An Ethnographic Investigation Tracking the Experience of Chronic Myeloid Leukemia (CML) Patients on Tyrosine Kinase Inhibitor (TKI) Therapies

Abstract Abstract 394 Background: The advent and approval of TKIs has dramatically improved the life expectancy of patients with CML. As treatment innovation has transformed CML into a chronically managed disease, we examined the impact of these changes on patients with CML in order to offer recommendations for healthcare providers (HCPs) to better support patients with CML. Method: 50 patients with CML from Brazil, France, Germany, Russia and Spain were included in this ethnographic investigation including: patients within 18 months of diagnosis and on frontline imatinib therapy (n = 20), patients with ongoing frontline treatment (> 18 months to 7 years, n = 20), and patients who were switched to second- or third-line TKI therapies (n = 10). Patients in all 5 countries participated in a 2.5-hour in-home interview, and patients in Brazil and France completed 7-day photo journals and an optional telephone debrief interview. Patients were asked to discuss and write about their perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and their relationship with HCPs. Result: This global ethnographic investigation generated a 5-stage, patient-centered model emphasizing emotions and experiences throughout the diagnosis, treatment and management of their disease: crisis, hope, adaption, normalcy, and uncertainty. Depending upon their circumstances, these experiential stages were found to be abbreviated or prolonged and influenced by patients having differentiating levels of knowledge about their disease, comfort levels with the treatment and/or their HCPs, as well as different degrees of optimism about their treatment and long-term prognosis. In addition, the study results showed that patients cycle through the various stages of the model throughout the course of their disease. The crisis phase occurred at diagnosis and tended to resolve upon HCP reassurance of the availability of successful treatments. Hope followed crisis when patients were educated about their disease and its treatments and responded to initial therapy. Adaption involved patients adjusting to any physical changes wrought by the disease, treatments, and associated adverse events. As well, they began to psychologically come to terms with the long-term nature of their disease and develop their drug-taking routines and compliance pattern. As patients attained stability in their disease and adapted to changes, a ‘new’ normal returned and patients began to refocus their life away from the disease back to social, work, and family matters. The uncertainty stage was found to be associated with drug resistance, disease progression, newly occurring adverse events, or due to limitations around access to therapy because of public health regulations or personal financial issues. While uncertainty arose for multiple reasons and could occur at any time after patients had advanced through the 4 preceding phases, patients who went through stages of uncertainty most often cycled back to phases of adaption or normalcy once the issues were resolved. Conclusions: Here, we have identified 5 common patient experience stages and we provide recommendations based on patient research for the management of CML. This investigation suggests that HCPs can help patients move through the early stages of crisis and hope by providing reassurance, along with information and resources regarding drug efficacy and product differentiation, while explaining the importance of speed and depth of responses. Once in the adaption/normalcy stages, HCPs should set expectations for the risk/benefits of long-term chronic drug therapy and long-term disease monitoring and continue to support patient compliance and adherence programs while helping patients achieve and maintain a normal lifestyle. Disclosures: Guilhot: Novartis: Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Zernovak:Novartis: Employment, Equity Ownership. Macdonald:Novartis: Consultancy. Shapiro:Novartis: Consultancy.

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Safety of Lenalidomide (LEN) 10mg in Non-Del(5q) Versus Del(5q) in the Treatment of Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS): Pooled Analysis of Treatment-Emergent Adverse Events (TEAEs)

Blood ◽

10.1182/blood.v126.23.2880.2880 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2880-2880 ◽

Cited By ~ 1

Author(s):

Antonio Almeida ◽

Valeria Santini ◽

Stefanie Gröpper ◽

Anna Jonasova ◽

Norbert Vey ◽

...

