Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of ...first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up.
Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 3 not treated). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted.
Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P <0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P <0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure).
Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively.
Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML.
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Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre:BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Hochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes:Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) approved for pts with CP-CML or Ph+ ALL for whom no other TKI therapy is indicated, or for pts with the BCR-ABL1 T315I mutation. ...The pivotal phase 2 ponatinib PACE trial (NCT01207440) enrolled pts with CML or Ph+ ALL resistant/intolerant to dasatinib or nilotinib, or with T315I. An accumulation of AOEs was observed with continued follow-up of patients in PACE, and in Oct '13, dose reductions were instructed to mitigate the risk of AOEs.
Aims:
Long-term follow-up (median of approximately 5 years) of the incidence and clinical characteristics of AOEs observed in CP-CML pts treated with ponatinib in PACE.
Methods:
The starting dose of ponatinib in PACE was 45 mg/day; protocol-defined dose modifications were in place for management of AEs. The primary endpoint in CP-CML was MCyR by 12 mos. Safety monitoring included collection of treatment-emergent AOEs (categorized based on a collection of >300 MedDRA preferred terms related to vascular ischemia or thrombosis), including: incidence, time to onset, dose at onset, and dose modifications due to AOEs. Exposure-adjusted incidence of new AOEs was calculated as the number of pts with events/100 pt-yrs. Final data as of 6 Feb '17 are reported, with a median follow-up of 56.8 mos in CP-CML pts.
Results:
Of 270 CP-CML pts enrolled and treated in PACE, median age at baseline was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 60% received ≥3 prior TKIs. In efficacy evaluable pts (n=267), cumulative response rates as of data cutoff were: MCyR, 60%; CCyR, 54%; MMR, 40%; and MR4.5, 24%; the 5-yr OS probability was 77%. The cumulative incidence of any AOE/serious AOE in CP-CML pts, regardless of investigator attribution of causality, was 31%/26% (by subtype, 16%/12%, 13%/10%, and 14/11% for CV, cerebrovascular, and peripheral vascular AOEs, respectively). Most common AOEs/serious AOEs are reported in Table 1. The median time to onset for first CV, cerebrovascular, and peripheral vascular AOEs was 14.2 (range: 0.5-59.7), 22.8 (0.4-53.5) and 20.5 (0.3-58.5) mos, respectively. Among pts who experienced ≥1 AOE, ponatinib dose at initial onset of any AOE/serious AOE was most commonly at 45 mg/day (36%/36%, Table 2; by subtype, 38%/39% for CV AOEs, 29%/36% for cerebrovascular AOEs, and 24%/19% for peripheral vascular AOEs). When considering baseline risk factors for the development of serious AOEs, pts with >2 risk factors, including history of ischemic disease, had a higher relative risk of serious AOEs (2.9 95% CI 1.8-4.9), as compared to pts with 1 or no risk factors. Among pts who experienced ≥1 AOE, most (61%) were managed with dose modification, including reduction and/or interruption or withdrawal; 39% had no dose modification following the AOE (Table 2). Of 86 pts without a history of AOEs who had a dose reduction in response to the Oct '13 instructions, 12 (14%) had a first AOE after Oct '13 (among pts who dose reduced from 45 mg, 5 11% experienced a first AOE), compared to 8/59 (14%) of those who did not have a dose reduction in response to the Oct '13 instructions (1 14% pt receiving 45 mg). While the cumulative incidence of AOEs has increased over time in PACE, exposure-adjusted incidence of new AOEs has shown some decline over time (yr 1, 15.8; yr 2, 15.6; yr 3, 13.4; yr 4, 9.8; yr 5, 4.9). The ponatinib median dose intensities in these pts by yr were 32.1 mg/d, 31.4 mg/d, 24.8 mg/d, 19.0 mg/d, 20.4 mg/d, respectively. Grade 5 AOEs were reported in 3 CP-CML pts (1%): myocardial infarction, cerebrovascular accident and hemorrhagic cerebral infarction.
Summary:
Final (5-yr) results from PACE demonstrate that ponatinib continues to provide efficacy benefit to CP-CML pts. While the cumulative incidence of AOEs increased over time, the exposure-adjusted incidence of newly occurring AOEs seemed to trend down after the 3rd year; the lower exposure-adjusted AOE incidence in later years could be due to the natural etiology of AOEs, dose modifications, or change in the patient population. The most commonly reported AOE was angina pectoris and most AOEs were managed with dose modification. While the mechanistic basis for ponatinib-associated AOEs is unknown, this vascular toxicity appears to be dose-related and modified by pre-existing CV disease and other risk factors.
