scholarly journals Thromboembolic Risk Reduction and High Rate of Complete Molecular Response with Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: Results from a Randomized Controlled Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 553-553 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Term Treatment ◽  
Control Group ◽  
Molecular Response ◽  
Allele Burden ◽  
Long Term Treatment ◽  
Jak2v617f Allele Burden ◽  
Complete Molecular Response

Introduction: The key treatment goals for polycythemia vera (PV) are to prevent thromboembolic events and minimize the risk of progression, ultimately modifying the natural history of the disease by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV study, long-term treatment with ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as hematological and molecular parameters over a four-year period. Methods: Cytoreduction-naïve or HU-pre-treated patients aged ≥18 years diagnosed with PV according to WHO 2008 criteria were eligible. A total of 257 patients were randomly allocated to ropeg or hydroxyurea at individualized doses for 12 months in the initial study phase (PROUD-PV). In the ongoing extension phase (CONTINUATION-PV), patients in the hydroxyurea arm were permitted to switch to best available treatment. Efficacy assessments included a longitudinal analysis of complete hematological response (CHR) and complete molecular response (CMR; JAK2V617F was determined using real-time PCR [ipsogen® JAK2 MutaQuant® kit; QIAGEN GmbH]), defined by modified ELN criteria. Discontinued patients were considered non-responders. A data snapshot was performed once all patients reached 48 months of treatment; all available safety data were included. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension phase. At the time of analysis 139 patients remained on study: 74/95 in the ropeg arm and 65/76 in the control arm. Almost all patients in the control arm (>97% at the last available assessment) continued on HU. The rate of patients in CHR was significantly higher in the ropeg arm than in the control arm in the 4th year (60.6% versus 43.4%; p=0.02), as seen after 2 and 3 years of treatment. In line with this effective control of hematologic parameters by ropeg, a very low rate of major thromboembolic adverse events was observed in the ropeg arm: 0.0%, 0.0% and 1.1% of patients in the 2nd, 3rd and 4th years, respectively. In the control arm, rates of major thromboembolic adverse events in the 2nd, 3rd and 4th year were 0.9%, 1.4% and 0.0%, respectively. The median JAK2V617F allele burden declined from 37.3% at baseline to 9.8% over 4 years in the ropeg arm, whereas in the control group, the median allele burden increased from 38.1% to 43.1% in the same period (p<0.0001). The rate of molecular response (partial or complete) at 48 months was significantly higher among ropeg-treated patients than in the control arm (67.0% versus 25.7%; RR: 2.5 [95% CI: 1.7 to 3.7; p<0.0001]). No patients achieved CMR in the control arm. In the ropeg arm, 13 patients had a JAK2V617F allele burden below the threshold of 1% at month 48, 11 of whom also had a CHR at this time point. An additional 34 patients in the ropeg arm achieved an allele burden <10% at 48 months, suggesting that further patients may reach the <1% threshold with ongoing treatment. In terms of safety, no new signals were detected in the 4th year. Rates of patients with treatment-related adverse events remained similar in the ropeg and control arms in the 4th year (ropeg: 28.7% of patients; control: 22.9%). Disease or treatment-related secondary malignancies reported in the entire study period comprised 2 cases of acute leukemia, 2 cases of basal cell carcinoma and 1 case of malignant melanoma, all in the control group; 1 case of disease-related transformation to myelofibrosis occurred in each treatment arm. Conclusions: Ropeg minimizes the occurrence of thromboembolic events in patients with PV over long-term treatment, without leukemogenic risk. In addition, we show for the first time in a randomized study that, in contrast to hydroxyurea, long-term ropeg treatment is capable of inducing deep molecular responses including CMR, which underscores its disease modifying potential. These results also suggest that selected patients could achieve operational cure (with both CHR and CMR) with ropeg, opening the way for treatment discontinuation. Disclosures Kiladjian: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Klade:AOP Orphan Pharmaceuticals AG: Employment. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Kralovics:Pharma Essentia: Honoraria; MyeloPro Diagnostics and Research: Equity Ownership; AOP Orphan Pharmaceuticals AG: Honoraria, Other: Advisory board; Qiagen: Honoraria; Novartis: Honoraria. Gisslinger:Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Roche Austria GmbH: Consultancy; Janssen-Cilag: Honoraria; Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding; Myelopro GmbH: Consultancy.

