scholarly journals Ruxolitinib for Patients (Pts) with Polycythemia Vera: Responders Vs Non-Responders As Defined in the Response Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2947-2947
Author(s):  
Srdan Verstovsek ◽  
Jean-Jacques Kiladjian ◽  
Monika Wroclawska ◽  
Tuochuan Dong ◽  
Alessandro M. Vannucchi
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematological Parameters ◽  
Jak2 V617f ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Allele Burden ◽  
To Receive ◽  
Response Trial

Introduction: The RESPONSE trial (NCT01243944) compared ruxolitinib (Rux) and best available therapy (BAT) in pts with polycythemia vera (PV) who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNET criteria. In the primary analysis, at week (Wk) 32, 60% of (pts) randomized to Rux achieved HCT control (HCT <45%). The present analysis evaluated the effect of baseline characteristics on HCT response at Wk 32, and aimed to determine the long-term clinical efficacy of Rux in pts who did and did not achieve the protocol-defined HCT control (i.e., HCT control responders and non-responders at Wk 32) in RESPONSE at Wk 256. Methods: Adult pts with phlebotomy-dependent PV with splenomegaly, and resistant to or intolerant of HU were enrolled. Pts were randomized to receive Rux (at a starting dose of 10 mg BID) or single-agent BAT (1:1). HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (HCT > 45% and ≥ 3 percentage points higher than baseline or > 48%, whichever was lower; regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In this analysis, a logistic regression model was fitted to identify the significant baseline factors to predict HCT control response at Wk 32. Time to phlebotomy eligibility in the HCT control responders and time from the first phlebotomy eligibility to the second phlebotomy eligibility in the HCT control non-responders were plotted, and the changes in hematological parameters (HCT, WBC and platelet count), spleen volume and allele burden over time, up to Wk 256, were studied in HCT control responders and non-responders who were randomized to Rux treatment arm in RESPONSE. Results: A total of 222 pts were randomized to receive either Rux (n = 110) or BAT (n = 112). Baseline WBC (P=0.0198) and baseline JAK2 V617F allele burden (P=0.0159), were found to be predictors of the HCT response within Rux treated pt group (n = 110). In the HCT responder subgroup of the Rux arm, 23% (15/66) pts needed their first phlebotomy by Wk 256. In the HCT non-responder subgroup of the Rux arm, out of 28 patients who experienced their first phlebotomy between Wk 8 and Wk 32, 64% (18/28) of pts required subsequent phlebotomy by Wk 256, with a median duration of 28.4 Wks (12.7, NA). Pts receiving Rux demonstrated controlled hematologic parameters (HCT, WBC, and platelets) over the course of study, regardless of whether they were HCT control responders and HCT control non-responders at Wk 32. From Wk 48 to Wk 80, 97% HCT control responder pts and 84% HCT control non-responder pts of the Rux treatment arm required no phlebotomies. From Wk 80 to Wk 256, 91% and 68% of the evaluable pts in the Rux treatment arm remained phlebotomy-free for HCT control responders and non-responders, respectively. By Wk 256, spleen volume on an average was reduced from baseline by approximately 35% and 50% for HCT control responders and non-responders, respectively. In pts with available assessments, allele burden on an average was reduced approximately from 80% at baseline to 55% at Wk 256 in the HCT control responders, and approximately from 70% at baseline to 40% at Wk 256 in the HCT control non-responders. Conclusions: The results from present analysis demonstrated that the benefits of the Rux treatment were not limited to pts who achieved HCT control at Wk 32. Patients treated with Rux were able to maintain hematological parameters, spleen volume reduction, and JAK2 V617F allele burden reduction for a longer duration (up to 5 years), regardless of whether they were HCT control responders or non-responders at Wk 32. Disclosures Verstovsek: Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. Wroclawska:Novartis Pharma AG: Employment. Dong:Novartis: Employment. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