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Cortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Nicolini:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Hochhaus:ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BMS: Research Funding; MSD: Research Funding; Pfizer: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. Kim:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pinilla-Ibarz:ARIAD: Consultancy, Honoraria; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Apperley:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses , Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Honoraria; Incyte: Honoraria; Therakos: Honoraria; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:Pfizer Inc: Consultancy, Other: Travel, Research Funding; ARIAD: Other: Travel, Research Funding. DeAngelo:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; BMS: Consultancy; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Celgene: Research Funding; Immunogen: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Shire: Honoraria; Blueprint Medicines: Honoraria, Research Funding; Incyte: Consultancy, Honoraria. Abruzzese:Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Rea:Novartis: Consultancy, Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Consultancy, Honoraria. Mueller:ARIAD: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; IHO GmbH: Equity Ownership. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Lustgarten:ARIAD: Employment, Equity Ownership. Neumann:Takeda Pharmaceuticals Inc: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Deininger:BMS: Consultancy, Research Funding; Incyte: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; ARIAD: Consultancy; Celgene: Research Funding; Gilead: Research Funding. Hughes:Ariad: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Shah:Bristol-Myers Squibb: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding. Kantarjian:Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction. Imatinib discontinuation in Chronic Myeloid Leukemia (CML) patients (pts) with minimal residual disease is a procedure that allows a treatment free remission in approximately 50% of ...them. However long term follow-up data are generally missing Here we report an update of the Imatinib Suspension And Validation (ISAV) study at 62 months (mts) of follow-up (FUP).
Aims. The ISAV study is aimed at validating the capability of digital PCR (dPCR) to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results and to evaluate relapse rate, time of recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL).
Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 mts, with a minimum of 3 Q-RT-PCR performed at their own sites. After discontinuation of imatinib therapy, Q-RT-PCR was performed monthly (mts 1-6), bimonthly for 36 mts and then every 6 months for additional 2 years, to assess the maintenance of the molecular remission. The loss of molecular remission was defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resumed imatinib treatment at the same dosage used before interruption. Patients' QoL during imatinib discontinuation/resumption was evaluated through the EORTC QLQ-C30 questionnaire.
Results. The ISAV study enrolled 112 pts with a median FUP time of 47.6 mts 95% CI: 42.8-53.0; 36.6% of them completed the study. The 59.3% of pts were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.4 mts before imatinib discontinuation. dPCR results showed that 23.1% of pts were positive and 75.9% negative at the time of discontinuation, with a Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.1 95% CI: 0.99-1.22. At 62 mts from imatinib discontinuation, 55 pts (50.9%, 95% CI: 41.1-60.7) of the 108 eligible ones relapsed and resumed imatinib with a relapse rate of 51.9% 95%CI: 42.5-61.0; 70.9% of them relapsed in the first 9 mts. Of the 53 not-relapsed pts, 40 (37.0% of the total) regained Q-RT-PCR positivity without losing MMR. The median time to Q-RT-PCR positivity was 3.2 mts 95% CI: 2.1-4.6 in the relapsed pts and 4.8 mts 95% CI: 2.9-7.8 in pts who developed only PCR positivity. In this latter group 2 pts experienced late relapses, at 30.6 and 45.5 mts respectively. A loss of CCyR occurred in 13 pts (34.2% of those tested): 10/13 CCyR losses were recovered, the remaining 3 were not be assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.8 95% CI: 1.1-2.1 mts. One patient, who relapsed, successfully managed a second attempt at discontinuation. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse was evident. Moreover, age and dPCR results together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation and in particular nausea, diarrhea and fatigue (p<0.01). An inverse and transient trend toward increased pain emerged at mts 1 and 3.
Conclusions. At 62 mts from the beginning of the study, with a median FUP of 47.6 mts, 50.9% of pts relapsed; the majority of relapses developed in the first 9 mts after imatinib discontinuation however late relapses also occurred, up to the 4th year. Therefore pts who discontinue imatinib should be monitored for a long period of time, especially if they showed positive PCR values after imatinib discontinuation. Age <45 years and dPCR positivity are significantly associated with relapses. QoL analysis showed a significant decrease in symptoms after imatinib discontinuation. Funded by Regione Lombardia.
le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; ARIAD: Honoraria. Abruzzese:BMS: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Incyte: Consultancy. Assouline:Novartis Canada Inc.: Honoraria; Bristol Myer Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Paladin: Speakers Bureau; Janssen: Honoraria. Stagno:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Iurlo:Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: Since many patients with chronic phase chronic myeloid leukemia (CP CML) achieve long-term survival, health-related quality of life (HR-QOL) as assessed by PROs is an important ...consideration. Bosutinib is a SRC/ABL tyrosine kinase inhibitor approved for Philadelphia chromosome-positive CML treatment in adults resistant or intolerant to prior therapy. In the BFORE trial (NCT02130557) of bosutinib versus imatinib a significantly higher major molecular response rate at 12 months (the primary endpoint) occurred with bosutinib. Here we report initial PRO results from BFORE.
