Impact of Age and Type of Underlying Disease on Long-Term Safety and Efficacy in Patients with Transfusional Hemosiderosis Treated with Deferasirox: Results from a 3-Year Non-Interventional Study (SENTINEL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4831-4831
Author(s):  
Mohsen Elalfy ◽  
Baba Inusa ◽  
David Beneitez ◽  
Blanca Xicoy ◽  
Maria Soledad Duran Nieto ◽  
...  
Keyword(s):  
Research Funding ◽  
Iron Chelation ◽  
Study Drug ◽  
Underlying Disease ◽  
Safety And Efficacy ◽  
Absolute Change ◽  
Time Period ◽  
Long Term Treatment ◽  
Over Time

Abstract Background: Hemosiderosis, due to frequent blood transfusions, is associated with liver, heart and endocrine dysfunction. Deferasirox (DFX), a once-daily oral iron chelator is used in the management of these patients (pts). The results of the 3-year (yr), non-interventional SENTINEL study demonstrated long-term safety and efficacy of DFX in a large cohort of pts with transfusional hemosiderosis. The current analysis was performed to further evaluate the long-term efficacy and safety of DFX by age and underlying disease. Methods: The SENTINEL study design was previously reported (El-Beshlawy et al. Haematologica 2016;101(s1):abst E1475). In this study, data were collected for 3 yrs from the initiation of treatment with DFX. Pts aged ≥2 yrs treated with DFX for transfusional hemosiderosis, enrolled according to the local prescription information, were included in the study. Safety was evaluated by regular monitoring and recording of adverse events (AEs) and is reported in all pts who received ≥1 dose of DFX and had ≥1 post baseline (BL) safety assessment (safety set). During each bi-annual time period, summary statistics are provided for the average SF values taken for each pt within that specific time period. Results: Of the120 pts enrolled, 49 (40.8%) were diagnosed with β thalassemia, 31 (25.8%) with sickle cell disease (SCD), 21 (17.5%) with myelodysplastic syndrome (MDS), and 19 (15.8%) with other anemias. The mean±SD age was 28.9±29.0 (range, 1-88) yrs (<18 yrs, n=69 [7.5±4.2]; ≥18 yrs, n=51 [57.9±22.1]). Overall, 42.5% (n=51; <18 yrs, n=45; ≥18 yrs, n=6) of pts completed the 3-yr study. Most common reasons for discontinuation (>10%) include pts no longer requiring study drug (19.2%), AEs (12.5%), and withdrawal of consent (10.8%). Median duration of DFX exposure was 29.9 months (mos), (<18 yrs, 36.0; ≥18 yrs, 10.0). Mean average actual dose was 23.2±8.2 mg/kg/d (<18 yrs, 25.7±6.6; ≥18 yrs, 17.7±8.9). Overall, 54.7% (n=64) of pts did not receive prior iron chelation therapy (ICT) and 45.3% (n=53) received prior ICT. Of the pts evaluable for average actual dose, 56.5% (26/46) of pts without prior ICT and 82.2% (37/45) of pts with prior ICT received treatment with an average actual dose of DFX ≥20 mg/kg/d. Pts without prior ICT received a lower average actual dose (mg/kg/d, mean±SD) of DFX compared to pts receiving prior ICT (<18 yrs, 23.8±5.2 vs 27.6±7.4; ≥18 yrs, 15.4±7.7 vs 20.3±9.7) (Table 1). Of the 117 pts evaluated for safety, increase in serum creatinine, >33% above BL and the age-adjusted upper limit of normal (ULN) on at least 2 consecutive measurements (≥7 days apart) were observed in 14 pts (12%; 95% confidence interval [CI], 7.1-19.2; MDS [n=3], SCD [n=7] and other anemias [n=4]). Increase in alanine aminotransferase (ALT), >5×ULN on at least 2 consecutive measurements (≥7 days apart) was observed in 1 pt (0.9%; 95% CI, 0.0-5.2) with β thalassemia (BL ALT missing). DFX-related AEs gradually decreased over time (Figure 1A). Overall incidence of AEs regardless of relationship with DFX also decreased over time (Figure 1B). In the overall pt population, the median absolute change in SF values (µg/L) from BL to last available post BL (end of study, EOS) was −359.8. In pts with β thalassemia, the median absolute change in SF values from BL to EOS was −491.0 (n=27) in pts <18 yrs and −79.0 (n=6) in pts ≥18 yrs (Figure 2). Conclusions: Nearly, 40% of the pts received treatment with DFX for 36 mos during the study, indicating good tolerance of DFX treatment, and 45% of the pts received prior ICT. Pts with prior ICT received a higher average actual dose of DFX compared to pts without prior ICT. Pediatric pts received a higher average actual daily dose compared to adult pts, irrespective of the chelation group. The majority of pts with prior ICT received an average actual dose of DFX ≥20 mg/kg/d. Long-term treatment with DFX demonstrated a gradual decrease in SF values in the overall pt population, though this was not immediate, likely because of delayed increases in dose based on weight gain and ongoing iron intake. DFX-related AEs gradually decreased over 3 yrs and demonstrated an acceptable safety profile. This reinforces that an average actual dose of DFX ≥20 mg/kg/d might be required in majority of pts for appropriate management of transfusional hemosiderosis in actual practice. Disclosures Bruederle: Novartis Pharmaceuticals Corporation: Employment. Azmon:Novartis Pharmaceuticals Corporation: Employment. El-Beshlawy:Novartis Pharmaceuticals Corporation: Research Funding; Apo Pharma Inc.: Research Funding.