Clinical Benefit of Ruxolitinib Treatment after Crossover from Best Available Therapy in Patients with Polycythemia Vera: Analysis of the RESPONSE Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3181-3181 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Alessandro M. Vannucchi ◽  
Martin Griesshammer ◽  
Tamas Masszi ◽  
Simon Durrant ◽  
...  
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
To Receive ◽  
Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis, and in many cases leukocytosis and thrombocytosis. PV is driven by activating mutations in the JAK/STAT pathway, primarily JAK2V617F. For high-risk patients, a commonly used first-line therapy is hydroxyurea (HU); however, a subgroup of patients become intolerant of or resistant to HU. The phase 3 RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU (modified European LeukemiaNet criteria). Patients randomized in the BAT arm were permitted to cross over to receive RUX from Week 32 of the study. The results of the primary analysis comparing RUX to BAT prior to crossover have been reported, in which RUX was superior to BAT in achieving hematocrit control, reductions in spleen volume, and improvements in PV-related symptoms. This current analysis was conducted to evaluate the efficacy of RUX treatment in patients who crossed over from BAT relative to their original BAT treatment and relative to those originally randomized to RUX. Methods : Enrollment criteria included PV diagnosis, age ≥18 years, resistance to or intolerance of HU, splenomegaly, and phlebotomy requirement to control hematocrit. Patients were randomized 1:1 to receive open-label RUX 10 mg BID or BAT administered based on investigator judgment. BAT may have included HU, interferon/pegylated interferon, pipobroman, anagrelide, immunomodulators (eg, lenalidomide or thalidomide), or no medication. The protocol allowed for dose modifications (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Patients in the BAT group could cross over to RUX from Week 32 if they had not met the primary endpoint, or after Week 32 due to protocol-defined disease progression. The primary study endpoint was a composite of hematocrit control and a ≥35% reduction in spleen size at Week 32. Hematocrit was assessed at screening, every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32, and 2, 4, 6, 8, 16, 24, and 32 weeks following crossover. Spleen volume was assessed by magnetic resonance imaging at screening and study Weeks 16, 32, 48, 64, 80 and every 32 weeks thereafter. The number of phlebotomy procedures was evaluated over time in each group. Results : A total of 110 patients were randomized to RUX and 112 to BAT; study discontinuation by Week 32 (before crossover was permitted) was 11% in both groups. However, most patients in the BAT arm crossed over to receive RUX treatment immediately after the Week 32 visit (84% between Weeks 32 and 48); only 3% of patients remained in the BAT arm compared with 85% in the RUX arm at the time of the data analysis (median 81-week follow-up). With up to 32 weeks on BAT therapy, 25% of patients in this group did not require a phlebotomy; in contrast, with up to 32 weeks on RUX, 79% of patients after crossover and 74% of patients initially randomized to RUX did not require phlebotomy. The number of phlebotomy procedures adjusted for 100 patient-years during BAT therapy was 196.8 vs 38.5 after crossover to RUX and 34.1 on randomized RUX treatment. Reduction in spleen volume from baseline at any visit occurred in 49% of patients receiving BAT, vs 73% of patients after crossover to RUX and 88% of patients initially randomized to RUX. The proportion of patients achieving at least a 35% reduction in spleen volume (best percentage change) was 1.8% during BAT treatment vs 38.5% after crossover to RUX and 60.0% during randomized RUX treatment. Conclusion : Treatment with RUX after crossover from BAT resulted in improved clinical outcomes compared with original BAT treatment. These findings support the primary RESPONSE results and further validate the efficacy of RUX in this patient population. Disclosures Kiladjian: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals : Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Verstovsek:Incyte Corporation: Research Funding.

Efficacy of Ruxolitinib By Baseline Spleen Volume in Patients with Polycythemia Vera Resistant to or Intolerant of Hydroxyurea

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1840-1840 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Srdan Verstovsek ◽  
Mark M Jones ◽  
Shui He ◽  
Jingjin Li ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Linear Regression ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm defined by erythrocytosis; patients may also have increased platelets and white blood cells as well as splenomegaly and disease-related symptoms. JAK/STAT activation is the primary driver of PV pathogenesis, in most cases resulting from the JAK2V617F mutation. The RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV and splenomegaly who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNet criteria. At the time of the primary analysis, RUX demonstrated superior improvements in hematocrit (HCT) control, symptom burden, and spleen volume compared with BAT. This post hoc analysis of RESPONSE was conducted to determine if treatment outcomes were influenced by baseline spleen volume. Methods : Patients with PV ≥18 years of age who were resistant to or intolerant of HU with palpable spleen (confirmed by MRI/CT to be ≥450 cm3) and phlebotomy requirement were randomized 1:1 to receive open-label RUX 10 mg BID or BAT. The primary endpoint was a composite that required a ≥35% reduction in spleen volume at Week 32 and hematocrit (HCT) control. HCT control was defined as lack of phlebotomy eligibility (based on HCT values) between Weeks 8–32 with no more than 1 phlebotomy eligibility between randomization and Week 8. A linear regression was conducted to determine the effect of baseline spleen volume on the percent change in spleen volume at Week 32. A logistic regression was conducted to determine the effect of baseline spleen volume on HCT control through Week 32. Spleen volume was measured by MRI at screening and Weeks 16 and 32. Hematocrit was assessed at screening, prerandomization, and every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32. Results :The RESPONSE trial enrolled 222 patients (RUX, 110; BAT, 112). Median (range) spleen volume at baseline was 1195 cm3 (396–4631 cm3) in the RUX arm and 1322 cm3 (254–5147 cm3) in the BAT arm. Baseline median (range) spleen length by palpation was 7.0 cm (0.0–24.0 cm) in the RUX arm and 7.0 cm (0.0–25.0 cm) in the BAT arm. In the 24 weeks prior to screening, most patients in both arms had ≥2 phlebotomy procedures (RUX, 87%; BAT, 80%). There was no correlation between the percentage change in spleen volume at Week 32 and baseline spleen volume; linear regression showed no significant effect of baseline spleen volume on the percentage change in spleen volume at Week 32 (P=0.40). No significant effect of baseline spleen volume on HCT control through Week 32 was identified based on logistic regression analysis (P=0.37). Conclusion : In PV patients with inadequate response to or intolerant of HU, the degree of splenomegaly at baseline did not influence achievement of HCT control or reduction in spleen volume with RUX therapy. Disclosures Vannucchi: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Verstovsek:Incyte Corporation: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3201-3201
Author(s):  
Srdan Verstovsek ◽  
Jean-Jacques Kiladjian ◽  
Ruben Mesa ◽  
Mark M Jones ◽  
Shui He ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Jak2 Inhibitor ◽  
Equity Ownership ◽  
To Receive ◽  
Response Trial