scholarly journals Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: 5-Year Results from a Randomized Controlled Study and Its Extension

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Extension Study ◽  
Molecular Response ◽  
Thromboembolic Events ◽  
Advisory Committees ◽  
Allele Burden ◽  
Long Term Treatment

Introduction: Patients with polycythemia vera (PV) require life-long treatment to prevent thromboembolic events and minimize the risk of progression. Ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) may ultimately modify the natural history of PV by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV studies, long-term treatment with ropeg was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as evolution of hematologic and molecular parameters over five years. Methods: Patients aged ≥18 years and diagnosed with PV according to WHO 2008 criteria who were either cytoreduction-naïve or hydroxyurea (HU)-pre-treated for < 3 years were enrolled. A total of 257 patients were randomized 1:1 (stratified by age > 60 years, prior thromboembolic events, and HU pre-treatment) to receive ropeg or HU at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the HU arm were permitted to switch to best available treatment. Efficacy assessments included hematologic parameters, phlebotomy need, JAK2V617F allele burden, and molecular response defined by modified ELN criteria. An interim analysis was conducted once all patients reached 5 years of treatment; efficacy data for patients enrolled in the extension study and all available safety data were analyzed. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension study. Most patients in the control arm continued to receive HU (88% at month 60). At the time of this 5-year analysis, 70 patients in the ropeg arm and 57 in the control arm remained on study; discontinuation rates were balanced between the treatment arms (ropeg: 26.3%; control: 25.0%). Hematocrit <45% was maintained without the need for phlebotomy in 81.8% patients in the ropeg arm in the fifth year of treatment, which was significantly higher than the rate of 63.2% observed in the control group (p=0.01). Very few patients experienced a major thromboembolic adverse event (4.2% [1.2%-patient year] of patients in the ropeg arm and 6.6% [1.2%-patient-year] of patients in the control arm during the entire treatment period). With respect to the causative JAK2V617F mutation, the median allele burden declined from 37.3% at baseline to 7.3% over 5 years of treatment in the ropeg arm, whereas in the control arm the median allele burden increased from 38.1% to 42.6% in the same period (p<0.0001). The rate of molecular response at 5 years was also significantly higher among ropeg-treated patients than in the control arm (69.1% versus 21.6%; RR: 3.2 [95% CI: 2.1 to 4.9; p<0.0001]). The sustained molecular response observed in ropeg-treated patients was accompanied by a low risk of disease progression; only 1 case of progression to myelofibrosis (0.20%-patient year) was reported during the entire study period and no leukemic transformation occurred. In contrast, 2 cases of progression to myelofibrosis and 2 cases of transformation to acute leukemia (1.0%-patient year in total) were reported in the control arm. A further analysis of combined hematologic and molecular parameters was performed, these being known to influence the risk of thrombosis and of progression in PV. At the 5 year visit, 58.5% of patients receiving ropeg had well-controlled hematocrit (<45%) without requiring phlebotomy, as well as achieving a molecular response, compared to 17.3% on standard treatment (RR: 3.52 [2.13 to 5.81]; p<0.0001). Regarding safety and tolerability, no new signals were detected in the fifth year. Treatment related adverse events were reported in 25.6% and 24.2% of patients in the ropeg and control arms, respectively, and one patient in each arm withdrew due to drug-related toxicity. Three patients (3.8%) in the ropeg arm reported grade ≥3 treatment-related adverse events in the fifth year; over the entire treatment period, the rate of grade ≥3 drug-related adverse events was the same in each study arm (16.5%). Conclusions: In a randomized controlled setting, ropeg treatment effectively controlled hematocrit and minimized the occurrence of thromboembolic events in patients with PV. Disease progression was very rare during long-term treatment with ropeg and this possible change in the disease natural history appears to be related to deep and durable molecular responses selectively achieved with ropeg. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; PharmaEssentia: Honoraria; MyeloPro Diagnostics and Research: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Celgene: Honoraria. Klade:AOP Orphan Pharmaceuticals AG: Current Employment. Illés:Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Mayer:Celgene: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Current Employment. Empson:AOP Orphan Pharmaceuticals AG: Current Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals AG: Honoraria. Kralovics:AOP Orphan Pharmaceuticals AG: Honoraria; Qiagen: Honoraria; Novartis: Honoraria; MyeloPro Diagnostics and Research: Current equity holder in private company; PharmaEssentia: Honoraria. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Long Term Efficacy and Safety Results and Analysis of Dose Correlations from the Phase I/II Peginvera Study of Ropeginterferon Alfa-2b, a Novel IFNa-2b, in Polycythemia Vera Patient

