Effect of Switching to Nilotinib in Patients with Imatinib-Related Low-Grade Non-Hematologic Adverse Events

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4422-4422 ◽  
Author(s):  
Jeffrey H. Lipton ◽  
Michael J. Mauro ◽  
Sikander Ailawadhi ◽  
Carole B. Miller ◽  
Lambert Busque ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Low Grade ◽  
Molecular Response ◽  
Employment Equity ◽  
Log Reduction ◽  
End Point ◽  
Severity Scores ◽  
Patient Reported ◽  
Equity Ownership

Abstract Abstract 4422 Background: Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult patients (pts) with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) and for adult pts with imatinib-resistant or -intolerant Ph+ CML-CP and CML-AP (accelerated phase). This ongoing study assesses the change in chronic low-grade (LG) non-heme adverse events (AEs) when pts are switched from imatinib (IM) to nilotinib. Methods: Adult CML-CP pts were eligible for the study if they were treated with imatinib 400 mg/d for ≥3 months (mos) and had imatinib-related Grade 1 or 2 non-heme AEs persisting ≥2 mos or recurring ≥3 times and recurring despite best supportive care. Pts are treated with nilotinib 300 mg twice daily on study for up to 1 year. The primary end point is to measure the improvement of imatinib-related LG non-heme AEs at the end of cycle (EOC) 3 after switching to nilotinib therapy. Disease response was monitored and patient-reported outcomes measured by 2 quality-of-life (QoL) questions and the MD Anderson Symptom Inventory (MDASI)-CML. Results: Thirty-eight pts were enrolled as of the data cut-off date (6/27/11) and were included in this analysis. The median time of nilotinib treatment was 7.2 mos. A total of 155 imatinib-related non-heme AEs were reported at baseline; 113 AEs were Grade 1 and 42 AEs were Grade 2. A total of 30 pts completed EOC 3 by the data cut-off date. These pts accounted for 126 of the baseline imatinib-related LG non-heme AEs (Grade 1 = 93, Grade 2 = 33). The median number of IM-related LG non-heme AEs at baseline was 3 per patient. Twenty-one pts reported 1–4 baseline IM-related AEs, 6 pts reported 5–9 IM-related AEs, and 3 pts reported 10–12 IM-related AEs. Of these AEs, 81 (64%) improved (primary end point) by EOC 3; 71 IM-related AEs resolved (51, 15, 5 resolved by mos 1, 2, 3, respectively) and 10 IM-related AEs decreased from Grade 2 to 1. Forty-two AEs were unchanged across 18 pts (20 of which were reported by 3 pts). Three AEs increased in severity by month 3. Overall, 31 (82%) pts had major molecular response (MMR) at entry. MMR is defined as a 3-log reduction of Bcr-Abl from a standardized baseline (Bcr-Abl ≤0.1% IS). All pts maintained MMR after switching to nilotinib on study. The remaining 7 pts achieved MMR during the study. At baseline, 15 pts had a 4-log reduction in Bcr-Abl (Bcr-Abl ≤0.01% IS) and 7 pts with complete molecular response (CMR = Bcr-Abl ≤0.0032% IS). Twelve additional pts achieved a 4-log reduction on study and 9 went on to achieve CMR. Patients completed 2 global QoL questions and the MDASI-CML questionnaire during the study. The MDASI-CML is a patient-reported outcome measure of symptom burden in patients with CML. These were administered at baseline, EOC 1, EOC 3, and then every 3 mos thereafter while on study. Compared to baseline, 68% and 62% of pts (n=34) reported an improvement in global QoL over the last 24 hours and last 7 days, respectively, by EOC 3. The mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were at EOC 1: 1.2 (n=26) and 1.5 (n=25) and at EOC 3: 1.2 (n=24) and 1.6 (n=23), respectively. Thirteen pts were dose reduced for nilotinib-related AEs and subsequently dose re-escalated if the AEs recovered to Grade 1 or resolved. Twenty-seven Grade 3 AEs occurred in 12 pts; of these, 17 AEs were investigator reported and suspected to be nilotinib related (increased bilirubin, hyperglycemia, hypokalemia, hypophosphatemia, increased lipase, pruritus, bronchitis, dehydration, exfoliative rash, rash erythematous, rash, and arthralgia). No pt had a Grade 4 AE. Most AEs were managed by brief dose interruption. A total of 5 pts discontinued, 4 for AEs, and 1 pt withdrew consent. No QTcF prolongation >500 msec occurred. Conclusions: In this analysis, at EOC 3, 64% of the chronic LG non-heme IM-related AEs showed improvement after switching to nilotinib. Twenty-eight of 30 pts who completed 3 mos on study had at least 1 LG non-heme IM-related AE improve after switching to nilotinib. At least 62% of pts improved in QoL. In addition, an overall improvement of symptoms as measured by MDASI-CML was seen by the reduction of severity scores. Disclosures: Lipton: Novartis Canada: Consultancy, Research Funding, Speakers Bureau. Mauro:Novartis Oncology: Consultancy, Research Funding, Speakers Bureau. Ailawadhi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau. Busque:Bristol-Myers Squibb: Consultancy; Novartis Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Shah:Novartis Pharmaceuticals: Employment, Equity Ownership. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Pfizer: Research Funding; Deciphera Pharmaceuticals: Research Funding.