Keyword(s):

Adverse Events ◽

Lower Risk ◽

Research Funding ◽

Pooled Analysis ◽

Employment Equity ◽

Pooled Data ◽

Starting Dose ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg. Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%. Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies. Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. Disclosures Almeida: Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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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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Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a

Blood ◽

10.1182/blood.v128.22.1413.1413 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1413-1413

Author(s):

Barbara Konkle ◽

K John Pasi ◽

David J Perry ◽

Johnny Mahlangu ◽

Savita Rangarajan ◽

...

Keyword(s):

Treatment Group ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Dosing Intervals

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylaxis with conventional FVIII products usually requires frequent intravenous injections (3-4 times/week). The safety, efficacy, and prolonged half-life of rFVIIIFc in previously treated adults and adolescents (≥12 y) with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01181128, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in study participants as of the second interim data cut (8 Dec 2014). Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the second interim data cut 8 Dec 2014) for subjects treated with ≥1 dose of rFVIIIFc. A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on Day 1 and 50 IU/kg on Day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment (ET). Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or ET groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) group. Subjects could change treatment groups at any point during ASPIRE. Efficacy analyses were performed using data summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL identified and confirmed on 2 separate samples drawn approximately 2-4 weeks apart and performed by the central laboratory as measured by the Nijmegen-modified Bethesda assay), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic consumption and dosing interval compared to pre-A-LONG (prestudy). Results: Of 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE; at the time of this second interim data cut, 97 subjects were ongoing in ASPIRE, 40 subjects had completed the study, and 13 subjects withdrew. Cumulatively, subjects had 38,662 rFVIIIFc exposure days (EDs), inclusive of surgery. As of this second interim data cut (8 Dec 2014), no inhibitors were observed; the type and incidence of adverse events (AEs) observed were typical of previous hemophilia A populations studied. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were lower with rFVIIIFc compared with prestudy FVIII for subjects on prestudy prophylaxis or ET (Figure). In the IP group, the median (interquartile range [IQR]) spontaneous ABRs in Years 1, 2, and 3 on-study were 0.0 (0.0, 2.0), 0.0 (0.0, 1.0), and 0.0 (0.0, 1.0), respectively. In the WP treatment group, the median (IQR) spontaneous ABRs in Years 1, 2, and 3 on-study were 1.0 (0.5, 3.0), 0.5 (0.0, 2.1), and 0.0 (0.0, 1.0), respectively. Overall, 88.5% and 97.0% of bleeding episodes were controlled with 1 or ≤2 intervenous injections, respectively. Among subjects treated with FVIII prophylaxis prestudy (n = 79), 86% were dosed at least 3 times/week prestudy. Compared with prestudy dosing intervals, dosing intervals with rFVIIIFc were extended in 96.2% of subjects, were shortened in 2.5% of subjects, and were unchanged in 1.3% of subjects. The median (IQR) total weekly prophylactic consumption was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.8] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE confirm long-term safety, with no inhibitors observed in any subject. Low median ABRs were maintained, and rFVIIIFc demonstrated efficacy in the prevention and treatment of bleeding episodes. Prophylactic dosing intervals were extended, without an increase in median prophylactic factor consumption. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Pasi: Biogen: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Bayer: Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Consultancy, Research Funding; Baxalta: Consultancy. Rangarajan:Baxter: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Biogen: Consultancy; Biotest: Research Funding; Grifols: Consultancy, Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding. Brown:Baxter: Consultancy; Biogen: Consultancy; Novo Nordisk: Consultancy. Hanabusa:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pabinger:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Glazebrook:Biogen: Employment, Equity Ownership. Lethagen:Sobi: Employment. Jackson:Biogen: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Baxter: Consultancy, Research Funding.