Treatment Outcomes in Patients with Transfusional Hemosiderosis Who Received Deferasirox for up to 3 Years: Results from Sentinel Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4834-4834
Author(s):  
Mohsen Elalfy ◽  
Baba Inusa ◽  
David Beneitez ◽  
Blanca Xicoy ◽  
Maria Soledad Duran Nieto ◽  
...  
Keyword(s):  
Research Funding ◽  
Patient Adherence ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Study Drug ◽  
Published Data ◽  
Liver Iron ◽  
Safety And Efficacy ◽  
Mortality And Morbidity ◽  
Absolute Change

Abstract Background: Adequate iron chelation therapy (ICT) and patient adherence are essential in the management of patients (pts) with chronic iron overload (IOL), which is an important cause of mortality and morbidity. Data from various clinical trials show that deferasirox (DFX), a once-daily oral iron chelator, at a recommended dose of 20 mg/kg/d stabilizes serum ferritin (SF) and liver iron concentration in transfusion-dependent pts (Chaudhary et al. J Blood Med. 2013;4:101-10). The non-interventional, SENTINEL study conducted in pts with transfusional hemosiderosis demonstrated the long-term safety and efficacy of DFX. The current analysis was performed to further evaluate the safety and efficacy of DFX in pts who completed the 3-year (yr) study, including pts who completed the study and received an overall average actual dose of DFX ≥20 mg/kg/d. Methods: The SENTINEL study design has been reported previously (El-Beshlawy et al. Haematologica 2016;101(s1):abst E1475). Pts aged ≥2 yrs with transfusional hemosiderosis treated with DFX in accordance with the local prescription information were enrolled. For this analysis, pts who completed the 3-yr study and/or completed the 3-yr study receiving an overall average actual dose of DFX ≥20 mg/kg/d were considered. Safety was assessed by regular monitoring and recording of adverse events (AEs) and efficacy was measured by SF levels, which were analyzed biannually, by providing summary statistics for the average SF values of each pt within that specific period. Results: Of the 120 pts enrolled, 51 (42.5%; <18 yrs, n=45; ≥18 yrs, n=6) with β thalassemia (n=30); sickle cell disease (SCD, n=18) and other anemias (n=3) completed the 3-yr study. 41/51 pts (80.4%; <18 yrs, n=37; ≥18 yrs, n=4) with β thalassemia (n=26), SCD (n=12), and other anemias (n=3) received an overall average actual dose of DFX ≥20 mg/kg/d. The most frequent reasons for study discontinuation (>10%) include pts no longer required study drug (19.2%), AEs (12.5%), and consent withdrawn (10.8%). Of the pts who completed the study, 14 (27.4%) had AEs suspected to be related to DFX, which included 10 pts receiving an overall average actual dose of DFX ≥20 mg/kg/d. The most frequent AEs (>5%) suspected to be related to DFX in pts who completed the 3-yr study were vomiting (7.8%), abdominal pain (5.9%) and lack of efficacy (5.9%). The overall incidence of AEs with suspected relationship to DFX, in pts who completed the study and received an overall average actual dose of DFX ≥20 mg/kg/d was consistent throughout the study without any unexpected safety findings (Figure 1). Increase in serum creatinine, >33% above baseline (BL) and the age-adjusted upper limit of normal (ULN) on at least 2 consecutive measurements (≥7 days apart), was observed in 7 (14.3%) pts who completed the study (Table 1), of whom 6 (SCD, n=5; other anemias, n=1) received an overall average actual dose of DFX ≥20 mg/kg/d. Increase in alanine aminotransferase (ALT), >5×ULN on at least 2 consecutive measurements (≥7 days apart), was observed in 1 pt with β thalassemia (BL ALT missing) during the last yr of study (Table 1). No notable increase in ALT was observed in pts, who received an overall average actual dose of DFX ≥20 mg/kg/d. In pts who completed the study, the median absolute change in SF (µg/L) values from BL to last available post BL (end of study [EOS]; n=37) was −275.0. In pts with β thalassemia and SCD, the median absolute change in SF values from BL to EOS were −284.0 (n=21) and −260.0 (n=13) respectively. In pts who completed the study and received an overall average actual dose of DFX ≥20 mg/kg/d, the median absolute change in SF values from BL to EOS (n=29) was −275.0 (Figure 2). Conclusions: Most of the pts who completed this 3-yr study had a diagnosis of β thalassemia and SCD. Overall, 42.5% of pts received DFX treatment for 3 yrs, and the majority of them were treated with an overall average actual dose of DFX ≥20 mg/kg/d. The observed safety profile of DFX was consistent with the previously published data. In pts who completed the study and received a dose of DFX ≥20 mg/kg/d, few had AEs suspected to be related to DFX. In pts who completed the study, the median change in SF values decreased from BL to EOS. The results demonstrate that an average actual dose of DFX ≥20 mg/kg/d might be required in the majority of pts, with appropriate dose adjustments based on iron intake and IOL to ensure an effective ICT, particularly in pediatric pts with transfusional hemosiderosis. Disclosures Bruederle: Novartis Pharmaceuticals Corporation: Employment. Azmon:Novartis Pharmaceuticals Corporation: Employment. El-Beshlawy:Novartis Pharmaceuticals Corporation: Research Funding; Apo Pharma Inc.: Research Funding.