Change in Chronic Low-Grade Nonhematologic Adverse Events (AEs) and Quality of Life (QoL) in Adult Patients (pts) with Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Switched From Imatinib (IM) to Nilotinib (NIL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3782-3782 ◽  
Author(s):  
Jorge E. Cortes ◽  
Jeffrey H. Lipton ◽  
Carole B. Miller ◽  
Sikander Ailawadhi ◽  
Luke Akard ◽  
...  
Keyword(s):  
Adverse Events ◽  
Median Duration ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Low Grade ◽  
Molecular Response ◽  
Employment Equity ◽  
End Point ◽  
Equity Ownership

Abstract Abstract 3782 Background: A large number of Ph+ CML pts treated with IM experience mild to moderate AEs that can negatively impact QoL. A recent study (Efficace F et al. Ann Hematol. 2012) reported that pts and healthcare professionals ranked several AEs induced by BCR-ABL tyrosine kinase inhibitors (fatigue ranked first) in the top 10 issues that adversely impact QoL in pts. The primary objective of the ongoing ENRICH study is to evaluate improvement of IM-related chronic low-grade nonhematologic AEs at the end of cycle (EOC) 3 (ie, after 12 weeks) in CML-CP pts when switched from IM to NIL because of chronic low-grade AEs. This is a report on 45 evaluable pts who completed EOC 3 as of the data cut-off (6/1/2012). Methods: Pts were eligible if they were treated with IM 400 mg/d for ≥3 mo and had IM-related grade (G) 1/2 nonhematologic AEs persisting '2 mo or recurring ≥3 times and recurring despite best supportive care. The study planned to enroll 50 pts in the US and Canada. Pts received NIL 300 mg twice daily for 1 y (or longer if NIL was not yet commercially available for frontline treatment). Nonhematologic AEs were graded using the Common Terminology Criteria for Adverse Events (version 4.03; 6/14/2010) grading scale. Molecular response was monitored by a central PCR lab monthly for the first 3 mo and then every 3 mo on study. Pt-reported outcomes, measured by 2 QoL questions and the MD Anderson Symptom Inventory (MDASI)-CML, were administered at baseline, EOC 1, EOC 3, and then every 3 mo thereafter. Results: 52 pts were enrolled into the study; enrollment closed in January 2012. The median duration (range) of previous IM treatment (tx) was 24.7 mo (2.3–123.0 mo); median duration (range) of NIL tx was 11.9 mo (0.2–23.7 mo). At baseline 199 IM-related nonhematologic AEs were reported (141 G1; 58 G2). Data for 49 pts were available and included in the safety and molecular response analyses; 45 pts were included in the primary end point analysis since 4 withdrew consent prior to EOC 3. These 45 pts accounted for 183/199 of the baseline IM-related AEs (130 G1; 53 G2); 1 AE evaluation is missing at EOC 3. 