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4056-4056
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Schlögl ◽  
Gunther Gastl ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Group ◽  
Low Dose ◽  
Term Treatment ◽  
High Dose ◽  
Individual Response ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Long Term Treatment

Abstract Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naïve and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct)<45%, platelet count≤400*109/L, WBC count≤10*109/L, normal spleen size by sonography, and absence of thromboembolic events. Partial response (PR) is defined as Hct<45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with < 50% mutant allele burden, or a reduction ≥ 25% in patients with > 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of <300 µg ("low dose", n=36), CR as best individual response was achieved in 20 (56%) patients, and PR in 14 (39%) compared to the CR and PR in the high dose (>300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of >80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

AOP2014, a Novel Peg-Proline-Interferon Alpha-2b with Improved Pharmacokinetic Properties, Is Safe and Well Tolerated and Shows Promising Efficacy in Patients with Polycythemia Vera (PV)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 175-175 ◽  
Author(s):  
Heinz Gisslinger ◽  
Robert Kralovics ◽  
Bettina Gisslinger ◽  
Daniel Lechner ◽  
Veronika Buxhofer-Ausch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Iii ◽  
Molecular Response ◽  
Overall Response ◽  
Long Term Treatment

Abstract Abstract 175 AOP2014 is a next generation long-acting pegylated IFNa-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. AOP2014 has a distinct pharmacokinetic and pharmacodynamic profile which may potentially allow reduced dosing frequencies compared to other pegylated IFNs. This is being expected to result in improved tolerability, better compliance, and, finally, favorable long-term treatment outcomes. AOP2014 is a designated Orphan Drug in EU for treatment of patients with PV. The maximum tolerated dose (MTD), long term safety and efficacy of AOP2014, administered subcutaneously every 14 days, are the main objectives of the study. Patients with confirmed PV diagnosis, age equal or older 18 years, both naïve and cytoreduction pre-treated are eligible. After establishing the MTD, an extended cohort of 25 additional patients was planned to be recruited. European LeukemiaNet criteria were used for response assessment. 34 patients, treated by March 31, 2012 were included into this analysis: 25 in Phase I (dose-finding) and 9 in the Phase II (cohort extension). Median time from diagnosis was 24 months (range 0–180). 12 patients (35%) were HU pre-treated (mean past duration of HU pre-treatment 39 months, mean daily HU dose 950 mg). Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 21 patients (62%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (32%) had a history of thrombotic complications. Median Hct at baseline was 42% (range 36–51). Median WBC and platelet counts were 10.6*109/l (range 3.9–20.4) and 452*109/l (range 141–1019), respectively. 17 patients (50%) had splenomegaly at baseline. The median reported treatment duration was 41 weeks (range: 1 day – 80 weeks), 11 patients completed 1 year on treatment. Doses from 50 to 540 ug every two weeks were tested, 540 ug has been concluded as MTD as the highest tested dose, since no DLTs occurred in the study. The mean administered dose (both Phase I and II patients) was 287 ug. After 28 weeks of treatment (21 evaluable patients), 71% of patients had hematological response (7 CR, 33%; 8 PR, 38%), at week 36 (19 evaluable patients) 8 patients (42%) achieved a CR and 8 patients (42%) a PR, overall response rate (ORR, CR+PR) was 84%. At week 52 (1 year; 11 evaluable patients), 5 patients (46%) had CR and 5 (46%) PR, ORR was 91%; 8 (73%) patients presented with completely normalized blood values, all evaluable patients were phlebotomy free at this timepoint. 4 patients (of 12 evaluable for this measurement, 33%) had still enlarged spleen at week 52. At week 76, 2 evaluable patients were complete responders. At week 52, 1 patient (of 9 evaluable, 11%) developed partial molecular response, at week 68 3 patients (of 7 evaluable, 43%) had partial molecular response. One patient with allelic burden of 22% at baseline developed complete molecular response at week 36 (still ongoing). Mainly grade 1 and 2 adverse events were reported. A total of 358 adverse events occurred. 27 patients (79%) suffered from drug-related adverse events. 9 patients (26%) developed serious adverse events; 4 SAEs were considered to be treatment related. 5 patients (15%) discontinued their study participation prematurely, 3 of them due to adverse events (deterioration of underlying disease and two cases of depression). Acceptable tolerability and durable clinical benefits have been demonstrated in PV patients measured as overall response rate of above 90% with CRs of 46% at one year after treatment start. Phlebotomy independence and normalization of hematological parameters could be seen in most of the patients. The study continues to recruit and collect long term follow up information. Presented data support further development of AOP2014 in PV, a Phase III study is planned to start early 2013. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Lechner:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

scholarly journals Reducing the Toxicity of Long-Term Glucocorticoid Treatment in Large Vessel Vasculitis

