The Use of Erythropoietic-Stimulating Agents (ESAs) with Ruxolitinib in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), and Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Abstract Abstract 2838 Background: Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 COMFORT studies in MF patients (pts). Consistent with rux's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable leading to discontinuation in only 1 pt. In clinical practice, anemia can be managed with ESAs, which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of rux in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of rux. This post hoc analysis evaluated the safety and efficacy of rux in pts receiving concomitant ESA in COMFORT-II. Methods: COMFORT-II is an open-label, randomized, multicenter study. Pts were randomized (2:1) to receive rux 15 or 20 mg bid or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa, epoetin nos), although not prohibited, was discouraged for pts randomized to rux because ESAs can increase spleen size, which could confound efficacy analyses. Spleen volume was assessed by MRI or CT every 12 wk. The rate of transfusions was calculated as the number of units transfused per exposure duration (typically 12 wk). Results: Concomitant use of ESA was reported for 13 (PMF, n = 10; PET-MF, n = 2; PPV-MF, n = 1) of the 146 pts who were treated with rux (darbepoetin alfa, 2% [n = 3]; epoetin alfa, 6% [n = 9]; epoetin nos, < 1% [n = 1]). The median exposure to rux was similar for pts who received an ESA (+ESA group; 500 d) vs those who did not receive ESA (468 d), and the median dose intensity of rux was the same for each group (30 mg/d). As shown in the table, 8 pts (62%) had no change, 2 pts (15%) had a decrease, and 3 pts (23%) had an increase in the rate of packed red blood cell (PRBC) transfusions per mo after the first administration of ESA compared with 12 wk before ESA use. Six wk prior to the first administration of ESA, 10/13 pts (77%) had grade 3/4 hemoglobin abnormalities; however, 6 wk after the administration of ESA, most pts' conditions improved to grade 2 (7/13 [54%]). The majority of pts (77%) did not have any change in their reticulocyte counts within the 6 wk before and after the administration of ESA; 1 pt (8%) had a marked increase; for 2 pts (15%), the data were not available. The AEs reported in pts who received ESA were similar to those previously reported with rux. Serious AEs were reported for 8 pts in the +ESA group (3 events in 2 pts that were possibly related to study drug). Within the last assessment prior to and the first assessment after the first administration of ESA, 7/9 evaluable pts (78%) had spleen volume reductions. Conclusions: In this analysis, although the sample size is small, rux was generally well tolerated in pts who received ESA, and the tolerability profile of rux was similar to that reported in previous studies. Rux-treated pts who received ESA generally did not have any change in their transfusion rates, but the rate of grade 3/4 hemoglobin abnormalities decreased within 6 wk of the first administration of ESA, suggesting that the use of ESA in combination with rux was beneficial in some pts. ESA did not appear to affect the efficacy of rux concerning spleen size reduction. The use of ESA for the treatment of anemia is common in clinical practice, and further analyses in combination with rux in this pt population are warranted. Disclosures: McMullin: Bristol Myers Squibb: Honoraria; Shire: Honoraria; Novartis: Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. Recher:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, travel to ASH, travel to ASH Other; sunesis: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. 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. Al- Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria.

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Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v120.21.801.801 ◽

2012 ◽

Vol 120 (21) ◽

pp. 801-801 ◽

Cited By ~ 21

Author(s):

Francisco Cervantes ◽

Jean-Jacques Kiladjian ◽

Dietger Niederwieser ◽

Andres Sirulnik ◽

Viktoriya Stalbovskaya ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Extension Phase ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian: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; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v128.22.3110.3110 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3110-3110 ◽

Cited By ~ 6

Author(s):