130/182 AEs (71.4%) improved by EOC 3 (primary end point): 117 resolved (90, 19, 8 by mo 1, 2, 3, respectively) and 13 improved from G2 to G1 (Table). By EOC 3, 64.1% and 53.8% of pts (n = 39) reported an improvement in global QoL from baseline over the last 24 h and last 7 d, respectively. Mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were 1.1 (n = 40) and 1.4 (n = 39) at EOC 1, and 1.2 (n = 39) and 1.7 (n = 38) at EOC 3, respectively. At baseline, 31/49 (63.3%) pts had major molecular response (MMR, 3-log reduction of BCR-ABL1; ≤0.1% IS); 18 and 10 pts had 4-log (MR4; BCR-ABL1 ≤0.01% IS) and 4.5-log reductions (MR4.5; BCR-ABL1 ≤0.0032% IS) in BCR-ABL1, respectively. After switch to NIL, all pts with a baseline MMR maintained MMR and 14/17 remaining pts without baseline MMR achieved MMR. Deeper responses were reported for 16 pts who reached MR4 after the switch, and 14 reached MR4.5. 20 pts were dose-reduced for NIL-related AEs, 2 of whom did not restart study drug. The other 18 pts were dose-reescalated to the original dose when the AEs improved to G1 or resolved. 40 G3 AEs occurred in 19 pts; of these, 24 AEs were investigator-reported as suspected to be NIL-related (hypophosphatemia, hyperglycemia, hypokalemia, increased bilirubin, increased lipase, arthralgia, pleural effusion, acute pancreatitis, dehydration, bronchitis, pruritus, rash, erythematous rash, exfoliative rash, papular rash, abdominal pain, gastroenteritis, and joint pain). 1 G4 AE (cardiac arrest, NIL-suspected) was reported; the pt recovered from the event but was discontinued from the study. Most AEs were managed by brief dose interruption. 9 pts discontinued study (5 due to AEs; 4 withdrew consent). No QTcF prolongation >500 msec occurred. Conclusions: The majority of IM-related nonhematologic AEs improved within 3 mo after switching to NIL; nearly half of the AEs resolved by EOC 1. More than half of pts experienced improvement in QoL and symptom burden on NIL. In general, pts achieved deeper molecular responses on study and approximately a quarter of pts reached MR4.5 after the switch to nilotinib. Disclosures: Cortes: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Lipton:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Ailawadhi:Millennium Pharmaceuticals: Consultancy, Honoraria. Akard:Cellerant: Research Funding; ChemGenex: Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers-Squibb: Honoraria; Pfizer: Research Funding. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding. Lin:Novartis Pharmaceuticals: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Mauro:Novartis Pharmaceuticals: Consultancy, Honoraria.

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2771-2771 ◽  
Author(s):  
Sikander Ailawadhi ◽  
Carole B. Miller ◽  
Anand P. Jillella ◽  
Nebu Koshy ◽  
Brian Tudor ◽  
...  
Keyword(s):  
Research Funding ◽  
Molecular Response ◽  
Employment Equity ◽  
Transcript Levels ◽  
Log Reduction ◽  
End Point ◽  
Day Range ◽  
Equity Ownership ◽  
Group 2 ◽  
Group 1