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Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Blood ◽

10.1182/blood.v124.21.1708.1708 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1708-1708 ◽

Cited By ~ 8

Author(s):

Ajay K. Gopal ◽

Brad S. Kahl ◽

Sven de Vos ◽

Nina D. Wagner-Johnston ◽

Stephen J. Schuster ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Employment Equity ◽

Non Hodgkin Lymphoma ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3 ◽

Systemic Therapies

Abstract Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes double-refractory to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease >7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p<.0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

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Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽

10.1182/blood-2019-127435 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Uwe Platzbecker ◽

David P. Steensma ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: 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; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, 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; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials

Blood ◽

10.1182/blood.v124.21.4552.4552 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4552-4552 ◽

Cited By ~ 7

Author(s):

Michael J. Mauro ◽

Jorge E. Cortes ◽

Andreas Hochhaus ◽

Michele Baccarani ◽

Timothy P. Hughes ◽

...

Keyword(s):

Research Funding ◽

Progressive Disease ◽

Phase 1 ◽

Efficacy And Safety ◽

Employment Equity ◽

Long Term Follow Up ◽

T315i Mutation ◽

Equity Ownership

Abstract Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in >1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Table. Responses at Any Time in Ponatinib Treated Pts with T315I Mutation Phase 1 PACE Phase 1 and PACE Pooled n (%) n (%) n (%) CP-CML N=12 N=64 N=76 MCyR 11 (92) 46 (72) 57 (75) CCyR 10 (83) 45 (70) 55 (72) MMR 9 (75) 37 (58) 46 (61) MR4 7 (58) 25 (39) 32 (42) MR4.5 4 (33) 21 (33) 25 (33) AP-CML N=1 N=18 N=19 MaHR 0 11 (61) 11 (58) BP-CML N=2 N=24 N=26 MaHR 0 7 (29) 7 (27) Ph+ ALL N=4 N=22 N=26 MaHR 2 (50) 8 (36) 10 (38) Disclosures Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

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Role of hnRNP K and Interacting mRNAs in Pathogenesis of AML with 9q Deletion

Blood ◽

10.1182/blood-2018-99-114699 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1531-1531

Author(s):

Kerstin Rahn ◽

Isabel Naarmann-de Vries ◽

Yvonne Sackmann ◽

Felicitas Klein ◽

Antje Ostareck-Lederer ◽

...

Keyword(s):