Efficacy and Safety of Deferasirox (Exjade®) in Patients with β-Thalassemia Major Treated for up to 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4063-4063 ◽  
Author(s):  
M. Domenica Cappellini ◽  
Silverio Perrotta ◽  
Leyla Agaoglu ◽  
Yesim Aydinok ◽  
Marcello Capra ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Iron Concentration ◽  
Term Treatment ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Absolute Change ◽  
Transfusion Requirements ◽  
Long Term Treatment

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.

Long Term Safety and Efficacy of Sustained Eculizumab Treatment In Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4237-4237 ◽  
Author(s):  
Robert A Brodsky ◽  
Carlos de Castro ◽  
Hubert Schrezenmeier ◽  
Antonio M. Risitano ◽  
Joerg Schubert ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Term Treatment ◽  
Advisory Committees ◽  
Serious Infections ◽  
Long Term Treatment ◽  
History Of ◽  
Terminal Complement

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.

scholarly journals BAX-Mutated Clonal Hematopoiesis in Patients on Long-Term Venetoclax for Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Piers Blombery ◽  
Ella R Thompson ◽  
Xiangting Chen ◽  
Tamia Nguyen ◽  
Mary Ann Anderson ◽  
...  
Keyword(s):  
Advisory Committee ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
Eliza Hall Institute ◽  
Hall Institute ◽  
Over Time