2020 ◽  
Vol 22 (12) ◽  
Author(s):  
Andriko Palmowski ◽  
Frank Buttgereit
Keyword(s):  
Adverse Events ◽  
Takayasu Arteritis ◽  
Term Treatment ◽  
Large Vessel Vasculitis ◽  
Large Vessel ◽  
Serious Adverse Events ◽  
Glucocorticoid Treatment ◽  
Long Term Treatment ◽  
Higher Doses

Abstract Purpose While glucocorticoids (GCs) are effective in large vessel vasculitis (LVV), they may cause serious adverse events (AEs), especially if taken for longer durations and at higher doses. Unfortunately, patients suffering from LVV often need long-term treatment with GCs; therefore, toxicity needs to be expected and countered. Recent Findings GCs remain the mainstay of therapy for both giant cell arteritis and Takayasu arteritis. In order to minimize their toxicity, the following strategies should be considered: GC tapering, administration of conventional synthetic (e.g., methotrexate) or biologic (e.g., tocilizumab) GC-sparing agents, as well as monitoring, prophylaxis, and treatment of GC-related AEs. Several drugs are currently under investigation to expand the armamentarium for the treatment of LVV. Summary GC treatment in LVV is effective but associated with toxicity. Strategies to minimize this toxicity should be applied when treating patients suffering from LVV.

scholarly journals Administration of ziprasidone for 10 days increases cocaine toxicity in mice

2008 ◽  
Vol 27 (6) ◽  
pp. 499-503 ◽  
Author(s):  
K Heard ◽  
S Krier ◽  
NR Zahniser
Keyword(s):  
Atypical Antipsychotic ◽  
Term Treatment ◽  
Toxic Effects ◽  
Neurotransmitter Receptors ◽  
Control Group ◽  
Long Term Treatment ◽  
Significant Difference ◽  
Group Survival ◽  
Cocaine Toxicity

Long-term treatment with antipsychotic medications alters the regional density of several of the neurotransmitter receptors that mediate cocaine toxicity. However, the effect of either up- or down-regulation of the neurotransmitter receptors on cocaine toxicity is unknown. In this study, we determined if subacute administration of the atypical antipsychotic ziprasidone altered the toxic effects of cocaine in mice. Ziprasidone (4 mg/kg) or placebo was administered to the first two groups of CF-1 mice for 10 days and, then on day 10, an estimated LD50 dose of cocaine (102 mg/kg) was given to these mice. In a third group, in order to produce a ziprasidone withdrawal state, we administered ziprasidone for 10 days, followed by no treatment for 2 days before cocaine administration. There was no significant difference among the three groups in overall survival: 63% in the treatment group, 60% in the withdrawal group, and 80% in the placebo group. Survival time was significantly shorter for the withdrawal group than for the control group. Our study may have been limited by lower than expected serum ziprasidone concentrations and lower than expected lethality from cocaine. However, our findings suggest that administration of an atypical antipsychotic for 10 days may increase the toxic effects of cocaine.

SAR302503: Interim Safety, Efficacy and Long-Term Impact on JAK2 V617F Allele Burden in a Phase I/II Study in Patients with Myelofibrosis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3838-3838 ◽  
Author(s):  
Animesh Pardanani ◽  
Jason Gotlib ◽  
Catriona Jamieson ◽  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Platelet Count ◽  
Research Funding ◽  
Jak2 V617f ◽  
Intermediate Risk ◽  
Spleen Size ◽  
Safety And Efficacy ◽  
Allele Burden ◽  
Jak2v617f Allele Burden