Srdan Verstovsek ◽

Vikas Gupta ◽

Jason R. Gotlib ◽

Ruben A. Mesa ◽

Alessandro M. Vannucchi ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Background:The Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been evaluated for patients with MF in the phase 3 COMFORT studies. In both trials, ruxolitinib prolonged OS, reduced splenomegaly, and improved MF-related symptoms and quality of life compared with controls. Here, we report the results of an exploratory pooled analysis of OS in the COMFORT studies at 5 years of follow-up. Methods: The double-blind COMFORT-I trial and the open-label COMFORT-II trial were randomized phase 3 studies that evaluated the safety and efficacy of ruxolitinib in patients with intermediate-2 (int-2) or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). The comparator was placebo in COMFORT-I and best available therapy (BAT) in COMFORT-II. The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline platelet counts (100-200 and >200 × 109/L, respectively); dose modifications were permitted for safety and efficacy. Patients were allowed to cross over to ruxolitinib from the control arm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-defined progression events; crossover was mandatory following treatment unblinding in COMFORT-I. OS was a secondary endpoint in both studies and was evaluated in an intent-to-treat (ITT) analysis using a Cox proportional hazard model that estimated the treatment effect stratified by clinical trial and International Prognostic Scoring System (IPSS) risk. The crossover-corrected treatment effect was estimated using a rank-preserving structural failure time (RPSFT) method. Results: Overall, 528 patients were randomized: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or BAT (n=73). All ongoing patients in the control arms crossed over to ruxolitinib by the 3-year follow-up. Patient populations were similar between the two trials and their details were previously published. In the combined ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had int-2 risk MF based on IPSS criteria. At the 5-year ITT analysis, 128 patients (42.5%) died in the ruxolitinib group compared with 117 (51.5%) in the control group. The risk of death was reduced by 30% with ruxolitinib compared with control (median OS: ruxolitinib, 63.5 mo; control, 45.9 mo; HR, 0.70; 95% CI, 0.54-0.91; P=0.0065; Figure A). After correcting for crossover using RPSFT, OS advantage was more pronounced for patients originally randomized to ruxolitinib (median OS: ruxolitinib, 63.5 mo; control, 27 mo; HR, 0.35; 95% CI, 0.23-0.59; Figure B). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged survival compared with control (median OS: ruxolitinib, 63.5 mo; control, 28.3 mo; HR, 0.53; 95% CI, 0.36−0.78; P=0.0013; Figure C). Among all patients treated with ruxolitinib, those with lower-risk disease had longer survival compared with those with high-risk disease (median OS: int-2, not reached [estimated, 102 mo]; high-risk, 50 mo; HR, 2.86; 95% CI, 1.95-4.20; P<0.0001; Figure D). In a subgroup analysis, OS favored ruxolitinib compared with placebo for patients with int-2 or high-risk MF (data not shown). At 5 years, median OS appeared to favor patients with int-2 (n=58) or high-risk (n=89) PMF who were originally randomized to ruxolitinib compared with historical (Cervantes et al; J Clin Oncol 30:2981-2987) controls (int-2 PMF, not reached [estimated, 70 mo] vs 48 mo; high-risk PMF, 34 vs 27 mo); OS was longer among patients with int-2 vs high-risk PMF (P=0.0003). Subgroup analyses showed that ruxolitinib provided an OS advantage regardless of age (>65 or ≤65 y), sex, disease type (PMF, PPV-MF, PET-MF), risk status (int-2 or high), JAK2V617F mutation status, baseline spleen volume (>10 or ≤10 cm), anemia, white blood cell count (>25 or ≤25 × 109L), or platelet count (>200 or ≤200 × 109/L). Conclusion: Long-term treatment with ruxolitinib up to 5 years prolonged survival in patients with MF compared with BAT or placebo. Corrections for patients who crossed over to ruxolitinib suggested that the separation between ruxolitinib and control OS curves was primarily caused by a delay in ruxolitinib treatment. The results suggest that earlier treatment with ruxolitinib may provide a greater survival advantage for patients with MF. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mesa:Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; CTI: Research Funding; Promedior: Research Funding; Galena: Consultancy; Gilead: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: 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. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Dong:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

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A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽

10.1182/blood.v128.22.390.390 ◽

2016 ◽

Vol 128 (22) ◽

pp. 390-390 ◽

Cited By ~ 8

Author(s):

Mark A. Schroeder ◽

H. Jean Khoury ◽

Madan Jagasia ◽

Haris Ali ◽

Gary J. Schiller ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Janus Kinase ◽

Cell Transplant ◽

Employment Equity ◽

Advisory Committees ◽

Daily Dose ◽

Equity Ownership ◽

Grade 3 ◽

Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

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

Blood ◽

10.1182/blood-2019-123406 ◽

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 >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.