Abstract Abstract 2771 Background: NIL is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult pts with Philadelphia-chromosome positive (Ph+) CML-CP and in Ph+ CML-CP and accelerated-phase pts who are resistant or intolerant to IM. Achieving complete cytogenetic response (CCyR) and major molecular response (MMR, 3-log reduction of Bcr-Abl transcript level from the baseline mean) are favorable prognostic factors for CML. This multicenter, open-label study (ENABL) was designed to explore nilotinib Bcr-Abl effects in pts with CCyR but who have suboptimal molecular response to IM. Methods: This study evaluates change in Bcr-Abl trends in 2 groups of CML-CP pts (total n = 18) who achieved CCyR but have suboptimal molecular response to IM defined as: (Group 1) treated ≥ 1 year with IM, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1-log increase in Bcr-Abl transcript levels from best response regardless of IM treatment duration. Pts are treated with NIL 300 mg twice daily for ≥ 1 year. RQ-PCR analysis is performed by a central lab at screening, then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR monthly for the first 3 mos, then every 3 mos. The 1° end point is change in Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR at 12 mos. The data cutoff date for this analysis was June 30, 2011. Results: Eighteen pts (Group 1, n = 17; Group 2, n = 1) have been treated with NIL for a median of 17 mos on study (range 3–34 mos). Thirteen pts have been treated for ≥ 6 mos and 10 for ≥ 12 mos. One pt was deemed ineligible due to lack of evidence of CCyR at baseline but is included in the analysis because there was at least 1 post-baseline evaluation performed. The remaining 17 pts had CCyR at baseline. Before enrollment, pts were treated with at least 400 mg once-daily IM; the mean dose of prior IM treatment was 487 mg/day (range 342–786 mg/day). Median duration of prior IM treatment was 3.4 yrs (range 1.3–10.2 yrs). Three pts had prior interferon treatment. All 18 pts were treated for ≥ 3 mos and had ≥ 1 post-baseline RQ-PCR result. Overall, 15 of 18 evaluable pts (83%) achieved MMR during treatment; 10 pts by 3 mos, 1 pt by 4.5 mos (measured at end of study), 1 pt by 6 mos, 2 pts by 9 mos, and 1 pt by 30 mos (Figure 1). The 3 pts who did not reach MMR at any point were only followed for up to 3 mos before discontinuing from the trial but showed a decreasing Bcr-Abl trend. Overall, pts achieved a median log reduction of PCR transcript levels of 3.1 (0.08% IS) at 3 mos; median 3.3-log reduction (0.05% IS) at 6 mos, and median 3.5-log reduction (0.035% IS) at 9 mos. Four pts had > 4-log (≤ 0.01% IS) reduction in Bcr-Abl; of these, 2 pts reached > 4.5-log (≤ 0.0032% IS) reduction in Bcr-Abl at least once during the study. Median Bcr-Abl transcript log reduction at 12 mos was 3.6 (0.025% IS, 1° end point) for 10 evaluable pts. All these pts reached MMR during NIL treatment; 9 pts by 12 mos, 1 pt after 30 mos. NIL was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Seven of 18 pts were dose reduced for NIL-related AEs and re-escalated if the patient recovered from the AEs. Patients were permitted to dose escalate to 400 mg b.i.d. per physician's discretion if MMR was not achieved after 6 mos (n = 1). The Grade 3 AEs reported include 2 cases of rash and 1 case each of pneumonia, squamous cell carcinoma, bladder prolapse, uterine prolapse, bradycardia, hypertension, hyperbilirubinemia and hypophosphatemia. The rashes and bradycardia were suspected to be related to NIL. No Grade 4 AEs were reported. The median dose intensity was 600 mg/day (range 300–683 mg/day). Five pts were discontinued from the study (3 due to abnormal laboratory values, 1 due to an AE, and 1 due to protocol violation). No pts who experienced QTcF changes had differences > 33 msec from baseline. No QTcF prolongation > 500 msec was observed. Conclusions: NIL treatment results in high molecular response rates in CML-CP pts with suboptimal molecular responses to IM. Overall 83% of pts who switched to NIL achieved MMR, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.6 (0.025% IS). The IRIS study has shown that MMR rates increase with time in pts treated with IM (Hughes Blood 2010); however, this study appears to demonstrate that MMR is achieved relatively quickly in suboptimal molecular IM-treated pts when switched to NIL. Disclosures: Ailawadhi: Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lin:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. DeAngelo:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