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control. Methods: Phlebotomy-dependent PV pts with splenomegaly, aged ≥18 years, and resistant to or intolerant of HU were enrolled. Pts were required to have HCT between 40%−45% 14 days prior to randomization; those who did not could enter a phlebotomy control period to achieve a HCT in this range within 14 days of randomization. Eligible pts were randomized 1:1 to RUX or BAT. BAT pts could cross over to receive RUX from Wk 32 if they had not met the primary endpoint, or after Wk 32 due to protocol-defined disease progression. The primary composite endpoint comprised HCT control and a ≥35% reduction from baseline in spleen volume (SV) at Wk 32. HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In pts who were HCT control non-responders (HCT-N) as defined by protocol, time to second phlebotomy eligibility was evaluated. For this analysis, pts without phlebotomy eligibility were excluded and phlebotomies in the first 8 wks were not considered. Patient-reported outcomes were evaluated in both HCT control responders (HCT-R) and HCT-N, including the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the Patient Global Impression of Change (PGIC). Results: Of 222 randomized pts (RUX, n=110; BAT, n=112), most were male (RUX, 60%; BAT, 71%) and the median age (range) was similar between treatment arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]). Although pts had a HCT between 40% and 45% within 14 days prior to randomization (with or without phlebotomy), 24% of pts had a HCT >45% on Day 1 (similar between treatment arms) illustrating that many pts have poor HCT control over short intervals of observation. RUX treatment resulted in long-term benefits on HCT levels, even in pts who did not achieve protocol-defined HCT control through Wk 32. Among the RUX HCT-R group, the probability of maintaining HCT response was 97% at 48 wks and 87% at 80 wks. Most BAT pts crossed over to receive RUX immediately after the Wk 32 visit (84% between Wks 32 and 48). In the RUX HCT-N pts, the median time to subsequent phlebotomy eligibility was 52 wks, compared with 21 wks for BAT HCT-N pts (Figure). Compared with the entire BAT group, more RUX-R and RUX-N pts had a ≥50% improvement in the MPN-SAF total symptom score at Wk 32 (RUX-N, 38%; RUX-R, 40%; BAT, 4%). Median changes from baseline at Wk 32 in key symptoms such as tiredness (RUX-N; −50%; RUX-R, −49%; BAT, −4%), itching (RUX-N, −88%; RUX-R, −97%; BAT, −2%), and night sweats (RUX-N, −100%; RUX-R, −97%; BAT, 4%) were also greater among RUX-R and RUX-N pts than BAT pts. RUX-N and RUX-R pts were also more likely to consider their symptoms to be “much improved” or “very much improved” on the PGIC compared with BAT pts (RUX-N, 57%; RUX-R, 74%; BAT, 13%). Conclusion: Among pts receiving RUX who did not achieve protocol-defined HCT control, the median time to subsequent phlebotomy eligibility was 1 year. In contrast, pts on BAT had a median time to subsequent phlebotomy eligibility of 21 wks. Furthermore, pts in the RUX arm achieved meaningful improvements in PV-related symptoms, regardless of meeting the endpoint of HCT control, while pts treated with BAT showed worsening or no improvement. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Reductions in JAK2 V617F Allele Burden with Ruxolitinib Treatment in Comfort-II, a Phase 3 Study Comparing the Safety and Efficacy of Ruxolitinib with Best Available Therapy (BAT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 802-802 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Francesco Passamonti ◽  
Haifa Kathrin Al-Ali ◽  
Giovanni Barosi ◽  
Claire N Harrison ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Jak2 V617f ◽  
Advisory Board ◽  
Spleen Volume ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Allele Burden ◽  
Equity Ownership