Methods: BFORE is an ongoing, multinational, phase 3, open-label study in patients with newly diagnosed CP CML. Patients are randomized 1:1 to bosutinib 400 mg once daily or imatinib 400 mg once daily. PROs, assessed as exploratory endpoints, included functional status using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and the European Quality of Life-5 Dimensions-Visual Analog Scale (EQ-5D-VAS) instruments. Assessments were conducted at baseline and every 3 to 6 months, to continue for up to 5 years after treatment initiation. Outcomes at month 12 are reported herein.
Results: Bosutinib and imatinib mean FACT-Leu scores were similar at baseline and at month 12 (Table). At month 12, significant improvement from baseline in FACT-Leu total score was observed for both bosutinib (mean change 3.1, P=0.0425) and imatinib (mean change 4.8, P=0.0008). For bosutinib at month 12, all FACT-Leu combined and subscale scores demonstrated either improvement (emotional well-being; leukemia symptoms; FACT-Leu total score) or maintenance (physical, functional, social well-being; FACT-General total score; trial outcome index).
Bosutinib and imatinib mean EQ-5D-VAS scores were similar at baseline and at month 12 (Table). At month 12, significant improvement in mean EQ-5D-VAS was observed for both bosutinib (mean change 4.4, P=0.0014) and imatinib (mean change 9.3; P <0.0001). Additional FACT-Leu and EQ-5D analyses yielded similar findings. For example, mean SD Functional Health Status as measured using the EQ-5D Utility Score was similar between groups at baseline (bosutinib: 0.688 0.2710 and imatinib: 0.657 0.2929) and improved from baseline for subjects in both treatment arms, with comparable scores seen at Month 12 (bosutinib: 0.722 0.2953 and imatinib: 0.724 0.2717).
Conclusion: In the BFORE trial of first-line CP CML therapy, PROs for bosutinib indicated improvement or maintenance of HRQoL at month 12, with effects comparable to those observed for imatinib, the standard of care for first-line CML treatment. These exploratory PRO results indicate fewer symptoms, better HRQoL, and improved functional health status at month 12 relative to baseline for both therapies.
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Cortes:ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:Novartis: Consultancy, Research Funding; Incyte: Consultancy; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. le Coutre:Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez:BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Hochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Background: The tyrosine kinase inhibitor (TKI) ponatinib has potent activity against native and mutant BCR-ABL1 and is approved for use in pts with relapsed/intolerant CML or Ph+ ...ALL, or with BCR-ABL1/T315I. Methods: In the pivotal PACE study (NCT01207440), ponatinib (starting dose 45 mg/d) was assessed in pts with CML or Ph+ ALL resistant/intolerant to dasatinib or nilotinib, or with T315I. In Oct ’13, dose reductions were implemented due to observed arterial occlusive events (AOEs). Efficacy and safety at 5 yrs (data as of 3 Oct ’16) for CP-CML pts are reported. Results: Of 270 CP-CML pts in the safety population, 60% received ≥3 prior TKIs. At initiation of study closure, 99 pts were ongoing; among these pts, minimum follow-up was 52 months, and most (78%) had 15 mg/d as their last dose. In all CP-CML pts (n = 267, efficacy evaluable), cumulative response rates were: MCyR, 60%; CCyR, 54%; MMR, 40%; and MR
4.5
, 24%. Among pts who achieved MCyR (n = 148) or MMR (n = 108), the Kaplan-Meier (KM) estimated probability of remaining in response at 5 yrs was 74% (95% CI, 62 – 83) and 61% (95% CI, 51 – 70), respectively. Regardless of dose reduction in Oct ’13, maintenance of response was high (Table). KM estimated 5-yr rate for PFS/OS was 49%/77%. TEAEs in ≥45% of CP-CML pts were rash 47%, abdominal pain 46%, and thrombocytopenia 46%. Most newly occurring AEs were observed within the first year. The incidence of any AOEs/serious AOEs for CP-CML pts was 29%/23%. Among CP-CML pts with no prior AOEs who had a prospective dose reduction, 17% (11/63) had a first AOE occurring after Oct ‘13. Conclusions: Long-term (5-yr) results from PACE demonstrate that ponatinib continues to show clinical benefit, irrespective of dose reductions, with deep and lasting responses in heavily pretreated CP-CML pts. Safety results were consistent with the safety profile across the ponatinib clinical program. Clinical trial information: NCT01207440. Table: see text
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Background: Many patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) achieve a sustained deep molecular response (DMR) with frontline nilotinib (NIL) therapy. ENESTfreedom ...(NCT01784068) is an ongoing phase 2 study evaluating the potential for such pts to stop treatment and remain in treatment-free remission (TFR). Initial results from ENESTfreedom showed that 51.6% of pts who attempted TFR remained off treatment without loss of major molecular response (MMR BCR-ABL1 ≤ 0.1% on the International Scale, BCR-ABL1IS) at 48 weeks. Despite the enrollment of pts with established tolerance of NIL, the frequency of adverse events (AEs) decreased during the first 48 weeks of TFR compared with the year prior to stopping treatment (65.8% vs 83.2%, respectively), while AEs related to musculoskeletal pain were more common during TFR (24.7% vs 16.3%, respectively). The quality of life (QOL) of tyrosine kinase inhibitor-treated pts has gained increasing interest in recent years. To evaluate the impact of TFR on QOL, we analyzed patient-reported outcomes prior to and during TFR.