Research Funding ◽

Transcriptional Control ◽

Mrna Level ◽

Rna Seq ◽

Employment Equity ◽

Knock Out ◽

Hnrnp K ◽

Qpcr Analysis ◽

Equity Ownership ◽

The Impact

Abstract Introduction: Acute myeloid leukemia (AML) is characterized by heterogeneous cytogenetic and molecular aberrations. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of AML patients. In about 24% of the cases, del(9q) is observed as sole karyotypic abnormality, while in the remaining 76%, it is associated with a t(8;21) translocation or other aberrations. Among all del(9q) AML cases, 36%-50% exhibit an additional t(8;21), whereas 7%-14% of AML cases with t(8;21) show del(9q) as an additional aberration. A commonly deleted region (CDR) of del(9q) was defined and further analysis specified a minimally deleted region (MDR) composed of seven annotated genes (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2) (Kronke J et al. Blood. 2013). However, the function of these genes and their impact on the pathogenesis of AML remain elusive. A recent study demonstrated that reduced expression of the HNRNPK gene product can contribute to leukemogenesis in AML (Gallardo M, Cancer Cell. 2015). The multifunctional protein hnRNP K interacts with other proteins, DNA and RNA, to modulate gene activity and gene expression on different levels. For example, hnRNP K not only regulates SRC gene transcription, but as well SRC mRNA translation and the activity of c-Src kinase. In the context of AML, hnRNP K was shown to interact with the mRNAs encoding C/EBPa (CEBPA) and p21 (CDKN1A). We analyzed a cohort of 31 del(9q) AML patients in order to further analyze the deleted region and to analyze the impact of HNRNPK deletion on leukemogenesis. Methods: 31 del(9q) patients were used for the characterization of the deleted region. mRNA level (determined by RT-qPCR analysis) and clinical parameters were compared with a cohort of 24 normal karyotype (NK) AML patients. HnRNP K immunoprecipitation was combined with RNA-Seq, a whole transcriptome shotgun sequencing application based on next generation sequencing and validated by RT-qPCR analysis. CRISPR-Cas9 genome editing has been applied to functionally characterize the impact of post-transcriptional control by hnRNP K in pathogenesis of AML. Results: Our analysis confirmed the MDR in a cohort of 31 AML del(9q) patients. Survival of patients and clinical parameters were not correlated with deletion size, further supporting the importance of the MDR, while other deleted genes seem to be less important for leukemogenesis. As demonstrated by qPCR analysis, the mRNA level of HNRNPK and other genes located in the MDR was reduced in patients carrying a del(9q) compared to NK patients. To further dissect a potential function of hnRNP K in AML del(9q), we characterized hnRNP K interacting mRNAs in the AML cell line KG-1a. Therefore, hnRNP K was immunoprecipitated from cytoplasmic extracts of KG-1a cells and interacting RNAs were identified by RNA-Seq analysis. This analysis revealed that 1076 RNAs are potentially associated with hnRNP K, among them the C/EBPa mRNA. Panther Protein Class analysis identified a high number of transcripts encoding nucleic acid binding proteins, mainly transcription factors. KG-1a cell lines harboring either a complete knock out of hnRNP K or a deletion of the RNA-binding KH-domain are currently generated by CRISPR-Cas9 genome editing to functionally analyze the impact of hnRNP K-mediated post-transcriptional control in AML. Conclusion and Outlook: The deletion of seven genes (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2) in the MDR is indispensable, indicating a crucial function for the development of AML del(9q). Among them HNRNPK seems to be a particularly important factor in this process. The identification of hnRNP K interacting RNAs provides the basis to further improve our insight in molecular mechanisms, which drive the pathogenesis of AML del(9q). HNRNPK knock out cell lines will be used to analyze the effect of HNRNPK deletion on post-transcriptional control of identified target genes. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Rollig:Janssen: Research Funding; Bayer: Research Funding. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership.

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Long-Term Outcomes of Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disorder (EBV+PTLD) Following Solid Organ (SOT) or Allogeneic Hematopoietic Cell Transplants (HCT) Treated with Tabelecleucel on an Expanded Access Program

Blood ◽

10.1182/blood-2019-124904 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4071-4071 ◽

Cited By ~ 1

Author(s):

Susan Prockop ◽

Ran Reshef ◽

Donald E. Tsai ◽

Nancy Bunin ◽

Rolla Abu-Arja ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Ventilatory Support ◽