An Ongoing Phase 3 Study of Bosutinib (SKI-606) Versus Imatinib In Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 208-208 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Dong-Wook Kim ◽  
Hagop M. Kantarjian ◽  
Tim H. Brummendorf ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Adverse Events ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 208 Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor (TKI), with minimal inhibitory activity against PDGFR or c-kit. In a phase 2 study, bosutinib demonstrated activity in patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) in the second- and third-line treatment settings (Cortes JE, et al. ASCO 2010, Abstract #6502; Khoury JH, et al. ASCO 2010, Abstract #6514), as well as in patients with advanced Ph+ leukemias (Gambacorti-Passerini C, et al. ASCO 2010, Abstract #6509) following resistance or intolerance to imatinib and other TKIs. The current randomized, open-label, phase 3 study compared the activity and safety of bosutinib with that of imatinib in newly diagnosed patients with CP CML. The study enrolled adults aged 318 years with cytogenetic diagnosis of Ph+ CP CML within 6 months, adequate hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomized to daily oral treatment with 500 mg bosutinib or 400 mg imatinib. Adverse events were graded using the National Cancer Institute Common Terminology Criteria, version 3.0. The primary efficacy endpoint was the rate of complete cytogenetic response (CCyR) at 1 year; the rates of hematologic response, molecular response, and progression and transformation to accelerated or blast phase were also evaluated. The study randomized 502 patients: 56.6% male, median age of 48 years (range, 18–91 years), and median time since diagnosis of 0.7 months (range, -0.3-7.9 months; the range minimum is negative due to CML diagnosis during the study screening period, and the range maximum is >6 months because of 1 patient considered a major protocol violator). The median duration of treatment was 11.1 months (range, 0.03–24.8 months). At Week 48 (approximately 11 months), 71.5% and 74.8% of patients (both treatment arms combined) were in CCyR and complete hematologic response (CHR), respectively. During the study, 81.4% of patients achieved a CCyR at or before Week 48, with a median time to CCyR of 24 weeks; 82.6% of patients achieved a CHR, with a median time to CHR of 8 weeks; and 40.6% of patients achieved a major molecular response (MMR), with a median time to MMR of 49 to 61 weeks for the 2 treatment arms. For the combined treatment arms, common treatment-emergent adverse events included diarrhea (43.7%), nausea (32.3%), vomiting (22.0%), rash (16.8%), pyrexia (11.6%), and fatigue (11.0%). The only grade 33 treatment-emergent adverse event observed in 32% of patients was diarrhea (5.2%), which was usually limited to the first weeks of treatment. Grade 33 hematologic laboratory abnormalities included neutropenia (14.2%), thrombocytopenia (12.4%), and anemia (5.8%). Other grade 33 laboratory abnormalities (35% of patients) included alanine aminotransferase elevation (11.6%), phosphatemia (7.6%), and aspartate aminotransferase elevation (6.4%). Overall, 22.2% patients discontinued therapy; adverse events led to discontinuation or death in 12.8% of patients, and 4.2% of patients discontinued due to disease progression. The high combined percentage of patients achieving MMR, CCyR, and CHR and the relatively low incidence of generally manageable grade 33 events observed suggest good efficacy and an overall favorable safety profile. Data for individual treatment arms will be unblinded by the end of August 2010, and will be presented at the meeting. Disclosures: Gambacorti-Passerini: Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; BMS, Pfizer: Research Funding. Brummendorf:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Griskevicius:Pfizer Inc: Research Funding. Goh:Novartis and Janssen Ciliag: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Cortes:Pfizer Inc: Consultancy, Research Funding.

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

Blood ◽  
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.

