Long-Term Treatment and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ) In Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1953-1953 ◽  
Author(s):  
Sundar Jagannath ◽  
Ravi Vij ◽  
Jonathan L. Kaufman ◽  
Thomas Martin ◽  
Ruben Niesvizky ◽  
...  

Abstract Abstract 1953 Background: Carfilzomib (CFZ) is a novel, selective proteasome inhibitor that differs from BTZ both structurally and mechanistically. CFZ overcomes BTZ-resistance in vitro, lacks the off-target activities of BTZ in preclinical studies, and does not cause neurotoxicity in long-term (6–9 month) chronic animal toxicology studies. Single-agent CFZ produces durable responses in relapsed and relapsed/refractory (R/R) multiple myeloma (MM) without dose-limiting PN, and can be given to pts with substantial renal dysfunction. Here we report on the clinical experience with long-term treatment (>12 cycles, >11 months) with single-agent CFZ in pts with MM. Methods: Included in the present analysis were pts with MM who initially enrolled in studies PX-171-002 (Phase 1), PX-171-003 (relapsed and refractory MM), PX-171-004 relapsed following 1–3 therapies), and PX-171-005 (relapsed and refractory MM with varying degrees of renal dysfunction). The majority of pts initially received CFZ at 20 mg/m2 IV, on Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C). In some trials, the dose was escalated following cycle 1 to 27 mg/m2 for up to 12 C. Recently, higher doses including 36 and 45 mg/m2 have been successfully attempted using a 30-min infusion. Pts who completed their full course of CFZ therapy on a given trial were given the option to enter the PX-171-010 extension study. In this extension study, CFZ was initially administered at the same dose-level and frequency as given in the last cycle of the pts’ previous CFZ study. CFZ could be administered at a reduced frequency of twice weekly every other week at the discretion of the investigator and pts could continue treatment until disease progression or unacceptable toxicity. Results: More than 10% of pts in studies PX-171-003 and PX-171-005, and approximately 24% of pts in PX-171-004 completed 12 cycles of induction therapy with CFZ (QDx2 weekly for 3 of 4 weeks). As of 31 July 2010, 42 of the pts completing 12 cycles of CFZ in a previous study either enrolled in PX-171-010 (N=38) or were treated on single-patient INDs prior to the availability of PX-171-010 (N=4). CFZ was administered as either a single agent (N=38) or combined with low-dose dexamethasone (N=4, all in PX-171-005). Twenty-five of the 42 MM pts (60%) remain on treatment: 24 receiving single agent CFZ at 27 mg/m2 (range 15–45 mg/m2) and 1 receiving CFZ + low dose dexamethasone. The median duration of CFZ treatment in this cohort is 14 months. The longest period of treatment is >27 months, and 12 pts have completed over 18 months of total continuous CFZ dosing. Of the 17 MM pts who discontinued therapy, 16 did so due to progressive disease and one pt had pneumonia, stopped therapy, and elected not to restart treatment. Cumulative toxicities were not observed, and AEs were similar to those reported in other studies of single-agent CFZ. There were 7 serious adverse events (SAEs, 1 patient each) reported in the extension study: 4 were possibly related and included infection, dyspnea, bronchitis and asthenia. Doses were interrupted and restarted or maintained for all of the pts with possibly related SAEs. Peripheral neuropathy and significant renal dysfunction were not observed with in this extension trial. Conclusions: CFZ is a highly selective proteasome inhibitor that can be administered to pts with MM for prolonged periods with no apparent cumulative toxicities. Disease control is possible with this single-agent treatment, even though many of the pts had disease that was refractory to multi-agent therapy prior to entering their initial CFZ trial. Following 12 cycles (11 months) of induction therapy (QDx2 weekly for 3 of 4 weeks) maintenance CFZ sustained disease control and provided excellent long-term tolerability, with the option for pts to switch to twice weekly dosing every other week. Disclosures: Jagannath: Celgene: Honoraria; Millenium/Takeda Pharma: Honoraria; J&J Family: Honoraria; Onyx: Honoraria; Merck: Honoraria. Vij:Onyx: Honoraria. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Martin:Celgene: Honoraria; Onyx: Consultancy. Niesvizky:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding. Gabrail:Millenium: Research Funding. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Wong:Onyx Pharmaceuticals: Employment. Le:Onyx Pharmaceuticals: Employment. McCulloch:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5581-5581
Author(s):  
Normand Blais ◽  
Charles A. Butts ◽  
Mark A. Crowther ◽  
Nanette Cox-Kennett ◽  
Josée Martineau

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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4056-4056
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Schlögl ◽  
Gunther Gastl ◽  
...  