Abstract Abstract 802 Background: Ruxolitinib is a potent oral JAK1 & JAK2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and quality of life compared with placebo (COMFORT-I) and best available therapy (BAT; COMFORT-II) for pts with or without the JAK2 V617F mutation. Change in JAK2 V617F allele burden (%V617F) as a metric of molecular response to treatment in JAK2 V617 F–positive pts was investigated as an exploratory endpoint. Previously, we reported allele burden reductions in pts receiving ruxolitinib in the COMFORT-II study and demonstrated a positive correlation with reduction in spleen volume after 24 and 48 wk of treatment (Vannucchi, et al. Haematologica.2012); here, we evaluate the correlation between changes in %V617F and spleen size reduction after 72 wk of ruxolitinib therapy. Methods: COMFORT-II is a randomized (2:1), open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib (n = 146) compared with BAT (n = 73) in pts with primary MF (PMF), post–polycythemia vera MF (PPV-MF), and post–essential thrombocythemia MF (PET-MF). Allele burden was measured from blood samples using allele-specific quantitative real-time polymerase chain reaction (qPCR) using the method outlined in Levine et al, 2006, using an Applied Biosystems ABI 7900 real-time PCR analyzer. Pts were stratified by absolute reduction in %V617F (< 10%, 10% to < 20%, ≥ 20%) and results were correlated with achievement and duration of a ≥ 35% reduction from baseline in spleen volume, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scans. Results: Overall, 110 (76%) pts in the ruxolitinib group and 49 (71%) pts in the BAT group were JAK2V617 F–positive at baseline. More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT at wk 48 (Table; 41% \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(2868\) \end{document} vs 5% \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(122\) \end{document}) and at wk 72 (40% \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(2153\) \end{document} vs 0). The majority of reductions ≥ 20% were gradual and progressive over the course of the study (Figure); 2 pts had rapid initial reductions in allele burden that were sustained over 72 wk, from absolute %V617F of 48% and 45% at baseline to < 10% at wk 72. The majority of patients who achieved a ≥ 20% reduction at wk 48 maintained their reduction at wk 72. Compared with wk 48, 4 additional pts were in the ≥ 20% group at wk 72: 1 pt achieved a > 20% reduction at wk 48 but the data were not available at the time of the 48-wk analysis, 2 pts did not have data at wk 48, and 1 pt achieved a 15% reduction at wk 48 that improved to a 21% reduction by wk 72. Among pts who achieved a ≥ 20% reduction in allele burden, 39% had PMF, 39% had PPV-MF, and 22% had PET-MF; this distribution was similar to that of the overall study population. In the ruxolitinib arm, significantly more pts with a ≥ 20% V617F reduction achieved a ' 35% reduction from baseline in spleen volume compared with pts with a < 10% reduction at both wk 48 (79% vs 30%) and wk 72 (69% vs 31%). Pts with a ≥ 20% reduction in allele burden maintained their spleen volume reductions from baseline out to 72 wk. In the 10% to < 20% group, a greater proportion of pts showed increases in spleen volume from nadir but spleen volumes still remained much reduced from baseline. Conclusions: Patients who received ruxolitinib had larger reductions in JAK2 V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the study and continued between wk 48 and 72 in some pts. In JAK2 V617 F–positive pts, reductions in %V617F were associated with spleen responses; in pts with a ≥ 20% reduction, spleen volume reductions were sustained out to 72 wk. These results, along with findings from COMFORT-I and the phase 1/2 study, suggest that ruxolitinib has the potential to alter the course of disease through a reduction in the burden of JAK2V671 F–mutated cells. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Sanofi: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Al-Ali:Sanofi Aventi: Consultancy, Honoraria; celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Sirulnik:Novartis: Employment. Stalbovskaya:Novartis: Employment, Equity Ownership. Squires:Novartis : Employment. Burn:Incyte: Employment, Equity Ownership. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cervantes:Bristol-Myers Squibb: Speakers Bureau; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Sanofi-Aventis: Advisory Board, Advisory Board Other; Novartis: AdvisoryBoard Other, Speakers Bureau. Barbui:Novartis: Honoraria. Gisslinger:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharma AG: Consultancy, Speakers Bureau. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.

Mutational Profile of Patients with Polycythemia Vera Treated with Ruxolitinib in the Phase III Controlled Response Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4087-4087
Author(s):  
Paola Guglielmelli ◽  
Annalisa Pacilli ◽  
Giada Rotunno ◽  
Alessandro Pancrazzi ◽  
Tiziana Fanelli ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Phase Iii ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Allele Burden ◽  
Response Trial

