Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor com- mercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Due to the lack of predictors of response, pts’ selection is based on clinical needs. dose ≤10mg BID in the first 12 wks (HR:2.29, 95%CI:1.1-4.3;p=0.02).Overall, 178 pts out of 217 symptomatic patients (82%) had a symptom response. Fac- tors associated with worse responses were: grade 3 marrow fibrosis (p=0.035), transfusion dependency (p=0.001) and RUX titrated dose ≤10 mg BID (p=0.014). In multivariate analysis, symptom response rate correlated only with RUX titrated dose (HR:2.4, 95%CI:1.1-4.9,p=0.016). Neither spleen or symp- toms response significantly correlated with survival. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of “real-life” MF pts. Methods: A multicenter observational study on WHO-defined MF was con- ducted in 11 Italian Hematology Centers. Data were extracted from an electronic database that included retrospective data on pts treated before January 2015. Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and June 2015, 266 pts with PMF (140 pts,52.6%), or PET-MF (51,19.2%) or PPV-MF (75,28.2%) were treated with RUX in participating Centers. At diagnosis, baseline characteristics were (medi- an): age, 64.2 y (range, 26-86); ≥65 y, 45.5%; male, 58%; hemoglobin (Hb), 11.5 g/dL (5-17.7); Hb <10 g/dL, 27.4%; PLT, 356×109/L (30-1110); PLT <100×109/L, 5.2%; spleen enlargement, 87.5% (spleen length ≥10cm: 40.6%); constitutional symptoms, 48.8%. Molecular analysis was performed on 215 pts (81%) and was positive in 90% (JAK2V617F), 7% (CALR), 1% (MPLW515K/L); 2% (triple negative). Karyotype was abnormal in 43 (30%) out of 145 evaluable pts (unfavorable: 9%). Median follow-up from MF diagnosis was 4 yr (0.5-29.6) and median RUX exposure was 22 mos (3-54). Overall, 92 out of 232 (39.7%) pts with spleen ≥5cm achieved a spleen response at any time during RUX therapy. At 3 and 6 mos, the response was achieved by 28.1% and 31% of evaluable pts, respectively. In univariate analysis, pre-treatment factors negatively corre- lating with spleen response were: transfusion dependence, platelet count ≤200x109/l, spleen palpable ≥10 cm below costal margin, grade 3 marrow fibro- sis and interval between MF diagnosis and RUX start ≥2y. Also, the rate of spleen response significantly correlated with RUX starting dose, with 18.5%, 33.8% and 47.7% of responses observed in pts treated with 5mg BID, 15mg BID and 20mg BID, respectively (p=0.008). Also, spleen response correlated with the average RUX dose in the first 12 wks, with pts treated with doses ≥10 mg BID having better response rates (44.4% vs 25.4% in pts treated with ≤10 mg BID, p=0.01). Three variables remained significant in multivariate regression logistic analysis: large splenomegaly (HR:2.01, 95%CI:1.1-3.1;p=0.015), time between MF diagnosis ≥2y (HR:1.8, 95%CI:1.0-3.2;p=0.037) and median RUX dose ≤10mg BID in the first 12 wks (HR:2.29, 95%CI:1.1-4.3;p=0.02).Overall, 178 pts out of 217 symptomatic patients (82%) had a symptom response. Fac- tors associated with worse responses were: grade 3 marrow fibrosis (p=0.035), transfusion dependency (p=0.001) and RUX titrated dose ≤10 mg BID (p=0.014). In multivariate analysis, symptom response rate correlated only with RUX titrated dose (HR:2.4, 95%CI:1.1-4.9,p=0.016). Neither spleen or symp- toms response significantly correlated with survival. Summary/Conclusions: In the real-life setting, IWG-MRT-defined spleen and symptoms response rates were observed in 40% and 70% of pts, respectively. Among pre-treatment features, large splenomegaly and a delay in treatment start ≥2 yrs from diagnosis identified pts with lower spleen response rates. Additionally, median titrated doses ≤10mg BID significantly correlated with poorer spleen and symptoms responses. Overall, these data point out the role of an early treatment in order to achieve better therapeutic results. Also, since drug-induced anemia was not significantly associated with RUX doses, the study supports the impor- tance to start and maintain over time the maximum tolerated RUX dose.