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Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽

10.1182/blood.v118.21.814.814 ◽

2011 ◽

Vol 118 (21) ◽

pp. 814-814 ◽

Cited By ~ 8

Author(s):

Paul G. Richardson ◽

Melissa Alsina ◽

Donna M. Weber ◽

Steven E. Coutre ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Treatment Phase ◽

Employment Equity ◽

Advisory Committees ◽

Overall Response ◽

Equity Ownership ◽

Grade 3 ◽

Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

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Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽

10.1182/blood.v120.21.4070.4070 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4070-4070 ◽

Cited By ~ 1

Author(s):

Ravi Vij ◽

Craig C. Hofmeister ◽

Paul G. Richardson ◽

Sundar Jagannath ◽

David S. Siegel ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Advisory Board ◽

Prior Exposure ◽

Employment Equity ◽

Advisory Committees ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: 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. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood.v124.21.1840.1840 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1840-1840 ◽

Cited By ~ 1

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.

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Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA)

Blood ◽

10.1182/blood.v126.23.679.679 ◽

2015 ◽

Vol 126 (23) ◽

pp. 679-679 ◽

Cited By ~ 32

Author(s):

Giovanni Martinelli ◽

Hervé Dombret ◽

Patrice Chevallier ◽

Oliver G. Ottmann ◽

Nicola Goekbuget ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Pcr Amplification ◽

Employment Equity ◽

Advisory Committees ◽

T315i Mutation ◽

Equity Ownership ◽

Grade 3

Abstract Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity. Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57). We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI. Methods. Eligible adult pts (≥18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib. All pts had to have >5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2. Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter). The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints. Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10-5. Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation). 53% of pts were men. Median (range) age was 55 (23-78) years (≥65 years, 27%). Ten pts (22%) had a BCR-ABL gene with T315I mutation. All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy. 38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT. Efficacy outcomes for key endpoints are shown in the table. 16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1. The patient who never received 2+ generation TKI did not respond to treatment. 12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response. Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response. Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response). One patient died in CR post alloHSCT. Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months). Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%). Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator. Three pts discontinued because of AEs. Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2). 21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption. Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity. AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab. Table 1. Table 1. Disclosures Martinelli: Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Bayer: Equity Ownership; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Erytech: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Gilead Sciences: Consultancy; Sanofi: Equity Ownership; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Fielding:Amgen: Consultancy, Honoraria. Sterling:Amgen: Employment, Equity Ownership. Benjamin:Amgen: Employment, Equity Ownership. Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding.

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Updated Results from an Open-Label, Multicenter, Expanded Treatment Protocol (ETP) Phase (Ph) 3b Study of Ruxolitinib (RUX) in Patients (Pts) with Polycythemia Vera (PV) Who Were Hydroxyurea (HU) Resistant or Intolerant and for Whom No Alternative Treatment (Tx) Was Available

Blood ◽

10.1182/blood-2018-99-111479 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1774-1774 ◽

Cited By ~ 2

Author(s):

Lynda Foltz ◽

Gian-Matteo Pica ◽

Hacene Zerazhi ◽

Jan Van Droogenbroeck ◽

Sorin Visanica ◽

...

Keyword(s):