Abstract Abstract 3838 Background: SAR302503 (SAR503, formerly TG101348), a potent, oral JAK2-selective inhibitor was studied in a Phase I/II trial for the treatment of patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF). SAR503 was administered orally once daily in 28-day cycles. Eligibility criteria included platelet count of ≥50 × 109/L. Interim safety and efficacy data from this study up to April 2010 have been previously published (JCO 2011, 29(7):789–796). The aim of this presentation is to report updated safety and efficacy of ongoing patients as well as an analysis of the JAK2V617F allele burden in this cohort. Results: Overall, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF and 3 post-ET MF; 86% were JAK2 V617F-positive. Median palpable spleen size was 18 cm at study enrollment. Twenty eight patients were treated in the dose-escalation cohort (30–800 mg administered as a single daily dose); thirty one patients were treated at the MTD (680 mg) in the dose confirmation cohort. 43/59 patients (73%) completed 6 cycles of treatment and continued treatment on the extension study. Currently, 22 patients (37%) remain on treatment with a median number of 28.5 cycles (24–41 range) and a median of last dose of 440 mg/day. Safety: Treatment-emergent toxicities in cycle 1–6 have been previously reported; toxicities were dose-dependent and generally alleviated with dose-reduction. Five patients discontinued treatment beyond cycle 6 for treatment-related adverse events: thrombocytopenia, depression, mental status changes, creatinine elevation and subdural hematoma. For the subgroup of patients with a baseline platelet count between 50–100 × 109/L (n =13; median 73, range 51–94); the platelet count at defined times points during follow up was: cycle 3; median 50, range 21–138 (p=0.09) and cycle 6; median 47, range 13–85 (p=0.01). Despite 7 of the 13 patients being treated at ≥680 mg/day, only 2 instances of Grade 4 thrombocytopenia were noted in this group Spleen response: As previously reported, spleen responses were seen early, usually within first 3 cycles, with half or more patients in each dose level ≥240 mg/day showing a durable ≥50% decrease in palpable spleen size. Spleen size (mean, median, range, and proportion with ≥50% reduction) at the following time points was: Baseline (n=58; 18.33cm, 18cm, 4–38cm, NA) ; 6 months (n=57; 9.05cm, 9cm, 0–30cm, 54.4%;) 12 months (n=42; 8.55cm, 9cm, 0–28cm, 66.7%) 18 months (n=36; 8.03cm, 8.5cm, 0–33cm, 52.8%); 24 months (n=31; 8.10cm, 8cm, 0–30cm, 54.8%,) 30 months (n=18; 6cm, 7.5cm, 0–16cm, 61.1%,and) 36 months (n=9; 5.89cm, 3cm, 0–16cm, 66.7%). JAK2V617F allele burden: We previously reported a significant decrease in JAK2V617F allele burden at the end of cycles 6 and 12. A durable decrease was also demonstrable after 24 cycles of treatment (n =21; median 9%, range 0–100%) relative to baseline (n =51; median 20%, range 3–100%) (p=0.03). Similarly, for patients with JAK2 V617F allele burden >20% at baseline; there was a significant decrease after cycle 24 (n =12; median 21%, range 6–100%) relative to baseline (n =23; median 60%, range 23–100%) (p=0.03). Conclusions: SAR503 is safe and efficacious treatment with long term effect on spleen size and JAK2V617F allele burden in patients with high- and intermediate-risk myelofibrosis. Additional follow up information will be updated at the time of meeting. Disclosures: Jamieson: Wintherix: Equity Ownership; Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria. Gao:Sanofi-Aventis: Employment. Zhang:Sanofi-Aventis: Employment. Neumann:Sanofi-Aventis: Employment.

Treatment Results and Malignant Complications in Patients on Long-Term Treatment with Tyrosine Kinase Inhibitors(TKIs) for Chronic Myeloid Leukemia(CML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3767-3767
Author(s):  
Taiichi Kyo ◽  
Kouhei Kyo ◽  
Takesi Okatani ◽  
Mitsuhiro Itagaki ◽  
Ryouta Imanaka ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Malignant Neoplasm ◽  
Incidence Rates ◽  
Term Treatment ◽  
Molecular Response ◽  
Malignant Diseases ◽  
Expected Number ◽  
Long Term Treatment