Solid Organ ◽

Employment Equity ◽

Cell Transplants ◽

Equity Ownership ◽

Epstein Barr

Background: Patients (pts) undergoing solid organ (SOT) or allogeneic hematopoietic cell transplants (HCT) are at risk for developing Epstein-Barr (EBV) virus-driven post-transplant lymphoproliferative disorder (PTLD). Pts with EBV+PTLD not responding to rituximab ± chemotherapy after SOT or HCT have poor outcomes. Many SOT and HCT recipients are also not good candidates for aggressive chemotherapy regimens. There is an unmet need for effective and well tolerated therapies in this patient population. Tabelecleucel (tab-cel®) is an investigational, off-the-shelf, allogeneic, EBV-specific, T-cell immunotherapy generated from healthy donors, which functions through native, endogenous T-cell receptors (TCRs) and HLA restrictions. Tabelecleucel is selected for an individual patient from an existing library, based on HLA restriction and matching. Here, we report long-term study results from US centers using tabelecleucel for subjects with EBV+PTLD following HCT or SOT. Methods: Subjects with EBV+PTLD after HCT (n=14) or SOT (n=12) were treated with tabelecleucel on Atara's expanded access program (EAP; ATA129-EBV-201, NCT02822495, ongoing). Subjects received tabelecleucel matched by ≥ 2/10 HLA alleles, including ≥1 HLA allele through which tabelecleucel exerts cytotoxicity (HLA restriction). Key inclusion criteria were: presence of biopsy-proven EBV+PTLD, adequate organ function (ANC ≥ 500/µL +/- cytokine support; platelets ≥ 20,000/µL +/- transfusion support if no ≥ grade 2 bleed in prior 6 months; ALT, AST, T. Bili < 3X ULN; Creatinine < 3X ULN) and performance status (ECOG ≤ 4 or Lansky ≥ 20), and lack of approved alternative therapies. Non-PTLD-related vasopressor or ventilatory support, pregnancy, concomitant need for T-cell inhibiting medications were exclusionary. Tabelecleucel was given at 1.6-2 x 106 cells/kg/dose on days 1, 8, and 15 of every 5-week cycle with imaging-based response assessment at ~d28 of each cycle. Subjects were treated to maximal response with up to 4 tabelecleucel products (cell lines) with different HLA restrictions, occurrence of an adverse event leading to tabelecleucel discontinuation, or withdrawal of consent. The results presented herein reflect a data snapshot from 3th June 2019. Results: All subjects had received prior rituximab and 7/12 SOT subjects received prior chemotherapy. Intermediate/high risk PTLD-prognostic index (PTLD-IPI; Choquet et al, Ann Hematol 2007) was noted in 79% and 42% of HCT and SOT subjects, respectively. The results are presented in table 1. While the median follow-up time in HCT subjects is short, 3 subjects were followed for over 12 months including 2 who were followed for more than 24 months. In subjects responding to tabelecleucel, 1-year OS was 85.7% in HCT and 100% in SOT, and no deaths were attributable to PTLD progression. In a subset of study subjects (HCT: n=11; SOT: n=11) with adequate ECOG, no CNS disease, and no PTLD-related ventilatory support, who would have likely been eligible for Atara's ongoing phase-3 trials, the ORR was 55% (HCT) and 82% (SOT), with a 2-yr OS of 79% (HCT) and 81% (SOT). The safety profile of tabelecleucel was consistent with previously published data. At the data snapshot for this abstract, no tabelecleucel-related adverse events led to treatment discontinuation or death. In addition, no cytokine release syndrome, organ rejection or tumor flare adverse events were reported in the PTLD subjects treated with tabelecleucel on this EAP. Conclusions: The data demonstrate a high response rate for tabelecleucel in PTLD in both HCT and SOT after initial treatment failure. Longer term follow-up shows a favorable 2-year OS in this predominantly high-risk population for whom there are no approved alternative therapies. Similar outcomes were observed in the subset of subjects potentially eligible for ongoing phase 3 studies of tabelecleucel in relapsed/refractory EBV+PTLD following SOT (NCT03394365) or HCT (NCT03392142). Tabelecleucel appears to be an effective and well-tolerated option in the subset of subjects with EBV+PTLD treated on this EAP. Disclosures Prockop: Atara Biotherapeutics: Other: Support for industry sponsored trails ; Mesoblast: Other: Support for industry sponsored trails . Reshef:Atara: Consultancy, Research Funding; BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Magenta: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Tsai:Eli Lilly and Company: Employment. Bunin:PRA Health Sciences: Other: Immediate family member employed. Mahadeo:PI for ATARA EBV CTL Trials: Other: Other ; Recipient of unrestricted medical education grant from Jazz: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Millenium/takeda: Research Funding; Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria. Hiremath:Atara Biotherapeutics: Employment, Equity Ownership. Yue:Atara Biotherapeutics: Employment, Equity Ownership. Sun:Atara Biotherapeutics: Employment, Equity Ownership. Navarro:GE: Equity Ownership; Pfizer: Equity Ownership; Atara Biotherapeutics: Employment, Equity Ownership, Patents & Royalties; Bluebird Bio: Equity Ownership.

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