Cell Carcinoma ◽

Board Of Directors ◽

Research Funding ◽

Blood Count ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Medical Need ◽

Equity Ownership ◽

Grade 3

Abstract BACKGROUND Few Tx options are available for pts with inadequately controlled PV. European LeukemiaNet defined resistance/intolerance was seen in ≈25% pts treated with HU (Alvarez-Larran et al, 2012). In the HU-resistant/intolerant PV pts evaluated in the pivotal RESPONSE study (week [wk] 208), RUX was well tolerated and superior to standard therapy in achieving durable hematocrit (HCT) control, hematologic response, and spleen size and symptom reductions. This Ph 3b ETP study was planned to provide RUX Tx to HU-resistant/intolerant PV pts, who have no alternative standard Tx, and are not eligible for any ongoing clinical studies. Results from wk 24 data cutoff of this study (Devos et al) were presented at ASH 2017. Here, we report consolidated findings from the ETP study at wk 96 data cutoff (Dec 29, 2017 [final database lock]) to further support the use of RUX in this pt population with an unmet medical need. METHODS RUX Tx was initiated at a starting dose of 10 mg bid (could be titrated to a maximum of 25 mg bid). Visits were scheduled every 4 wks until wk 24 and every 12 wks thereafter; final analysis was done when all pts had been followed for 30 days after discontinuation of Tx or completion of Tx per protocol (transitioned to commercial RUX or until Dec 31, 2017, whichever date occurred first). The primary endpoint was to assess the safety of RUX. Secondary endpoints included change in HCT level, change in spleen length, and pt-reported outcomes (change in MPN-SAF TSS score). HCT control at wk 24 was defined by absence of phlebotomy (PBT) eligibility starting at wk 8 and continuing through wk 24, with no more than 1 PBT eligibility occurring after first dose date and prior to wk 8. PBT eligibility was defined by confirmed HCT >45% (at least 3 percentage points higher than HCT at baseline [BL]), or confirmed HCT >48%. Blood count remission at wk 24 was defined by HCT control, and white blood cell count <10 × 109/L, and platelet count ≤400 × 109/L. RESULTS At data cutoff, 161 pts with PV were enrolled (BL characteristics similar to that presented at ASH 2017). End of Tx was reported for all 161 pts: Tx duration completed per protocol (141 pts), adverse event (AE [12 pts]), consent withdrawal (3 pts), pt decision (2 pts), disease progression (2 pts), and death (due to accident [1 pt]). The median exposure was 25.1 wks (range, 0.4-104.7), and median dose intensity of RUX was 20.0 mg/day (range, 6.7-47.7). AEs (regardless of study drug relationship) led to dose adjustment/interruption in 37.9% pts and study drug discontinuation in 8.7% pts. The most common hematologic AEs (rate=number of events per 100 pt-year exposure [pt-year exposure=110.2]; all grades]) included anemia (31.8) and thrombocytosis (10.0), while headache (24.5), diarrhea (14.5), constipation (12.7), and fatigue (12.7) were the most frequent non-hematologic AEs. For all reported grade 3/4 AEs, exposure-adjusted rate was less than 3. Thromboembolic events (all grade; Standardized MedDRA Query) were reported in 3 pts. Disease progression was reported in 4 pts (myelofibrosis=3 pts; acute myeloid leukemia=1 pt). The incidence of other neoplasms (regardless of study drug relationship) was low (leiomyoma, malignant melanoma, marginal zone lymphoma, renal cancer [1 pt each]; squamous cell carcinoma [2 pts]; basal cell carcinoma [3 pts]). Infections (all grades) were reported in 57 pts (grade 3/4 in 5 pts). At wk 24, 73 pts (45.3% [95% CI, 37.5%-53.4%]) achieved HCT control; hematologic remission was seen in 29 pts (18% [95% CI 12.4%-24.8%]). Changes in blood count parameters over time are shown in Fig. 1. In evaluable pts (N=105), use of PBT decreased from BL (39 PBTs between screening and BL) to end of Tx (5 PBTs in 12 wks prior). Best spleen response from BL for each pt by wk 96 is shown in Fig. 2. At least 50% spleen length reduction was seen in 86.7% (78/90) of pts from BL at any time in the study. Overall, 33.8% (46/136) of pts had ≥50% reduction in MPN-SAF TSS from BL at the end of Tx. CONCLUSION The observed safety profile of RUX in the ETP study was consistent with that of the RESPONSE studies. Efficacy results were close to the observed values in the RESPONSE studies. RUX Tx resulted in HCT control, hematologic remission, spleen response, and symptom reduction in this HU-resistant/intolerant pt population in need of a viable Tx option. Safety and efficacy findings from this ETP study support the use of RUX for pts with inadequately controlled PV, an unmet medical need. Disclosures Foltz: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. de Almeida:Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ranta:Novartis: Consultancy. Cartes:Novartis: Honoraria. Kiladjian:Celgene: 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; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chrit:Novartis: Employment, Equity Ownership. Yin:Novartis: Employment. Morando:Novartis: Employment, Equity Ownership. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

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Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study

Blood ◽

10.1182/blood.v128.22.1949.1949 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1949-1949 ◽

Cited By ~ 3

Author(s):

Hans Michael Kvasnicka ◽

Juergen Thiele ◽

Carlos E. Bueso-Ramos ◽

William Sun ◽

Ahmad Naim ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

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Abstract Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

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