Abstract Background. The JAK1/2 inhibitor ruxolitinib (RUX) demonstrated clinical benefit compared with best available therapy (BAT) in patients (pts) with polycythemia vera (PV) in a phase 3 study (RESPONSE TRIAL) (NEJM 2015; 372:426). A reduction of JAK2 V617F allele burden of 12.1% from baseline at week (w)32 was observed in pts receiving ruxolitinib compared to BAT (1.2%). Conversely, no information was available about other mutations that may occur in some PV pts. Aim. To analyze the molecular landscape of PV pts enrolled in the RESPONSE trial specifically as regarded subclonal mutations. Methods: In the RESPONSE study, PV pts with intolerance or refractoriness to hydroxyurea, showing an enlarged spleen volume (SV) >450 ml and phlebotomy requirement, were randomized (1:1) to receive RUX (n = 110) or BAT (n = 112). After institutional approval and informed written consent, samples for genotyping were available in 150 cases (67.5% of total, 75 each RUX and BAT). Mutations in 22 genes (JAK1, JAK2, JAK3, EZH2, ASXL1, TET2, IDH1, IDH2, CBL, SRSF2, DNMT3A, NFE2, SOCS1, SOCS2, SOCS3, SH2B3, STAT1, STAT3, STAT5A, STAT5B, SF3B1, U2AF1) were analyzed in blood DNA at baseline and at the latest available sample by deep sequencing with Ion Torrent-PGM. CALR mutations were analyzed by capillary electrophoresis. JAK2 V617F allele burden was confirmed by RT-qPCR assays. Results. 149/150 patients had informative sequencing results (RUX, n = 74 and BAT, n = 75). Mutation frequency at baseline in RUX pts was: JAK2 V617F 97.3% (mean allele burden=83.7±20.0%); JAK2Exon12 1.3%; other mutations in JAK2 5.4%; JAK3 1.3%; ASXL1 4.0%; TET2 20.3%; EZH2 4.0%; CBL 1.3%; SH2B3 2.0%; SOCS1 2.7%; NFE2 2.7%; STAT5A 1.3%. No somatic variants were detected in CALR, JAK1, SRSF2, IDH1, IDH2, SOCS2, SOCS3, DNMT3, STAT1, STAT5B, SF3B1, U2AF1. These frequencies were comparable in BAT arm. One patient was un-mutated in all assessed genes. 28.4% and 8.1% of RUX and 32.0% and 8.0% in BAT pts had 1 and >2 subclonal mutations, respectively. The proportion of PV pts harboring at least 1 mutation in either ASXL1, EZH2, SRSF2, IDH1/2, was significantly lower (8.1% in RUX and 10.6% in BAT) compared to reference series of primary myelofibrosis pts (31%) as it was for those having >2 HMR mutations (0.0 in RESPONSE vs 7.4% in PMF) (Leukemia 2014;28:1804) The median duration of treatment corresponding to the latest available sample for analysis was 82.8w; at that time, 43 pts (58.1%) randomized to RUX achieved a JAK2 V617F allele burden reduction ≥10%, of which 15 (20.3%) had >50% reduction. Among the latter pts, the median allele burden was 83.7% at baseline, 84.9%, 55.1% and 44.3% at 1, 2, and 3 years. Three patients attained an allele burden below 5% (from 65.1%, 17.3% and 83.7% at baseline to 3.2%, 0.5% and 1.4%, respectively, at latest follow up). Of the 27 pts harboring subclonal mutations at baseline, 12 (44.4%) presented a reduction of mutational allele burden ≥10%: 4 in JAK2 (other than JAK2 V617F/exon 12 mutations), 4 in TET2, 3 in ASXL1 and 1 each in JAK3, EZH2 and SH2B3. In 10 of the 12 pts, comparable decreases in JAK2 V617F allele burden were observed, suggesting reduction of a single clone expressing both mutations. Conversely, in 5 pts (18.5%) the allele burden of a baseline TET2 clone at increased by ≥10% (range: 10-37%); of these, one had concurrent reduction of JAK2 V617F burden from 17.3 to 0.5, thereby suggesting two independent clones. Eight pts (29.6%) acquired new mutations: 3 in TET2, 3 in U2AF1, 1 in DNMT3A and 1 in IDH1. Among these, 4 pts had achieved a reduction ≥10% of JAK2 V617F allele burden (18.4%, 25.4%, 30.5% and 39.4%, respectively). Three pts (4.0%) progressed during treatment (2 myelofibrosis,1 acute leukemia); no novel acquired mutation in the 22 genes was observed in these pts. All 3 pts were homozygous for V617F (92.3%, 72.7% and 59.0%) and did not show appreciable changes of allele burden during treatment. Conclusions. The current study identifies mutations and mutational combinations at baseline and during follow up in a representative cohort of pts enrolled in RESPONSE trial and treated with Ruxolitinib. We observed progressive reduction of JAK2 V617F allele burden that in some cases was associated with concurrent reduction of subclonal mutations. Conversely, emergency of novel clones as observed in some pts, whose significance might be clarified by ongoing analysis of hydroxyurea and phlebotomy treated patients that will be presented at the meeting. Disclosures Mahtab: Novartis Pharma AG: Employment. Rodriguez:Novartis Pharma: Employment. Vannucchi:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Oral JAK2/IRAK1 Inhibitor Pacritinib Demonstrates Spleen Volume Reduction in Myelofibrosis Patients Independent of JAK2V617F Allele Burden

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1674-1674 ◽  
Author(s):  
Srdan Verstovsek ◽  
Bart L. Scott ◽  
Jason A Taylor ◽  
John Mascarenhas
Keyword(s):  
Retrospective Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Jak2 V617f ◽  
Spleen Volume ◽  
Jak Inhibitors ◽  
Phase 3 ◽  
Advisory Committees ◽  
Allele Burden ◽  
Allelic Burden