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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1054-1054 ◽  
Author(s):  
James B. Bussel ◽  
Shah N. Mahmud ◽  
Sophie L Brigstocke ◽  
Sarah M Torneten

Abstract Background: Thrombopoietin receptor agonists (TPO-RA) eg eltrombopag (Epag), are highly effective treatments of ITP as demonstrated in multiple randomized studies. Studies have shown effective and safe long-term use; toxicity appears tolerable with thromboembolism the most common serious adverse event. An important question is if there will be an indefinite long-term need for treatment with these agents once initiated. The aim of this study is to taper eltrombopag in a single arm study to determine how many and which patients will be able to discontinue treatment over time. It specifically targets patients with adequate counts ie 50-100,000/uL, not waiting for patients whose counts spontaneously increase to high levels and thus indicate that they are being over-dosed. Methods: All patients on eltrombopag at doses of 75 mg daily or less for at least 4 months were offered study entry; only one refused. Initially the study tapered Epag rapidly but then changed to slow tapering over up to 2 years. Patients whose platelet counts were >50,000/uL were tapered at 4 week intervals in 10-20% dose increments. Tapering could be postponed for clinical reasons ie impending procedure or trip, infection skewing count, sports or other physical activity, etc. Analysis was descriptive and t test comparisons used to assess variables associated with successful tapering. Results: Patients were divided into 3 groups: 10 responders (those able to discontinue eltrombopag completely within 2 years, fig 1A), 10 tapering (those still tapering who have reduced their medication but not discontinued it, fig 1B), and 12 non-responders (those who tried and failed to discontinue within 2 years). To complete being a responder required >12 weeks without any ITP treatment, platelet count > 30,000/uL and 20,000/uL more than baseline after the last dose of eltrombopag. Eight of the 10 responders have remained off therapy for more than 1 year with platelet counts consistently > 50,000/uL. No medication was provided in the study. No serious AEs occurred and no serious bleeding events were seen. Fig 1a illustrates the discontinuation of eltrombopag treatment in responders: 4 discontinued within 8 weeks while the longest discontinuation required a full 2 years. Fig 1b shows patients who are tapering eltrombopag but have not reached 2 years by indicating how many are on <70% and <40% of their starting doses; it shows that tapering is typically a slow process but that at least dose reduction can be achieved in many patients even if they do not discontinue their eltrombopag. Table 1 compares means and medians of the 3 groups for a number of clinical variables. While the numbers are small and the results preliminary, it surprisingly shows that patients who have been on eltrombopag longer prior to tapering and those who have received more treatments are more likely to successfully discontinue eltrombopag. In contrast, non-responders failed splenectomy and rituximab more often than did those tapering and responders. Finally AIPF at initiation of study did not predict a successful taper. Summary: A substantial fraction of patients with chronic ITP will be able to successfully taper off eltrombopag; the exact number (somewhere between 10 and 20 of the 32 patients) depends upon the group still tapering. The tapering schedule selected is slow and requires regular monitoring and individualization/flexibility. Even if patients do not fully taper off eltrombopag, they may be able to substantially reduce their dose. We speculate that tapering eltrombopag as outlined here may reduce the toxicity and costs of long-term treatment without diminishing hemostatic efficacy. Table 1. Comparison Table (Responders, Tapering, Non-Responders) Responders (n=10) Tapering (n=10) Non-Responders (n=12) Age (years) (median/average) 29/37.4 11/25.70 21/30.58 Gender (m/f) 3/7 6/4 5/7 Duration ITP (years) (median/average) 8.75/11.95 5.5/17.45 7/8.25 Duration of TPO-RA Therapy (years) (median/average) 5/4.2 5.5/7.45 2.5/3.38 # of prior ITP treatments (median/average) 4.5/5.5 2/2.14 3.5/3.83 # of patients with previous splenectomy 4 0 6 patients with previous Rituximab treatments 5 4 9 Baseline AIPF (tapering counts) (*10E2/uL) (median/average) 81.75/75.5 63/57.43 75/69 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Bussel: Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; BiologicTx: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Momenta: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4063-4063 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Silverio Perrotta ◽  
Leyla Agaoglu ◽  
Yesim Aydinok ◽  
Marcello Capra ◽  
...  