Abstract Abstract 3767 Background With the introduction of imatinib (IM) and subsequent TKIs such as nilotinib (NI) and dasatinib (DA), deaths due to progression of chronic myeloid leukemia (CML) have decreased dramatically. In such circumstances, the new occurrence of other malignant diseases in patients with CML on treatment with TKIs always causes distress. With the increase in long term surviving patients with CML, there is concern over whether these malignancies are related to treatment with TKIs or not. We investigated the improved prognosis in patients with CML on long-term treatment with TKIs and the occurrence of complicating malignancies. Methods We evaluated 173 patients (101 males, 72 females) in the chronic phase of CML, all of whom had CML diagnosed at our hospital between January 1990 and June 2011 and received treatment with TKIs for at least 1 year. The median age at the start of treatment with TKIs was 57 (19 – 92) years. Patients aged 60 years and older accounted for 72 (42%). The median follow-up period after the start of treatment with TKIs was 68 (12 – 128) months. Before the onset of CML, 11 patients had prior malignancies. Treatments for CML administered before use of TKIs were hydroxyurea (HU) alone 3, HU + interferon-α (IFN-α) 47, IFN-α alone 7, chemotherapy for AML + IFN-α 2 and chemotherapy for ML + IFN-α 1. TKIs were used as frontline therapy in 113.TKI treatment of all patients initially consisted of IM at the dose of 100 mg per 12 kg body weight. We switched the drug to NI when complete molecular response (CMR) was not achieved after long-term treatment with IM. In addition, a switch to DA was used to consolidate CMR. Treatments that contained TKIs consisted of IM alone in 42, IM → NI in 46, and IM →NI → DA in 85. Two patients with a complete cytogenetic response (CCR) underwent bone marrow transplantation. Results Among 173 patients, the best response to treatment in patients treated with TKIs was CMR in 72, a major molecular response (MMR) in 84, CCR in 15, and refractory CML in 2. Currently, 22 have maintained CMR for 6 to 111 months after discontinuation of TKIs, and 19 (11%; 17 males, 2 females) have developed new onset of a malignancy. In these 19, the median age at the onset of cancer was 70 (31 – 85) years. Patients aged 60 years and older accounted for 15 (79%). The median period from the start of TKIs to the onset of cancer was 38 (10 – 117) months. Affected organs were bladder 5; stomach 3; rectum 3; large intestine 2; lung 2; and esophagus, appendix, prostate, and pancreas each in 1. The TKIs given to the patients with malignant diseases were IM alone in 13, IM → NI in 4, and IM → NI → DA in 2. Prior treatments included HU + IFN-α in 8 and IFN-α alone in 1. The observed number of patients who were diagnosed as malignant neoplasm was compared with the expected number. The expected number was obtained through integration of age specific incidence rate of malignant neoplasm from the start age taking medicine to the age at which the diagnosis as malignancy was made or the follow up was finished for censoring. The age specific incidence rates were estimated by interpolating five year old specific incidence rates from of the 2007's survey that was conducted by Center for Cancer Control and Information Services, National Cancer Center, Japan. The observed number/expected number (O/E) ratio for the occurrence of all malignant diseases was 1.00 (19/18.97), and the O/E for gastrointestinal cancer was 1.118 (11/9.84). Therefore, no increase in the incidence of malignant diseases was observed in patients treated with TKIs. However, the O/E for bladder cancer was 4.525 (5/1.11) with a 95% confidence interval of 1.42 – 9.32 (P = 0.0002), which means that the incidence of bladder cancer in patients treated with TKIs was higher than that in the general Japanese population. So far 19 patients have died and the median age at death was 79 (59 – 94) years. In these patients, 8 deaths were related to cancer and the others were caused by diseases associated with old age that were unrelated to the worsening of CML. Conclusion The introduction of TKIs has undoubtedly improved the prognosis of patients with CML. Based on the results of this investigation, the apparent increase in malignant diseases observed during the long-term follow-up of patients treated with TKIs was generally considered to be attributable to the aging of patients. We should however further investigate whether the higher incidence of bladder cancer seen in patients treated with TKIs is incidental or not. Disclosures: No relevant conflicts of interest to declare.

