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
... -
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Low-dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment-free remission in chronic myeloid leukemia patients: Results of a retrospective study.
Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). In clinical practice, tyrosine kinase inhibitor (TKI) dose reductions can be considered a means of preventing adverse effects and improving quality of life. We hypothesized that administration of low-dose TKIs before treatment discontinuation does not impair TFR in patients with CML who have a deep molecular response (DMR, ≥MR4 ).
We conducted a retrospective analysis of 77 patients with CML who discontinued treatment with TKIs. Twenty-six patients had been managed with low-dose TKIs before stopping treatment. Patients were to be exposed to TKIs for ≥5 years and to low-dose TKIs for ≥1 year and in DMR for ≥2 years. The loss of major molecular response (MMR) was considered a trigger for restarting therapy.
In the low-dose group, 61.5% of patients received second-generation TKIs, and dose reduction was ≥50% for 65.4% of patients. With a median follow-up of 61.5 months, TFR at 12 months was 56.8% in the full-dose TKI group and 80.8% in the low-dose group, and TFR at 60 months was 47.5% and 58.8%, respectively. The median time to molecular recurrence (≥MMR) from TKI discontinuation in the entire cohort was 6.2 months. All patients quickly achieved MMR after resuming TKI therapy. Results appear independent of both dose reduction and potential pretreatment with interferon-α.
This retrospective study shows that TFR was not impaired by low-dose TKI regimens before TKI cessation in Patients with CML. Nevertheless, prospective randomized clinical trials must be undertaken to analyze the probability of successful TFR in patients managed with TKI dose de-escalation strategies before TKI discontinuation.
Cayssials E
，Torregrosa-Diaz J
，Gallego-Hernanz P
，Tartarin F
，Systchenko T
，Maillard N
，Desmier D
，Machet A
，Fleck E
，Corby A
，Motard C
，Denis G
，Herbelin A
，Gombert JM
，Roy L
，Ragot S
，Leleu X
，Guilhot F
，Chomel JC
... -
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Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials.
Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP.
In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression.
Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR(4·5) response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason.
Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy.
MD Anderson Cancer Center, National Cancer Institute.
Jain P
，Kantarjian H
，Alattar ML
，Jabbour E
，Sasaki K
，Nogueras Gonzalez G
，Dellasala S
，Pierce S
，Verstovsek S
，Wierda W
，Borthakur G
，Ravandi F
，O'Brien S
，Cortes J
... -
《Lancet Haematology》
ResearchGate
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