Abstract Abstract 4063 Poster Board III-998 Background In a large, 1-yr Phase 3 clinical trial, patients (pts) with β-thalassemia (aged ≥2 yrs) were randomized to receive deferasirox (Exjade®) or deferoxamine (DFO), with doses assigned according to baseline liver iron concentration (LIC). Pts completing the 1-yr core were permitted to enter a 4-yr extension; those receiving deferasirox continued on this therapy (deferasirox cohort), while those receiving DFO crossed over to deferasirox (crossover cohort). This analysis evaluates the efficacy and safety of deferasirox over 5 yrs. Methods Based on analyses showing that iron burden and transfusional iron intake need to be considered for appropriate dosing of deferasirox, dose adjustments were permitted in the extension to ensure optimal dosing. Deferasirox dose in the extension was initially based on dose response in the core (deferasirox cohort only) and end-of-core LIC (biopsy or SQUID); subsequent adjustments in steps of 5–10 mg/kg/day were based on serum ferritin (SF) levels and safety markers. Efficacy was assessed by monthly SF levels and LIC at baseline, end of 1-year core and end of study (EOS) (or upon discontinuation). Safety was assessed by incidence and type of adverse events (AEs) and changes in laboratory parameters. Results 296 pts (deferasirox cohort) and 259 pts (crossover cohort) received ≥1 dose of deferasirox; 181 (61%) & 190 (73%) pts from each cohort respectively completed the extension. Most common reasons for discontinuation: consent withdrawal (n=62) and AEs (n=43). Most common AEs leading to discontinuation: increased ALT [n=5], increased transaminases [n=4], glycosuria [n=4]. 2 deaths occurred during the extension in the deferasirox cohort (cardiac failure, cardiomyopathy); 2 in the crossover cohort (cardio-respiratory arrest, road traffic accident); none considered to be related to study drug. Median duration of deferasirox treatment was 61.2 & 48.1 mths in deferasirox & crossover cohorts, respectively. At start of deferasirox, mean LIC was 14.0 ± 9.8 & 10.4 ± 7.6 mg Fe/g dry weight (dw) and median SF was 2211 & 1758 ng/mL in deferasirox and crossover cohorts, respectively. Transfusion requirements at start of deferasirox were comparable; most pts (81% & 83%, respectively) receiving 7–14 mL/kg/mth. Mean deferasirox dose during study: 21.6 ± 6.4 & 23.2 ± 5.9 mg/kg/d (final actual dose: 24.4 ± 8.7 & 27.0 ± 8.0 mg/kg/d) in deferasirox and crossover groups, respectively. Most pts were receiving 15–<35 mg/kg/day at EOS (75% & 78%, respectively); 11% & 17% were receiving ≥35 mg/kg/day. In pts who received at least 5 yrs of deferasirox and at least 4 yrs in the crossover group, mean absolute change in LIC were –5.3 ± 10.1 mg Fe/g dw (n=173; P<0.001) & –2.4 ± 7.6 mg Fe/g dw (n=99; P<0.001) and median absolute change in SF were –775 ng/mL (range: –10164–2572; n=182; P<0.001) & –371 ng/mL (range: –4498–2636; n=151; P<0.001), respectively (Figure). Percentage of pts with LIC<7 mg Fe/g dw increased from 35% to 45% & SF≤1000 ng/mL increased from 12% to 33% from the start of deferasirox to EOS (LIC: EOS, last available value; SF: EOS, average of at most 3 available values after start of deferasirox). Most common drug-related AEs (≥5% overall) after start of deferasirox in deferasirox & crossover cohort, respectively: increased blood creatinine (n=42, 14%; n=20, 8%), nausea (n=28, 10%; n=13, 5%), vomiting (n=18, 6%; n=17, 7%), diarrhea (n=13, 4%; n=15, 6%) & rash (n=17, 6%; n=19, 7%). Frequency of drug-related AEs decreased from year to year. In deferasirox & crossover cohorts, 26 (9%) & 11 (4%) pts had 2 consecutive serum creatinine increases >33% above baseline & upper limit of normal (ULN) & 3 (1%) & 2 (1%) pts had ALT >10 x ULN on 2 consecutive visits, respectively, after start of deferasirox. Conclusions Long-term treatment with deferasirox (for up to 5 yrs) significantly decreased iron burden in β-thalassemia pts aged ≥2 yrs with an increasing percentage of pts achieving therapeutic goals of LIC<7 mg Fe/g dw and SF≤1000 ng/mL. Significant improvements in LIC and SF were also observed after switching from DFO. Deferasirox was well tolerated over this long-term treatment, and the frequency of AEs decreased over time. Disclosures: Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Perrotta:Novartis: Consultancy, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Piga:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Griffel:Novartis Pharmaceuticals: Employment, Equity Ownership. Lagrone:Novartis Pharmaceuticals: Employment. Clark:Novartis Pharma AG: Employment. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4237-4237 ◽  
Author(s):  
Robert A Brodsky ◽  
Carlos de Castro ◽  
Hubert Schrezenmeier ◽  
Antonio M. Risitano ◽  
Joerg Schubert ◽  
...  

Abstract Abstract 4237 PNH is a chronic, life-threatening, acquired disease associated with deficiency of GPI-anchored complement inhibitory proteins on blood cells. The resulting defective regulation of terminal complement activation is responsible for hemolysis and can lead to thromboembolism (TE), chronic kidney disease (CKD) and pulmonary hypertension. The risk of TE is high, with an observed 6.24 venous TE events per 100 patient years, or approximately 62-fold higher compared to the general population: in fact, TE accounts for 40–67% of PNH related deaths. The effectiveness of anticoagulation (AC) in PNH patients (pts) is uncertain, as AC treated PNH may still experience TE. The terminal complement inhibitor eculizumab reduces intravascular hemolysis rapidly and significantly; it also leads to a reduction in TE events, pulmonary hypertension and improvements in CKD and quality of life. Here, we report on prolonged treatment of PNH patients with eculizumab for safety and sustained patient outcomes. Methods: All pts (N=195) in the PNH eculizumab clinical trials (Pilot (N=11), TRIUMPH (N=87) and SHEPHERD (N=97)) and subsequent Extension studies were assessed for long term safety and efficacy. Median age was 40 yrs, 54% female, 29% had a history of aplastic anemia and 1.5% with history of myelodysplasia. TE was reported in 32% (63/195) of pts prior to eculizumab treatment. There was high adherence to long term treatment; 90% (175/195) of pts completed the parent and extension trials. Results: The median eculizumab treatment duration was 29 mo (1 -66; IQR:23-32m); with a total eculizumab exposure of 474.1 patient-years. Intravascular hemolysis was rapidly reduced in 100% of pts after eculizumab treatment. LDH was reduced from a median of 2,133 U/L (∼10x ULN) at baseline to 310 U/L at 1 month of treatment (P<0.0001) and was sustained at 272U/L at 36 months (P<0.0001). There was an 81% (P<0.0005) reduction in TE events from 52 pre treatment events to 10 trial events using a match time analysis (P<0.0005). Of the 7 (7/195) pts who experienced a TE on drug, 5 had a history of TE and 2 were concomitantly treated with AC. Of pts treated with AC, 59% (58/98) experienced at least 1 TE prior to treatment. In 11 pts who discontinued AC, there were no TE reported with eculizumab treatment during or following AC discontinuation. Prevalence of CKD was reduced from 69% of pts at baseline to 31% (n=29) after 36 months of treatment, consistent with previous results. A fraction of pts still require blood transfusions and a fraction of pts, even without need for blood transfusions, had no significant increase (>1gm/dL) in steady state hemoglobin level over baseline. Eculizumab was well tolerated. Twenty pts (∼10%) did not complete the trial including 9 pts following a reported adverse event (AE). In 16 week follow-up to the 20 pts who discontinued eculizumab treatment, TE was reported in 3 pts, including 1 death. Most AEs (95%) were mild or moderate in severity and 90.8% of adverse events were deemed unrelated to study drug. Frequent AEs were: nasopharyngitis, (40%); headache (37%) and upper respiratory tract infection, (31%). There were 2 cases of meningococcal sepsis and both were successfully