Introduction: The presence of a molecular driver mutation such as JAK2 V617F is a major criterion for diagnosing myeloproliferative neoplasms. JAK2 V617F allelic burden (percentage of cells harboring the mutation) has been associated with varying disease phenotypes and outcomes. Myelofibrosis (MF) with low allelic burden is associated with a myelodepletive phenotype, which includes shorter overall survival, anemia, leukopenia, and lesser degree of splenomegaly. Some JAK inhibitors utilized in patients with low allelic burden (<50%) may achieve smaller spleen volume reduction (SVR), therefore, treatment of the lower allelic burden population remains clinically challenging. Pacritinib is an oral JAK2/IRAK1 inhibitor with demonstrated efficacy based on SVR from two phase 3 studies in MF patients including those with severe thrombocytopenia (PERSIST-1 [P1] and PERSIST-2 [P2]). These studies were unique in that the combined P1/P2 median allelic burden is 47% as compared to other phase 3 studies of JAK2 inhibitors with a median allelic burden >80%. To better evaluate the impact of allelic burden on pacritinib-induced SVR in MF patients, a retrospective analysis was performed on the combined data from the P1 and P2 studies. Methods: Patients ≥18 years of age with primary or secondary MF, palpable splenomegaly ≥5 cm below the left costal margin, and DIPSS risk category of intermediate-1, intermediate-2, or high-risk were eligible for the studies. Patients with any baseline platelet count were eligible for P1, while P2 included only those with baseline counts ≤100,000/μL. Prior JAK inhibitor therapy was allowed in P2, but not P1. Patients in P1 received pacritinib 400 mg once daily (QD) or best available therapy (BAT); those in P2 received pacritinib 400 mg QD, pacritinib 200 mg twice daily (BID), or BAT. In both studies, BAT consisted of physician-selected treatments for MF (including symptom-directed treatment or watch and wait); treatment with ruxolitinib was allowed as BAT only in P2. The percentage of patients achieving ≥35% SVR at week 24 was a primary endpoint for both studies. This retrospective analysis assessed those patients with JAK2 V617F for possible relationship between allelic burden and SVR at 24 weeks. Results: JAK2 V617F allelic burden data were available for 363 patients that received pacritinib and 173 patients that received BAT. 19.6% of BAT subjects received ruxolitinib during study. Pacritinib demonstrated similar SVR across all allelic burden quartiles, including the lowest quartile. In contrast, SVR responses with BAT were more frequently observed in those patients with higher allelic burden (>75-100% quartile; Figure 1). The percentage of patients with ≥35% SVR was significantly higher with pacritinib compared with BAT for those with an allele burden ≤50% (allele burden >0-25%: pacritinib=18/86 [21%], BAT=0/46, P<0.001; allele burden >25-50%: pacritinib=14/91 [15%], BAT=0/33, P=0.020); there was no significant difference in the >50-75% (pacritinib=9/53 [17%], BAT=1/26 [4%], P=0.153) and >75-100% quartiles (pacritinib=14/72 [20%], BAT=5/49 [10%], P=0.209). Conclusions: Myelofibrosis (MF) with JAK2 V617F allelic burden <50% is associated with a myelodepletive phenotype and a worse prognosis. MF patients with low allelic burden may have a non-JAK mediated disease which could explain why other JAK inhibitors have been shown to be less effective in patients with low allelic burden. Pacritinib provides similar SVR across all levels of allelic burden, including levels <50% unlike BAT (which included ruxolitinib). This data suggests that pacritinib may provide benefit over a wider range of patients with MF compared to other JAK inhibitors. Disclosures Verstovsek: Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Scott:Celgene: Consultancy; Novartis: Consultancy; Agios: Consultancy; Incyte: Consultancy. Taylor:Baxalta: Research Funding; CTI BioPharma: Employment, Equity Ownership. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1504-1504
Author(s):  
Srdan Verstovsek ◽  
Andrew T. Kuykendall ◽  
Ronald Hoffman ◽  
Yelena Ginzburg ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Data Safety Monitoring Board ◽  
Publicly Traded ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Advisory Committees ◽  
To Receive

Abstract Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit &lt;45% at Week 0 prior to randomization. Subjects who meet the eligibility criteria will be stratified by ongoing PV therapy (TP only, TP+hydroxyurea, TP+ruxolitinib, TP+interferon, TP+other) and randomized 1:1 to treatment with rusfertide or placebo added on to the subject's ongoing PV therapy at Week 0. The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; 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; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; 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.

An Individual Patient Supply Program for Ruxolitinib for the Treatment of Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2844-2844
Author(s):  
Giovanni Barosi ◽  
Mohan Agarwal ◽  
Sonja Zweegman ◽  
Wolfgang Willenbacher ◽  
Sima Pakstyte ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Jak2 V617f Mutation ◽  
Phase 3 ◽  
Advisory Committees ◽  
The Us