Predictors for response to ruxolitinib in real-life: an observational independent study on 266 patients with myelofibrosis

BONIFACIO, Massimiliano;SCAFFIDI, Luigi;
2016-01-01

Abstract

Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor com- mercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Due to the lack of predictors of response, pts’ selection is based on clinical needs. dose ≤10mg BID in the first 12 wks (HR:2.29, 95%CI:1.1-4.3;p=0.02).Overall, 178 pts out of 217 symptomatic patients (82%) had a symptom response. Fac- tors associated with worse responses were: grade 3 marrow fibrosis (p=0.035), transfusion dependency (p=0.001) and RUX titrated dose ≤10 mg BID (p=0.014). In multivariate analysis, symptom response rate correlated only with RUX titrated dose (HR:2.4, 95%CI:1.1-4.9,p=0.016). Neither spleen or symp- toms response significantly correlated with survival. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of “real-life” MF pts. Methods: A multicenter observational study on WHO-defined MF was con- ducted in 11 Italian Hematology Centers. Data were extracted from an electronic database that included retrospective data on pts treated before January 2015. Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and June 2015, 266 pts with PMF (140 pts,52.6%), or PET-MF (51,19.2%) or PPV-MF (75,28.2%) were treated with RUX in participating Centers. At diagnosis, baseline characteristics were (medi- an): age, 64.2 y (range, 26-86); ≥65 y, 45.5%; male, 58%; hemoglobin (Hb), 11.5 g/dL (5-17.7); Hb <10 g/dL, 27.4%; PLT, 356×109/L (30-1110); PLT <100×109/L, 5.2%; spleen enlargement, 87.5% (spleen length ≥10cm: 40.6%); constitutional symptoms, 48.8%. Molecular analysis was performed on 215 pts (81%) and was positive in 90% (JAK2V617F), 7% (CALR), 1% (MPLW515K/L); 2% (triple negative). Karyotype was abnormal in 43 (30%) out of 145 evaluable pts (unfavorable: 9%). Median follow-up from MF diagnosis was 4 yr (0.5-29.6) and median RUX exposure was 22 mos (3-54). Overall, 92 out of 232 (39.7%) pts with spleen ≥5cm achieved a spleen response at any time during RUX therapy. At 3 and 6 mos, the response was achieved by 28.1% and 31% of evaluable pts, respectively. In univariate analysis, pre-treatment factors negatively corre- lating with spleen response were: transfusion dependence, platelet count ≤200x109/l, spleen palpable ≥10 cm below costal margin, grade 3 marrow fibro- sis and interval between MF diagnosis and RUX start ≥2y. Also, the rate of spleen response significantly correlated with RUX starting dose, with 18.5%, 33.8% and 47.7% of responses observed in pts treated with 5mg BID, 15mg BID and 20mg BID, respectively (p=0.008). Also, spleen response correlated with the average RUX dose in the first 12 wks, with pts treated with doses ≥10 mg BID having better response rates (44.4% vs 25.4% in pts treated with ≤10 mg BID, p=0.01). Three variables remained significant in multivariate regression logistic analysis: large splenomegaly (HR:2.01, 95%CI:1.1-3.1;p=0.015), time between MF diagnosis ≥2y (HR:1.8, 95%CI:1.0-3.2;p=0.037) and median RUX dose ≤10mg BID in the first 12 wks (HR:2.29, 95%CI:1.1-4.3;p=0.02).Overall, 178 pts out of 217 symptomatic patients (82%) had a symptom response. Fac- tors associated with worse responses were: grade 3 marrow fibrosis (p=0.035), transfusion dependency (p=0.001) and RUX titrated dose ≤10 mg BID (p=0.014). In multivariate analysis, symptom response rate correlated only with RUX titrated dose (HR:2.4, 95%CI:1.1-4.9,p=0.016). Neither spleen or symp- toms response significantly correlated with survival. Summary/Conclusions: In the real-life setting, IWG-MRT-defined spleen and symptoms response rates were observed in 40% and 70% of pts, respectively. Among pre-treatment features, large splenomegaly and a delay in treatment start ≥2 yrs from diagnosis identified pts with lower spleen response rates. Additionally, median titrated doses ≤10mg BID significantly correlated with poorer spleen and symptoms responses. Overall, these data point out the role of an early treatment in order to achieve better therapeutic results. Also, since drug-induced anemia was not significantly associated with RUX doses, the study supports the impor- tance to start and maintain over time the maximum tolerated RUX dose.
ruxolitinib, myelofibrosis, predictors of outcome
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/955235
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