treated without sequelae. Serious infections were reported in 21% of pts and 2 pts discontinued therapy due to infections (meningococcal, staphylococcal sepsis: both resolved). Most commonly reported serious infections included pyrexia (4.6%) and viral (3.1%), lower respiratory tract (1.5%) and urinary tract (1.5%) infections. There were 4 patient deaths during treatment. Three deaths were considered not related to study drug and 1 possibly related to study drug by the investigator. Causes of death were progression from myelodysplasia to chronic myelomonocytic leukemia, adenoma progressing to adenocarcinoma, brain herniation following trauma injury, and TE of the small bowel. Conclusion: Long term treatment of PNH pts with eculizumab is associated with a favorable benefit/risk ratio and the clinical benefits demonstrated at earlier timepoints are sustained over 36 months. Improvement in TE and CKD was maintained over 36 months when compared to baseline and previous published data. Considering that thrombosis and CKD have been demonstrated to be significant causes of death in PNH, it is reasonable to expect that eculizumab treatment, by decreasing the risk of thrombosis and improving renal function, may increase the life expectancy of PNH pts. Disclosures: Brodsky: Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion Pharmaceuticals, Inc: Speakers Bureau. Schrezenmeier:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schubert:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria. Maciejewski:Alexion Pharmaceuticals, Inc: Consultancy. Duehrsen:Alexion Pharmaceuticals, Inc: Honoraria, Research Funding. Luzzatto:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding. Szer:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socié:Alexion Pharmaceuticals, Inc: Consultancy. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2732-2732 ◽  
Author(s):  
Jorge E. Cortes ◽  
Cristina Papayannidis ◽  
Catriona Jamieson ◽  
Gary J. Schiller ◽  
Anna Candoni ◽  
...  

Abstract Background: Novel agents are frequently added to standard acute myeloid leukemia (AML) treatment backbones yet it is unclear how much additional toxicity this introduces, with the potential for adverse events (AEs) to be caused by the backbone chemotherapy or the disease itself. Glasdegib (PF-04449913) is an investigational, oral small molecule inhibitor of the Hedgehog (Hh) pathway component Smoothened (SMO), currently in clinical development for AML treatment. In a Phase 2 randomized study, addition of glasdegib to low-dose cytarabine (LDAC) improved overall survival (OS) vs LDAC alone and combination therapy was generally well tolerated with minor differences in AE rates vs chemotherapy alone. Here, we analyzed specific 'on target' AEs consistent with inhibition of the SMO component of the Hh pathway to assess impact on overall toxicity. Methods: We pooled safety data from both portions of a Phase 1b + Phase 2 multicenter study (NCT01546038), including AML patients assigned to glasdegib 100 mg QD with LDAC (non-intensive treatment) or with cytarabine/daunorubicin on a 7+3 schedule (intensive treatment) (figure 1). We assessed 'on target' all-causality treatment-emergent AEs of muscle spasms, alopecia, and dysgeusia. We also compared AE onset in defined study time-periods (non-intensive: 0-6, 6-12, or >12 months; intensive: induction, consolidation, maintenance); defining long-term treatment as >12 months for non-intensive and maintenance for intensive. Results: Across studies, 93 patients were enrolled in the non-intensive group and 80 in the intensive group. Here, we focused on patients treated with glasdegib: 89 patients in the non-intensive group and 78 in the intensive group. Table 1 shows baseline characteristics; median treatment duration was 69 days (range 3-1280) and 51 days (10-539), respectively. Rates of treatment discontinuation due to all AEs (inclusive of 'on target' and others), deemed by the investigator to be related to study drug (glasdegib and/or