Long Term Treatment and Prevention Of Recurrent VTE In Cancer Patients: Results Of The Canadian Proact Survey

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5581-5581
Author(s):  
Normand Blais ◽  
Charles A. Butts ◽  
Mark A. Crowther ◽  
Nanette Cox-Kennett ◽  
Josée Martineau
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Term Treatment ◽  
Advisory Committees ◽  
Extended Treatment ◽  
Treatment And Prevention ◽  
Long Term Treatment ◽  
Recurrent Vte

Abstract Introduction Cancer associated thrombosis (CAT) is the second leading cause of death in cancer patients after death from cancer. Despite multiple available guidelines for CAT management, there remains variability in treatment practices. In order to gain insight on this variability in Canada, a survey was conducted to identify the perceived importance of managing CAT, identify differences in the pharmacological management of CAT, highlight the main barriers to optimal extended treatment and prevention of recurrent venous thromboembolism (VTE), outline challenges associated with long term treatment adherence, and identify predictors of patient non-adherence. Methods A survey was designed targeting physicians involved in the management of CAT. The questionnaire included queries on physician practice, 37 items related to beliefs and attitudes about extended treatment for prevention of recurrence of VTE, and a 30-item patient-specific profile. Results Responses were obtained from 21 professionals from four Canadian provinces (Nova Scotia, Quebec, Ontario, and Alberta); 76% were hematologists and/or oncologists, 14% were internists and 10% were pharmacists. Community and academic centers were well represented. Specific management profiles were obtained for 131 patients. Most care givers felt that VTE recurrence was an important issue deserving extended therapy for most patients. Although more than 90% believed bleeding and recurrent VTE risk should influence the length of treatment, only 62% believe that VTE recurrence risk should modify the type of treatment and 52% were concerned of the risk of bleeding with long term therapy (≥6 months). 71% of respondents believed patients’ lack of awareness of the risk of recurrent VTE reduces adherence to anticoagulant therapy for extended treatment of VTE. Although 100% of respondents detailed giving verbal patient counseling, only 19% provided written information to patients. 95% stated they assessed compliance verbally; less than 20% used more objective measures (pharmacy records, laboratory monitoring). Participants admitted to using results of clinical trials (95%) more than clinical guidelines (48%) as most felt that the published guidelines contained conflicting recommendations. The main drivers of treatment choice were clinical evidence, efficacy, and personal experience. No respondents indicated they preferred to use oral anticoagulants for extended therapy of CAT and 43% believed that LMWHs should not be used interchangeably. Most (95%) stated they follow-up with patients directly to reassess therapy after 3-6 months of treatment. The patient profile information showed the median age of patients was 62 years and 60% were female. Lung cancer, colon cancer, breast cancer, and lymphoma were the most common tumor sites and accounted for 50% of described cases. Cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) were evenly represented and 82% were symptomatic. Most events were temporally related to cancer therapy (69%), presence of a central venous catheter (18%), and recent surgery (17%). Less than 5% of these cases presented with a contraindication to anticoagulation therapy (severe thrombocytopenia, active bleeding) at CAT diagnosis. Most patients were treated in the outpatient setting. Nonetheless, hospitalization was required in 33% of cases with an average patient stay of 10.8 days. Hospitalized patients were preferentially treated with LMWH (84%) and usually stayed on the same regimen upon discharge (8.3 ± 6.4 months). Long term treatment was largely managed with LMWHs (most frequently dalteparin – 80% of all treated patients) while few were managed with vitamin K antagonists (6%) or novel direct antithrombotics (2%). Anticoagulant therapy for outpatients was prescribed for 9.0 ± 7.7 months after the most recent VTE episode. Conclusion In Canada, CAT is believed to be an important complication of cancer. Extended therapy is indicated for most patients with CAT.  Although bleeding risk is perceived as an important reason to modify therapy, contraindications to LMWHs were rare in the reported cases. Uptake of outpatient therapy of CAT is widespread in this country, yet hospitalization is still frequently required at diagnosis and is associated with prolonged inpatient stays. Even if non-adherence to antithrombotic therapy was believed to be rare among patients with CAT, this was rarely rigorously monitored. Disclosures: Blais: Pfizer: Consultancy; Sanofi: Consultancy; Leo: Consultancy. Butts:Pfizer: Consultancy, Honoraria, Speakers Bureau. Crowther:Pfizer: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees. Cox-Kennett:Pfizer: honorarium as a speaker Other. Martineau:Pfizer: honorarium as a speaker Other; Boehringer: honorarium as a speaker, honorarium as a speaker Other; Bayer: honorarium as a speaker, honorarium as a speaker Other; Sanofi: honorarium as a speaker and participated in clinical trial, honorarium as a speaker and participated in clinical trial Other; BMS: honorarium as a speaker Other.

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