Venetoclax (Ven) is an effective element of treatments for chronic lymphocytic leukemia (CLL) with high response rates observed in the upfront and relapsed/refractory (R/R) settings. In addition to inducing apoptosis in CLL cells, Ven also induces apoptosis within normal and malignant myeloid lineage populations (accounting for its efficacy in the treatment of acute myeloid leukemia). We investigated the effects of Ven outside the target tumor compartment in patients (pts) with CLL receiving long-term continuous Ven and make the novel observation of the development of BAX-mutated clonal hematopoiesis in this heavily pre-treated patient group. 92 pts with CLL receiving continuous non time-limited Ven have been treated at our institutions on clinical trials. Of these, 41 had sufficient (&gt;6 mo) follow up (median 70; range 14-95 mo) and suitable samples available for further analysis. 38/41 (93%) pts had received previous treatment with alkylators and/or fludarabine. In order to assess the non-CLL compartment in these 41 pts we identified those with peripheral blood or bone marrow aspirate samples taken during deep response to Ven demonstrating either minimal (&lt;5%) or no CLL involvement by flow cytometry (sensitivity 10-4). We initially performed unique molecular index (UMI)-based targeted next generation sequencing of apoptosis pathway genes as well a panel of 60 genes recurrently mutated in lymphoid and myeloid malignancy. From these 41 pts we identified mutations in the apoptosis effector BAX in samples from 12 (29%). 20 different BAX mutations were observed across these 12 pts at variant allele frequencies (VAF) consistent with their occurrence in the non-CLL compartment. Mutations included frameshift, nonsense, canonical splice site and missense mutations occurring in key structural elements of BAX consistent with a loss-of-function mechanism (Fig 1A). Interestingly, an enrichment of missense and truncating mutations predicted to escape nonsense mediated decay were observed at the C-terminus of the BAX protein affecting the critical α9 helix. Mutations in this region have previously been shown in cell lines to cause aberrant intracellular BAX localization and abrogation of normal BAX function in apoptosis (Fresquet Blood 2014; Kuwana J Biol Chem 2020). For comparison, NGS targeted sequencing for BAX mutations was performed on samples from cohorts of pts with (i) myeloid or lymphoid malignancy (n=80) or (ii) R/R CLL treated with BTK inhibitors (n=15) after a similar extent of preceding chemotherapy. Neither of these cohorts had previous exposure to Ven. BAX mutations were not detected in any samples from these pts. Longitudinal sampling from pts on Ven harboring BAX mutations in the non-CLL compartment was performed to further understand compartment dynamics over time (in 9 pts over 21-93 months of follow up). Multiple pts demonstrated a progressive increase in VAF of single BAX mutations over time to become clonally dominant within the non-CLL compartment and with observed VAFs consistent with their presence in the myeloid compartment. Mutations in other genes implicated in clonal hematopoiesis and myeloid malignancy including ASXL1, DNMT3A, TET2, U2AF1 and ZRSR2 were also detected in these pts samples. Targeted amplicon single cell sequencing (Mission Bio) demonstrated the co-occurrence of clonally progressive BAX mutations within the same clones as mutations in DNMT3A and ASXL1 as well as the existence of further BAX mutations at low VAF outside these dominant clones which remained non-progressive over time (Fig 1B). In addition, fluctuations in the presence and VAF of myeloid-disease associated mutations was noted with Ven exposure. In aggregate these data are consistent with the existence of a selective pressure within the myeloid compartment of these pts and an interplay of BAX with other mutations in determining survival and enrichment of these clones over time with ongoing Ven therapy. In summary, we have observed the development of BAX-mutated clonal hematopoiesis specifically in pts with CLL treated with long-term Ven. These data are consistent with a multi-lineage pharmacological effect of Ven leading to a survival advantage for clones harboring BAX mutations within the myeloid compartment during chronic Ven exposure. Finally, our data support the further investigation of BAX mutations as a potential resistance mechanism in myeloid malignancies treated with Ven. Disclosures Blombery: Invivoscribe: Honoraria; Amgen: Consultancy; Janssen: Honoraria; Novartis: Consultancy. Anderson:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Seymour:Celgene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Mei Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Nurix: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria. Huang:Servier: Research Funding; Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.; Genentech: Research Funding. Wei:Janssen: Honoraria, Other; Walter and Eliza Hall Institute: Patents & Royalties; AMGEN: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties.

scholarly journals Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3512-3512
Author(s):  
Rachael F. Grace ◽  
D. Mark Layton ◽  
Frédéric Galactéros ◽  
Wilma Barcellini ◽  
Eduard J. van Beers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
The Core ◽  
Equity Ownership ◽  
Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses &gt;25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY

2021 ◽  
Author(s):  
Maria Fleseriu ◽  
Dagmer Führer-Sakel ◽  
Aart J van der Lely ◽  
Laura De Marinis ◽  
Thierry Brue ◽  
...  
Keyword(s):  
Drug Withdrawal ◽  
Tumour Size ◽  
Pituitary Tumour ◽  
Risk Profile ◽  
Interventional Study ◽  
Safety And Efficacy ◽  
Active Acromegaly ◽  
Liver Tests ◽  
Over Time

Objective: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. Design: Global (15 countries), multicentre, non-interventional study (2004-2017). Methods: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. Main endpoints were long-term safety (comorbidities, adverse events [AEs], pituitary tumour volumes, liver tests) and efficacy (IGF-1 changes). Results: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF-1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with use of ≥30 mg PEGV/day in an increasing proportion of patients. Conclusion: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

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.

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