Abstract Abstract 2844 Background: Myeloproliferative neoplasms, including PMF, PET-MF, and PPV-MF, are a group of clonal stem cell–derived diseases characterized by bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies (COMFORT-I and -II). Due to unmet medical need, rux has been made available through an individual patient supply program (IPSP) outside the US. Methods: Patients (pts) with PMF, PPV-MF, or PET-MF requiring treatment (as determined by their physician) and classified as high-, intermediate (int)-2–, or int-1–risk with an enlarged spleen were evaluated for eligibility on an individual basis by the sponsor, irrespective of JAK2 mutation status. The starting dose of rux was determined on the basis of baseline platelet count (15 or 20 mg twice daily for pts with platelet counts of 100–200 × 109/L and > 200 × 109/L, respectively) and can be adjusted for efficacy and safety. Dose changes during treatment, adverse events (AEs), and serious AEs (SAEs) are registered throughout the program. Results: To date, 1339 requests have been received from > 800 physicians in 48 countries, including locations in Europe, Latin America, the Middle East, and Asia. The baseline characteristics are shown in the Table for pts whose requests for access were approved (n = 1240). Drug resupply requests are received every ≈ 3 months. Follow-up information, based on the first resupply request, was available for 381/639 (60%) of the pts who were enrolled in the program prior to February 2012; 303 (80%) remain on rux therapy, 37 (10%) have discontinued, 11 (3%) died, and 30 (8%) did not initiate therapy. Spleen response was available for 247 pts (decreased, n = 201; unchanged, n = 39; increased, n = 7). Changes in constitutional symptoms were available for 203 pts (decreased, n = 151; unchanged, n = 49; increased, n = 3). In pts enrolled in the IPSP undergoing rux treatment, most pts who had a decrease in spleen length also had a decrease in symptoms. Dose-modification information was available for 259 pts, of whom 44 had dose increases and 89 had dose decreases. Reasons for dose modifications included efficacy (n = 28), safety (n = 69), and other reasons (n = 36). Safety information was available for 266 pts; 75 reported significant AEs or SAEs as determined by investigators. Enrolled pt characteristics are generally similar to those expected in the overall MF pt population. Thus far, the proportion of pts enrolled in the IPSP with the JAK2 V617F mutation (73%) is higher than that for the general MF population (50%-60%). This may reflect a misconception that JAK inhibition is primarily effective in pts who have the JAK2 V617F mutation, when in fact rux has demonstrated similar efficacy in both pt types in the phase 1/2 251 study and the two phase 3 COMFORT trials. This may also be reflected in the higher proportion of PPV-MF pts in the IPSP than in the general MF population (28% vs 10%-15%), of whom 95% are JAK2 V617 F–positive. Conclusions: Considerable requests for access to rux have been received through the IPSP, highlighting the need for an effective treatment in pts with a range of IPSS risk-assessment scores. The demographics of the IPSP pts are similar to those expected in the overall MF population. Responses and safety patterns observed in the IPSP appear to be comparable to those from the COMFORT trials. Disclosures: Off Label Use: Jakafi™ (ruxolitinib) is indicated in the United States for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. In Canada, JAKAVI ® is indicated for the treatment of splenomegaly and/or its associated symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. This abstract reports on a clinical study conducted outside the US including patients of all risk categories. All patients have provided written informed consent. Zweegman:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Raymakers:Novartis: Consultancy. Cantoni:CSL Behring Switzerland: Research Funding; Robapharm/Pierre Fabre Oncology Switzerland: Research Funding; Janssen-Cilag Switzerland: Consultancy; Novartis Oncology Switzerland: Consultancy, Research Funding. Modi:Novartis Pharmaceuticals Corporation: Employment. Khan:Novartis: Employment. Perez:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Gisslinger:AOP Orphan Pharmaceuticals AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Lavie:Novartis: Membership on an entity's Board of Directors or advisory committees. Harrison:Sanofi Aventis: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding.

Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 179-179 ◽  
Author(s):  
Gabriela M. Baerlocher ◽  
Elisabeth Oppliger Leibundgut ◽  
Christina Ayran ◽  
Martha Blaney ◽  
Bart Burington ◽  
...  
Keyword(s):  
Platelet Count ◽  
Maintenance Therapy ◽  
Progenitor Cells ◽  
Board Of Directors ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Jak2 V617f ◽  
Advisory Committees ◽  
Allele Burden ◽  
Prior Therapy

Abstract Abstract 179 Background: Myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), are driven by neoplastic progenitor cells. The JAK2 V617F mutation can be detected in approximately 50% of patients (pts) with ET, and the JAK2 V617F allele burden can be used to measure the treatment-induced molecular response (MR) over time. Telomerase is upregulated in neoplastic progenitor cells and sustains indefinite replication. Imetelstat is a first in class, potent, specific inhibitor of telomerase which selectively distributes to bone marrow and inhibits thrombopoiesis. In vitro studies demonstrate that imetelstat selectively inhibits spontaneous megakaryocytic colony-forming unit (CFU-Meg) growth from the blood of pts with ET but not from healthy individuals. Phase I studies have demonstrated that imetelstat inhibits telomerase activity in pts at doses of 7.5 mg/kg and above. Therefore, unlike conventional cytoreductive therapy and JAK2 kinase inhibitors, imetelstat may be uniquely able to selectively inhibit proliferation of neoplastic clonogenic cells in pts with ET and modify the biology and progression of the disease. Methods: A phase II study enrolled pts with ET who had failed or were intolerant to at least one prior therapy, or who refused standard therapy. Pts were treated with imetelstat 7.5 mg/kg or 9.4 mg/kg IV weekly. After attainment of best platelet response in the induction phase, maintenance dosing with imetelstat was commenced with dosing based upon platelet count. Primary endpoint was best overall hematologic response (HR) with complete response (CR) defined as platelet count <400 × 103/μl maintained for at least 4 consecutive weeks in the absence of new thromboembolic events. A key secondary endpoint was rate of MR in patients with JAK2 V617F molecular mutations. JAK2 V617F allele burden was measured by allele-specific quantitative real-time PCR with a limit of detection of 0.1%. CFU-Meg growth pre- and post-treatment and tolerability were also assessed. Results: As of July 9, 2012, 13 pts were treated. Median age was 60 yrs (range 21–83) with a median of 2 prior treatments (range 1–3). Median years since initial diagnosis were 5.8 (range 0.3 to 24.9) and initial platelet count was 809 × 103/μl (range 601 to 1359 × 103/μl). Best overall HR was 100%, with 11 of 13 pts achieving a confirmed CR after a median of 6.1 weeks (range 5.1 to 14.1 wks). Twelve of 13 pts remain on maintenance therapy (median time on study 26.1 weeks) and despite transient elevations of platelets above best response, pts continue to be responsive to imetelstat. Four pts have reached 1 year of therapy and continue to be treated with ongoing HR. Dosing frequency on maintenance therapy was generally reduced with time. A substantial decrease in JAK2 V617F allele burden was demonstrated in all 5 JAK2 V617F-positive pts (mean allele burden reduction of 82%; range of 59–94%, see table below). Four pts who were eligible for MR assessment by LeukemiaNetcriteria (initial JAKV617F allele burden >10%) reached molecular partial responses (PR): one pt after 12 weeks, which has been maintained through 1 year, and 3 other pts at 24, 36 and 48 weeks of therapy. One additional pt with JAK2 V617F levels of 4.8% prior to therapy has also had a 75% reduction after 12 weeks of treatment. A reduction in the spontaneous growth of CFU-Meg was also observed in the 2 pts tested, with 93% and 96% reduction from baseline, respectively. Long-term administration of imetelstat was generally well tolerated. Common adverse events reported on therapy were mild to moderate gastrointestinal toxicities, reductions in neutrophil counts, and fatigue. Conclusions: Imetelstat rapidly induces and maintains hematologic responses in pts with ET who have failed or are intolerant to conventional therapies. Importantly, substantial MR is observed in all JAK2 V617F-positive pts and inhibition of the neoplastic clonogenic growth ex-vivo is demonstrated. The reduction in JAK2 V617F allele burden and cytokine-independent growth of CFU-Meg suggests that imetelstat has a relatively selective inhibitory effect on the growth of the neoplastic clone(s) which drive ET and has the potential to modify the underlying biology of MPNs. Additional data will be presented from this ongoing study. Disclosures: Baerlocher: Geron Corporation: Research Funding. Oppliger Leibundgut:Geron Corporation: Research Funding. Ayran:Geron Corporation: Employment. Blaney:Geron Corporation: Employment. Burington:Geron Corporation: Employment. Morfeld:Geron Corporation: Employment. Odenike:Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reddy:Geron Corporation: Employment. Roeth:Geron Corporation: Research Funding. Stuart:OncoMed Pharmaceuticals: Consultancy; Geron Corporation: Consultancy, Employment.