backbone chemotherapy) were similar (non-intensive, 10 patients [11.2%]; intensive, 15 patients [19.2%]). Frequency of muscle spasms was similar for the 2 groups; observed in 19 of the non-intensive group (21.3%) and 18 (23.1%) of the intensive group (table 1), with few grade 3 events (non-intensive 4.5%; intensive 1.3%), and the number of patients who developed muscle spasms (nearly all grade 1) when exposed to long-term treatment was small (4 non-intensive patients; 7 intensive patients) with no cases of rhabdomyolysis. Alopecia was reported for 8 (9.0%) of the non-intensive group and 16 (20.5%) of the intensive group (table 1). Alopecia had earlier time to onset in the intensive arm than in the non-intensive arm (table 1), likely reflecting the concomitant chemotherapy. Alopecia was less frequent during glasdegib maintenance monotherapy (5.3%) in the intensive arm than when given with 7+3 (16.7%). Dysgeusia was similar for the 2 groups, observed in 22 of the non-intensive group (24.7%) and 24 (30.8%) of the intensive group (table 1). For both groups, dysgeusia had similar time to onset and was less common during long-term treatment. The number of patients having a dose modification as a consequence of class-related AEs was low (for non-intensive and intensive, respectively: dose reduction, 5.6% and 2.6%; temporary discontinuation, 4.5% and 2.6%; permanent discontinuation, 1.1% and 2.6%). Conclusions: Glasdegib 'on target' AEs of muscle spasms, alopecia, and dysgeusia were mainly of mild severity, had infrequent dose modifications or permanent discontinuations, and did not appear to impair tolerability of combination treatment. In comparison, muscle spasms and dysgeusia occurred in ≤5% for the LDAC alone arm, and no alopecia was reported. Although muscle spasms and dysgeusia occurred with similar frequency, dysgeusia occurred earlier, for a shorter duration, and was more persistent at the time of discontinuation compared with muscle spasms. Similar safety profiles were observed when combining glasdegib with LDAC or 7+3, suggesting that glasdegib in combination with standard chemotherapy has a manageable safety profile and thus can be an acceptable combination partner in the treatment of AML. Our results are consistent with previously reported safety outcomes for glasdegib as monotherapy in hematologic malignancies. Clinical trials of glasdegib in combination with other standard of care AML agents are ongoing. Disclosures Cortes: Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Candoni:Pfizer: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau. Leber:Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuko: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ma:Pfizer Inc: Employment, Equity Ownership. Gallo Stampino:Pfizer Inc: Employment, Equity Ownership. O'Connell:Pfizer Inc: Employment, Equity Ownership. Zeremski:Pfizer Inc: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  

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 &lt; 3 years were enrolled. A total of 257 patients were randomized 1:1 (stratified by age &gt; 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 &lt;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&lt;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&lt;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 (&lt;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&lt;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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1059-1059
Author(s):  
John C. Chapin ◽  
James B. Bussel ◽  
Christina S Lee ◽  
Joseph H Oved