Methods: Pts with CML-CP and ≥ 2 years of frontline NIL therapy (400 to 600 mg/day for the previous ≥ 1 year) who achieved MR4.5 (BCR-ABL1IS ≤ 0.0032%) on NIL were enrolled and entered a 1-year consolidation phase, during which they continued NIL with RQ-PCR assessments every 12 weeks. Pts with sustained DMR during the consolidation phase (no assessment worse than MR4 BCR-ABL1IS ≤ 0.01%, ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment) entered the TFR phase and stopped treatment. Pts with loss of MMR during the TFR phase reinitiated NIL treatment (reinitiation phase). At specified time points, pts completed the MD Anderson Symptom Inventory for CML (MDASI-CML, in which pts rate the levels of severity and interference with daily life for a defined set of symptoms on a scale from 0 to 10, with 0 indicating the lowest severity/interference). At each time point, pts also completed the EQ-5D-5L questionnaire, in which they report the presence/absence and severity (slight, moderate, severe, or extreme) of problems related to mobility, self-care, usual activities, anxiety/depression, and pain/discomfort and rank their overall level of health from 0 to 100 using the EQ VAS scale, with 0 indicating the poorest level of health.
Results: Among 215 pts enrolled, 190 remained in sustained DMR during the consolidation phase and entered the TFR phase. Mean MDASI-CML severity and interference scores and EQ VAS scores, respectively, among pts who completed each questionnaire were 1.4, 1.7, and 80.5 at week 48 of the consolidation phase; 1.1, 1.3, and 81.1 at week 12 of the TFR phase; and 1.2, 1.4, and 81.4 at week 48 of the TFR phase (Table). Among pts who sustained TFR and who had scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, no impact of stopping treatment on MDASI-CML or EQ VAS scores was detected. Among evaluable pts who lost MMR during the TFR phase and reinitiated NIL, mean scores at 24 weeks after treatment reinitiation were 1.3 (MDASI-CML severity), 1.5 (MDASI-CML interference), and 77.8 (EQ VAS). Among pts evaluable at both week 48 of the consolidation phase and week 24 of the reinitiation phase, mean scores were similar at both time points.
Among pts who completed the EQ-5D-5L questionnaire, the proportions reporting problems (of any severity) at week 48 of the consolidation phase, weeks 12 and 48 of the TFR phase, and week 24 of the reinitiation phase tended to be similar. The proportion of pts reporting problems with anxiety/depression was lowest during the reinitiation phase (Table).
Conclusion: Minimal changes in patient-reported outcomes were observed after stopping treatment. This may be related to pts having a relatively high QOL prior to stopping treatment, given that they had tolerated ≥ 2 years of NIL prior to enrollment. These data suggest that the higher frequency of musculoskeletal pain-related AEs in the TFR phase did not substantially impact pts’ QOL; however, only a subset of pts were evaluable for changes in reported outcomes over time. Although many pts have fears about TFR, reported levels of anxiety/depression were similar before and after stopping treatment but decreased among pts who reinitiated treatment.