Incidence and Characteristics of Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis in Thailand: A 5-Year Retrospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5563-5563
Author(s):  
Archrob Khuhapinant ◽  
Kamoltip Lertchaisataporn ◽  
Ployploen Phikulsod ◽  
Noppadol Siritanaratkul
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Jak Inhibitor ◽  
Vascular Events ◽  
Advisory Committees ◽  
V617f Mutation

Abstract Background: Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are members of myeloproliferative neoplasm group. They shared common features such as JAK2 V617F+ mutation, thrombosisor hemorrhage, progression to marrow fibrosis or acute leukemia. Objective: To study incidence and clinical characteristics of PV, ET and PMF with complications and treatment modalities in Thailand. Study Designs: Retrospective chart review Methods: All JAK2 V617F+ and V617F- mutation patients during 2008-2012 were reviewed for demographic data, diagnosis of PV, ET and PMF according to WHO 2008 criteria, complications and treatment. Results: 363 of 735 patients were 140 PV, 172 ET, 47 PMF and 4 MPN-U. 372 patients were excluded due to routine thrombotic workup (98), secondary erythrocytosis (97), reactive thrombocytosis (55), CML (26), HES/eosinophilia (24), MPN/MDS (3), others (69). In PV, JAK2 V617F+ and JAK2 exon 12 mutation patients were 106 and 2. PV showed male:female ratio of 85:55, mean age 57.7 year (11-86), mean hemoglobin 17.6 g/dl (6.7-24.6), and received aspirin (125), hydroxyurea (116), phlebotomy (84), clopidogrel (10), warfarin (7), anagrelide (6), busulfan (5) and each for interferon, oxymethalone, corticosteroid, and JAK inhibitor. Thrombosis:hemorrhage was 34:16. Myelofibrosis and AML transformation were 7 and 2. In ET, JAK2 V617F+ patients were 121. ET showed male:female ratio of 83:89, mean age 59.45 year (14-91), mean platelet count 924,168/mm3 (283,000-2,235,000), and received aspirin (140), hydroxyurea (139), anagrelide (47), warfarin (11), clopidogrel (7), erythropoietin (6), oxymethalone (3), busulfan (3), corticosteroid (2), interferon (1) and splenectomy (1). Thrombosis:hemorrhage was 52:16. Myelofibrosis and AML transformation were 4 and 1. In PMF, JAK2 V617F+ patients were 32. PMF showed male:female ratio of 21:26, mean age 62.2 year (23-81), mean hemoglobin 8.6 g/dl (3.7-15.5), mean subcostal splenic size 10 cm (1-26) and received hydroxyurea (26), erythropoietin (16), corticosteroid (10), oxymethalone (8), JAK inhibitor (7), transfusion dependency (6), aspirin (3), warfarin (2) and each for anagrelide, thalidomide, splenectomy and allogeneic transplantation. Thrombosis:hemorrhage was 4:5. AML transformation was 4. In multivariate analysis, previous thrombosis, clopidogrel use, splenomegaly, alcohol use and JAK2 V617F+ were independent risk factors for thrombosis. Conclusion: PV, ET and PMF carry high risk for vascular events. Disclosures Khuhapinant: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Phikulsod:Novartis: Honoraria. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding.

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