Abstract Background: Therapies in ITP primarily increase the platelet count while treatment continues: IVIG, steroids, IV RhIg, romiplostim, eltrombopag and others. Curative effects of treatments other than splenectomy are uncertain; 2 recent studies with rituximab provided disappointing results. ITP in children often spontaneously improves but in children with chronic ITP and adults, this is much less common and management may be difficult. The aim of this study is to explore the efficacy and safety of R+3D. Methods : ITP patients were managed with R+3D if appropriate. Forty-nine adults and 33 children with ITP (newly diagnosed, persistent, and chronic) were treated at Weill Cornell Medical College with the previously described R+3D treatment plan: weekly rituximab infusion 375mg/m2 x 4 weeks + three 4-day cycles of 28mg/m2 (max. 40mg) dexamethasone at 2-week intervals. Patients who came to the platelet disorders center were included even if they received all or part of their treatment elsewhere. Counts were obtained weekly, monthly, and 2-3x monthly thereafter for responders. Response was either partial (PR, plt count > 50,000-100,000) or complete (CR > 100,000). Analysis was descriptive and by Kaplan-Meier. Children and adults are presented separately. Results : The overall estimated response (initial and long-term) in the 49 adults (22 men, 27 women) was associated with greater initial platelet response, female gender, and duration of ITP < 1 year. There was a significant difference in the projected 78% lasting response rate at 5 years in women with ITP of < 1 yr duration. All other groups (men < or > 1 yr duration of ITP and women > 1 yr duration of ITP) had highly inferior results (<25%). Ninety % of the 49 adults (44/49; 11 PRs and 33 CRs) initially responded to R+3Dex at 8 weeks. Children had lower initial responses at 45% (15/33; 2 PRs and 13 CRs). Four adults further improved from PR to CR and 2 children, 1 NR, 1 PR, to CR. Kaplan Meier projected long-term treatment-free response for all adults treated with R+3Dex is 33.5%. Only 1 PR but 22/37 (59.5%) of CRs continue to maintain adequate platelet counts. Parallel projection of long-term response for children is 23.9%. In children, 10/16 (62.5%) responders continue to maintain their response at last follow-up., Female patients maintained a 44% long-term response at 5 years whereas male patients projected a rate of only 19% (p value = 0.009). In children, girls projected a 37% long-term response and boys projected 11% at 5 years. Further divided by the duration of ITP, both adult and pediatric female patients with duration of ITP less than 12 months fared better than females with longer duration of disease (and males of any duration). Conclusions: ITP does not typically display a large gender disparity compared to other autoimmune diseases such as systemic lupus erythematosus), (1.5F:1Mcompared to 9F:1M ). No gender differences were found in responses to first- and second-line treatments in a previous report (Andres et al., 2012). However, gender bias in especially long term response is dramatic and is shown separately in both children and adults; when combined with earlier treatment initiation, the difference in projected long-term, treatment-free remission is remarkable (Table 1). Studies in lymphoma and 2 other indications have also suggested a gender effect in response to rituximab, but attributed it to Pk in elderly women. The influence of gender on autoimmune diseases, ITP in particular, is complicated and warrants further study as to the mechanism of effect. Table 1.Adults (n=49) Female: n=27 // Male: n=22Children (n=33) Female: n=18 // Male: n=15Initial ResponseNR = 5 (10.2%)NR = 18 (54.5%)PR = 11 (22.4%)PR = 2 (6.1%)CR = 33 (67.4%)CR = 13 (39.4%)Female: 26/27 (96.3%) Male: 18/22 (81.8%)Female: 8/18 (44.4%) Male: 7/15 (46.7%)Best ResponseNR = 5 (10.2%)NR = 17 (51.5%)PR = 7 (14.3%)PR = 1 (3.0%)CR = 37 (75.5%)CR = 15 (45.5%)Female: 26/27 (96.3%) Male: 18/22 (81.8%)Female: 9/18 (50%) Male: 7/15 (46.7%)Relapsed21/44 (47.7%)6/16 (37.5%)Female: 10/26 (38.5%) Male: 10/18 (55.5%)Female: 2/9 (22.2%) Male: 4/7 (57.1%)Ongoing23/44 (52.3%)10/16 (62.5%)Female: 16/26 (61.5%) Male: 8/18 (44.4%)Female: 7/9 (77.7%) Male: 3/7 (42.9%) Disclosures Bussel: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; protalex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.


Sign in / Sign up

Export Citation Format

Share Document