Background: In the last 10 years different studies analyzed the outcome of patients (pts) with sustained complete molecular remission (CMR) who discontinued imatinib, reporting rates of treatment-free remission (TFR) ranging from 33 to 66% depending on the definition of molecular relapse. On these bases it is judged safe to discontinue treatment with tyrosine-kinase inhibitors (TKIs) in experimental contexts. Aims: To evaluate TFR in the setting of clinical practice according to the Italian experience where most of the pts who discontinued TKIs were not included in prospective protocols. Methods: We retrospectively analyzed the outcome of pts treated in 23 Divisions of Hematology in Italy, who discontinued TKIs in deep molecular response (MR). General and clinical information such as TKI at discontinuation, line of treatment, type of MR at discontinuation, reasons for discontinuation were collected. We estimated TFR with the Kaplan-Meier method. Prognostic factors for TFR were assessed by univariate Cox regression model analysis. Results:We analyzed a total of 208 pts who discontinued TKIs from June 2003 to October 2015. Median age was 59 years (Interquartile Range, IQR, 46-72). 102 were male, 106 female; 52%, 35% and 13% were low, intermediate and high Sokal score respectively. 168 pts (81%) discontinued in first line; 38 pts in second line (63% for intolerance to prior TKIs) and 2 pts in third line. 153 pts (74%) were on treatment with imatinib (all frontline), 26% with either nilotinib or dasatinib. Median duration of treatment with the last TKI was 75.2 mos (IQR 50-114); median time to CMR (undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 23.3 mos (IQR 11.1-45.2). Median duration of CMR was 23 mos (IQR 11-45) before stop. At 3 mos of last TKI 28% of pts were in MR3, 26% were in PCyR and/or had a transcript <10%, 45% were in CCyR and/or had a transcript <1%, and 1% had no response. 184 pts had a response defined according to molecular standardization: 8% were MR3, 30% were MR4, 36% were MR4.5, 26% were MR5. Reasons for discontinuation were: toxicity for 28% of pts, pregnancy for 10%, pt request for 56%, enrollment in ISAV protocol for 10 pts. After a median follow-up of 11 mos (IQR 1-149), estimated TFR was 71% (95%CI 64.6%>78.1%) (figure 1). 69 pts restarted treatment. Reasons for restarting were: loss of MR4 for 20% of pts, loss of MR3 for 55%, loss of CCyR for 12%, other reasons for 13%. Median time to restart treatment was 6 mos (IQR 4-11). We assessed age, sex, Sokal score, type of transcript, previous IFN therapy, duration of TKI therapy, response at 3 mos, time to CMR, CMR duration, line of therapy at stop, depth of MR, reasons for stop as potential prognostic factors for TFR, but no statistically significant association were found, with the exception of response MR5 at stop (MR5 vs MR4, HR: 0.43, 95%CI 0.21-0.87, p=0.02) and age [HR 0.62 (95%CI 0.42-0.93, p=0.02), i.e. a decreased risk in older vs younger pts (difference of age=26 years)]. Pts who had to restart therapy were treated with imatinib (57), nilotinib (10), dasatinib (2). All of them regained at least MR3. No pts progressed. All pts were alive at the last follow up with the exception of 7 who died for reasons unrelated to CML.

TYROSINE KINASE INHIBITORS DISCONTINUATION IN CHRONIC MYELOID LEUKEMIA: A RETROSPECTIVE ANALYSIS OF 208 ITALIAN PATIENTS

CAVAZZINI, Francesco;
2016

Abstract

Background: In the last 10 years different studies analyzed the outcome of patients (pts) with sustained complete molecular remission (CMR) who discontinued imatinib, reporting rates of treatment-free remission (TFR) ranging from 33 to 66% depending on the definition of molecular relapse. On these bases it is judged safe to discontinue treatment with tyrosine-kinase inhibitors (TKIs) in experimental contexts. Aims: To evaluate TFR in the setting of clinical practice according to the Italian experience where most of the pts who discontinued TKIs were not included in prospective protocols. Methods: We retrospectively analyzed the outcome of pts treated in 23 Divisions of Hematology in Italy, who discontinued TKIs in deep molecular response (MR). General and clinical information such as TKI at discontinuation, line of treatment, type of MR at discontinuation, reasons for discontinuation were collected. We estimated TFR with the Kaplan-Meier method. Prognostic factors for TFR were assessed by univariate Cox regression model analysis. Results:We analyzed a total of 208 pts who discontinued TKIs from June 2003 to October 2015. Median age was 59 years (Interquartile Range, IQR, 46-72). 102 were male, 106 female; 52%, 35% and 13% were low, intermediate and high Sokal score respectively. 168 pts (81%) discontinued in first line; 38 pts in second line (63% for intolerance to prior TKIs) and 2 pts in third line. 153 pts (74%) were on treatment with imatinib (all frontline), 26% with either nilotinib or dasatinib. Median duration of treatment with the last TKI was 75.2 mos (IQR 50-114); median time to CMR (undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 23.3 mos (IQR 11.1-45.2). Median duration of CMR was 23 mos (IQR 11-45) before stop. At 3 mos of last TKI 28% of pts were in MR3, 26% were in PCyR and/or had a transcript <10%, 45% were in CCyR and/or had a transcript <1%, and 1% had no response. 184 pts had a response defined according to molecular standardization: 8% were MR3, 30% were MR4, 36% were MR4.5, 26% were MR5. Reasons for discontinuation were: toxicity for 28% of pts, pregnancy for 10%, pt request for 56%, enrollment in ISAV protocol for 10 pts. After a median follow-up of 11 mos (IQR 1-149), estimated TFR was 71% (95%CI 64.6%>78.1%) (figure 1). 69 pts restarted treatment. Reasons for restarting were: loss of MR4 for 20% of pts, loss of MR3 for 55%, loss of CCyR for 12%, other reasons for 13%. Median time to restart treatment was 6 mos (IQR 4-11). We assessed age, sex, Sokal score, type of transcript, previous IFN therapy, duration of TKI therapy, response at 3 mos, time to CMR, CMR duration, line of therapy at stop, depth of MR, reasons for stop as potential prognostic factors for TFR, but no statistically significant association were found, with the exception of response MR5 at stop (MR5 vs MR4, HR: 0.43, 95%CI 0.21-0.87, p=0.02) and age [HR 0.62 (95%CI 0.42-0.93, p=0.02), i.e. a decreased risk in older vs younger pts (difference of age=26 years)]. Pts who had to restart therapy were treated with imatinib (57), nilotinib (10), dasatinib (2). All of them regained at least MR3. No pts progressed. All pts were alive at the last follow up with the exception of 7 who died for reasons unrelated to CML.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/2372179
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