japan Adult Leukemia Study Group ... -  《-》

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.

Atallah E ，Schiffer CA ，Radich JP ，Weinfurt KP ，Zhang MJ ，Pinilla-Ibarz J ，Kota V ，Larson RA ，Moore JO ，Mauro MJ ，Deininger MWN ，Thompson JE ，Oehler VG ，Wadleigh M ，Shah NP ，Ritchie EK ，Silver RT ，Cortes J ，Lin L ，Visotcky A ，Baim A ，Harrell J ，Helton B ，Horowitz M ，Flynn KE ... -  《-》

BCR-ABL1 transcript doubling time as a predictor for treatment-free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase.

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

Kim DDH ，Kim TS ，Atenafu EG ，Novitzky Basso I ，Forrest D ，Bence-Bruckler I ，Savoie L ，Busque L ，Keating MM ，Delage R ，Xenocostas A ，Liew E ，Paulson K ，Stockley T ，Laneuville P ，Lipton JH ，Kamel-Reid S ，Leber B ... -  《-》