Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice.

It is judged safe to discontinue treatment with tyrosine kinase inhibitors (TKI) for chronic myeloid leukemia (CML) in experimental trials on treatment-free remission (TFR). We collected a total of 293 Italian patients with chronic phase CML who discontinued TKI in deep molecular response. Seventy-two percent of patients were on treatment with imatinib, and 28% with second generation TKI at the time of discontinuation. Median duration of treatment with the last TKI was 77 months [Interquartile Range (IQR) 54;111], median duration of deep molecular response was 46 months (IQR 31;74). Duration of treatment with TKI and duration of deep molecular response were shorter with second generation TKI than with imatinib (P<0.001). Eighty-eight percent of patients discontinued as per clinical practice, and reasons for stopping treatment were: toxicity (20%), pregnancy (6%), and shared decision between treating physician and patient (62%). After a median follow up of 34 months (range, 12-161) overall estimated TFR was 62% (95%CI: 56;68). At 12 months, TFR was 68% (95%CI: 62;74) for imatinib, 73% (95%CI: 64;83) for second generation TKI. Overall median time to restart treatment was six months (IQR 4;11). No progressions occurred. Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and second generation TKI is feasible and safe in clinical practice.

Fava C ，Rege-Cambrin G ，Dogliotti I ，Cerrano M ，Berchialla P ，Dragani M ，Rosti G ，Castagnetti F ，Gugliotta G ，Martino B ，Gambacorti-Passerini C ，Abruzzese E ，Elena C ，Pregno P ，Gozzini A ，Capodanno I ，Bergamaschi M ，Crugnola M ，Bocchia M ，Galimberti S ，Rapezzi D ，Iurlo A ，Cattaneo D ，Latagliata R ，Breccia M ，Cedrone M ，Santoro M ，Annunziata M ，Levato L ，Stagno F ，Cavazzini F ，Sgherza N ，Giai V ，Luciano L ，Russo S ，Musto P ，Caocci G ，Sorà F ，Iuliano F ，Lunghi F ，Specchia G ，Pane F ，Ferrero D ，Baccarani M ，Saglio G ... -  《-》

[Observational study of chronic myeloid leukemia Chinese patients who discontinued tyrosine kinase inhibitors in the real-world].

Zhao HF ，Yang YF ，Liu BC ，Li WM ，Xu N ，Liu XL ，Jiang Q ，Dang HB ，Liang LX ，Zhang Y ，Song YP ... -  《-》

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 ... -  《-》

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 ... -  《-》

The e13a2 BCR-ABL transcript negatively affects sustained deep molecular response and the achievement of treatment-free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors.

Stopping tyrosine kinase inhibitor (TKI) treatment has become a realistic and safe objective for patients who have chronic myeloid leukemia (CML). Both a sustained deep molecular response (sDMR) and the lack of a molecular recurrence after TKI discontinuation are required to reach a durable treatment-free remission (TFR). The potential predictive role of BCR-ABL transcripts in attaining an sDMR and a TFR was analyzed in a strictly consecutive, unselected series of 194 patients who were diagnosed and treated with TKIs at the authors' center. Of 173 fully evaluable patients, 67 (38.7%) had the e13a2 transcript, and 106 (61.3%) had the e14a2 transcript. Complete cytogenetic and major molecular remissions were not affected, whereas the achievement of both a DMR (P = .008) and an sDMR (P = .004) was favored significantly in patients who had the e14a2 transcript. After a median of 68 months, the sDMR rate was 39.6% in those with the e14a2 transcript and 19.4% in those with the e13a2 transcript. In addition to transcript type, both the early achievement of a molecular response and starting treatment with a second-generation TKI positively affected the attainment of an sDMR in multivariate analysis. The use of a second-generation TKI as frontline treatment increased the sDMR rate in both transcript types. However, in patients who had the e13a2 transcript, the probability of attaining an sDMR was 37% after 60 months and did not increase further despite continuing therapy. Among 51 of 60 patients who attained an sDMR after discontinuing TKIs, 24 experienced a molecular relapse, but all regained molecular remission after resuming TKI treatment. Again, transcript type influenced TFR maintenance (P = .005), because only 2 patients (3%) with the e13a2 transcript enjoyed a durable TFR compared with 25 (23.5%) of those with the e14a2 transcript. The e13a2 transcript hinders the achievement of deep responses and the possibility of stopping TKI treatment in patients with CML.

D'Adda M ，Farina M ，Schieppati F ，Borlenghi E ，Bottelli C ，Cerqui E ，Ferrari S ，Gramegna D ，Pagani C ，Passi A ，Maifredi A ，Tucci A ，Capucci MA ，Ruggeri G ，Rossi G ... -  《-》