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Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Casares:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Stentoft:Pfizer: Research Funding; Ariad: Research Funding; Bristol-Myers-Squibb: Research Funding; Novartis: Research Funding. Conneally:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. García-Gutiérrez:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gattermann:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accomodation expenses, Research Funding. Wiktor-Jedrzejczak:Sandoz: Consultancy; BMS: Research Funding; Novartis: Consultancy, Research Funding; Janssen-Cilag: Consultancy; Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Amgen Inc.: Research Funding. Le Coutre:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Saussele:ARIAD: Honoraria; Novartis: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria, Other: Travel grants; BMS: Honoraria, Other: Travel grants, Research Funding. Giles:Novartis: Consultancy, Research Funding. Radich:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy, Research Funding. Ross:BMS: Honoraria; Novartis Pharmaceuticals: Honoraria, Research Funding. Menssen:Novartis Pharma AG: Employment. Deng:Novartis Phamaceuticals Corp.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Bedoucha:Novartis: Employment. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has proved superior to placebo and best available therapy in the phase 3 COMFORT studies for patients (pts) with intermediate (Int)-2- or ...high-risk myelofibrosis (MF). Ruxolitinib-treated pts demonstrated improvements in splenomegaly and MF-related symptoms as well as improved overall survival. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of ruxolitinib in pts with MF and includes those with no access to ruxolitinib outside of a clinical trial. Here, we report updated safety and efficacy findings for the full enrollment of JUMP, which includes 2233 pts in 26 countries.
METHODS: Eligible pts had Int-2- or high-risk MF, with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of ruxolitinib based on platelet counts at baseline (5 mg twice daily bid; ≥ 50 to < 100 × 109/L, 15 mg bid 100 to 200 × 109/L, 20 mg bid > 200 × 109/L). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores. The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study.
RESULTS: This analysis includes 2233 pts (primary MF, 59.4% n = 1326) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2016). At baseline, median age was 67 y (range, 18-89 y); 54.5% were male; median palpable spleen length was 12 cm below the costal margin; median time since diagnosis was 25.8 months. Median hemoglobin (Hb) was 106 g/L, and 38.3% of pts had Hb levels < 100 g/L; median platelet count was 254 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.9 and 33.4, respectively. At data cutoff, 15.8% of pts (353/2233) remained on treatment and 45.1% (1006/2233) completed treatment per protocol (ie, transitioned to commercial ruxolitinib). The primary reasons for treatment discontinuation were adverse events (AEs; 17.7%), disease progression (8.6%), and death (4.1%).
Median exposure was 12.4 months; the median average daily dose of ruxolitinib was 23.1 mg for pts starting at 15 mg bid (n = 647 29.0%) and 36.5 mg for pts starting at 20 mg bid (n = 1384 61.9%). Overall 66.7% of pts had dose modifications and 26.3% had a dose interruption. Grade (G) 3/4 hematologic AEs included anemia (34.1%), thrombocytopenia (16.3%), and neutropenia (4.5%), which led to discontinuation in 1.5%, 2.7%, and 0.1% of pts, respectively. Nonhematologic AEs were primarily G1/2, and the most common (≥ 10%) were pyrexia (15.6%; G3/4, 2.3%), asthenia (14.9%; G3/4, 2.2%), and diarrhea (12.0%; G3/4, 1.1%). Rates of other G3/4 AEs were low (≤ 2%), except pneumonia (4.3%), which led to discontinuation in 10 pts (0.5%). Rates of infections were generally low; all-grade infections in ≥ 5% of pts included pneumonia (6.8%), urinary tract infection (5.6%), and nasopharyngitis (5.0%). Herpes zoster was reported in 4.6% of pts (G3/4, 0.5%), tuberculosis in 0.2% (G3/4, 0.04%) and hepatitis B in 1 pt (G3/4, 0.04%).
At wk 24 and 48, 56.6% (874/1545) and 61.6% (658/1069) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 23.3% (360/1545) and 18.9% (202/1069) had 25% to 50% reductions, respectively. Most pts (70.2% 1441/2054) experienced a ≥ 50% reduction at any time; 23.7% had complete resolution of splenomegaly (Figure). At wk 24 and 48, 97.1% (67/69) and 92.3% (48/52) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (42.4% 596/1406; 46.6% 675/1447) and wk 48 (42.9% 404/941; 45.4% 434/957). Overall, 221 patients received ESAs to manage anemia (G1, 7.2%; G2, 49.8%; G3, 38.9%; G4, 4.1%), and the majority had improved (32.6%) or resolved (31.7%) anemia (worsened, 16.3%; no change, 19.5%).
CONCLUSIONS: This study includes the largest cohort of pts with MF treated with ruxolitinib to date. Consistent with findings from other studies, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the COMFORT studies.
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Foltz:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Le Coutre:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Vannucchi:Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Bouard:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Khanna:Novartis Healthcare Pvt. Ltd: Employment. Zaritskey:Janssen: Consultancy; Novartis: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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