Hospitalizations of Patients with Newly Diagnosed CML-CP Treated with Nilotinib or Imatinib: Results From a Randomized Phase III Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3826-3826
Author(s):  
Jennifer L Beaumont ◽  
John Coombs ◽  
amsi Bollu ◽  
Richard C. Woodman ◽  
David Cella
Keyword(s):  
Research Funding ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Phase Iii Trial ◽  
Equity Ownership ◽  
Hospital Days

Abstract Abstract 3826 Background: Imatinib is the current standard of care for chronic myelogenous leukemia (CML). Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL. A Phase III multi-center, open label, randomized study (ENESTnd) was conducted comparing these two therapies in adult patients with newly diagnosed Philadelphia Chromosome positive (Ph+) CML in chronic phase. The primary endpoint analysis at 12 months demonstrated that major molecular response (MMR) was significantly improved with nilotinib 300 mg BID (44%) and nilotinib 400 mg BID (43%) compared to imatinib 400 mg QD (22%; p < 0.001). The discontinuation rate due to adverse events was lowest among the nilotinib 300mg BID treatment arm (5%) compared to 7% in the imatinib arm, and nilotinib 400 mg BID (9%). Based on the results of this clinical trial, nilotinib 300 mg BID was approved for initial use for CML-CP in the US. Aim: To evaluate the occurrence and rate of hospitalizations and time away from usual activities in this phase III trial. Methods: A total of 846 patients were randomized to receive nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281) or imatinib 400mg QD (n=283). Hospitalizations, defined as any visit to the hospital requiring an overnight stay, excluding pre-planned or elective surgery, were assessed throughout the study period. Overdispersed Poisson regression models were used to compare the days hospitalized per 1,000 patient-days on study. Patients were asked to report time-off, defined as average number of hours per week taken away from all usual activities due to CML and side effects of CML treatment over the past 4 weeks, at Baseline and at the end of Months 3 and 12. The Wilcoxon rank-sum test was used to compare the time off from usual activities at each assessment; and t-tests were used to evaluate the within-group changes in time off. Results: There were a total of 57 hospitalizations in the imatinib arm versus 48 hospitalizations in the nilotinib 300 mg BID arm, and 74 hospitalizations in the nilotinib 400 mg BID arm (Table). Descriptive statistics for length of stay (LOS) are presented in the Table. The hospitalization rate, expressed as hospital days per 1,000 patient days, was 47% higher in the imatinib arm compared to the nilotinib 300 mg BID arm (p=0.057) and 8% higher compared to the nilotinib 400 mg BID arm (p=0.68). Patients in the nilotinib 300mg BID arm had fewer stays and shorter LOS than the imatinib arm, whereas patients in the nilotinib 400mg BID arm had more stays than the imatinib arm but shorter LOS on average resulting in fewer total hospital days. The majority of hospitalizations (56%) in all three arms occurred within the first 9 months. Time off from usual activities, which began at an average level of 8–10 hours per week at Baseline, decreased in each arm, but the decrease did not significantly differ between arms (Table). Similar results were observed when patients reporting zero hours of time off were excluded from the analysis. There was no association between time off and age. Summary/conclusions: In patients with newly diagnosed CML-CP, nilotinib resulted in less hospital time compared to imatinib, although this difference did not reach statistical significance. Additionally, patients in all three treatment groups reported significant improvements from baseline in time off from usual activities. Disclosure: Beaumont: Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Bollu:Novartis: Employment, Equity Ownership. Woodman:Novartis Oncology: Employment. Cella:Novartis: Research Funding.

Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1637-1637 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
Stefan W. Krause ◽  
Stefan Kallert ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 452-452 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp D. LeCoutre ◽  
Ricardo Pasquini ◽  
Saengsuree Jootar ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Safety Data ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Does Faster Rituximab Infusion for Patients with NHL Lower Cancer Care Costs?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2063-2063
Author(s):  
John Hornberger ◽  
Minghan Dai ◽  
Hans-Peter Goertz ◽  
Keith L Dawson ◽  
Carolina Reyes
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Target Population ◽  
Employment Equity ◽  
Medical Resources ◽  
Off Label ◽  
Group Research ◽  
The Us ◽  
Equity Ownership

Abstract Abstract 2063 Introduction Rituximab in combination with chemotherapy is a recommended regimen for non-Hodgkin's lymphoma (NHL), which has been shown in randomized trials and real-world studies to provide a survival benefit compared with chemotherapy alone. Per the US Prescribing Information (USPI), rituximab is typically administered over 4–6 hours for the first infusion and 3–4 hours for subsequent infusions. A 90-minute infusion schedule for rituximab has been found to be safe and feasible in NHL patients who tolerate their first infusion administered at the standard rate and who do not have significant cardiovascular disease or high circulating lymphocytes. This study's primary objective was to assess the cost from a US societal perspective of faster 90-minute rituximab infusion vs the conventional 4–6 hour rituximab infusion. Methods Analyses were performed in accordance with best research guidelines of the International Society of Pharmacoeconomic Outcomes and Research. The target population was patients with previously untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) who were scheduled to receive rituximab 375 mg/m2plus CHOP or CVP chemotherapy. Medical resources assessed were: chemotherapy administration, chemotherapy and pre-treatment drugs, and Grade 3/4 adverse events. Indirect costs include societal resources such as income foregone by patients and informal caregivers/spouses as a result of visit duration for infusion. Trial data were used to extract event rates of adverse events and duration of infusions, and patient drop-out rate by cycle. Prices for medical resources were obtained from publicly available Medicare Fee Schedules. Per capita hourly wage rates were extracted from statistics of the US Labor Department. Outcomes were costs per year for patients treated in the US and cost per infusion and per course of therapy in 2012 US dollars. Results A projected 23,519 newly diagnosed DLBCL and FL patients comprise the target population. Estimated total direct medical cost for conventional infusion is $925,318,162 and $9,855,416 in foregone income for patients and caregivers. The 90-minute infusion reduced direct medical costs by $22,362,397 (2%) and foregone income for patients and caregivers by $5,115,629 (52%). The average cost savings were $359 per infusion and $2,119 per course. The most influential parameters were administration cost and patient foregone income due to time for infusions. The savings per course may be greater if infusion centers are able to spread fixed costs, e.g., overhead, among a greater number of patients resulting from increased capacity to schedule more patients. Conclusion The 90-minute rituximab infusion has been found to be a safe and feasible alternative to conventional rituximab infusion for patients with untreated DBLCL or FL. In an era of landmark legislation (The Patient Protection and Affordable Care Act of 2010) designed to address concerns about rising costs of healthcare and place more emphasis on patient-centered research, the faster rituximab infusion regimen offers direct medical savings and reduces foregone income to patients and caregivers. Disclosures: Hornberger: Cedar Associates LLC: Employment; Genentech, A Member of the Roche Group: Research Funding. Off Label Use: Rituxan (Rituximab) - faster infusion is off-label. Dai:Cedar Associates: Employment; Genentech, Inc, A Member of the Roche Group: Research Funding. Goertz:Genentech, Inc, A Member of the Roche Group: Employment, Equity Ownership. Dawson:Genentech, A Member of the Roche Group: Employment, Equity Ownership. Reyes:Genentech, Inc, A Member of the Roche Group: Employment, Equity Ownership.

Monitoring of Calr Allele Burden in Patients with Essential Thrombocythemia Treated with Imetelstat, a Telomerase Inhibitor, Reveals Rapid and Substantial Molecular Responses

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 408-408
Author(s):  
Gabriela M. Baerlocher ◽  
Monika Haubitz ◽  
Oliver G. Ottmann ◽  
Olatoyosi Odenike ◽  
Alexander Roeth ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Research Funding ◽  
Mutant Allele ◽  
Rapid Decrease ◽  
Molecular Response ◽  
Employment Equity ◽  
Allele Burden ◽  
Equity Ownership ◽  
Calr Mutations

Abstract Background: In essential thrombocythemia (ET), mutations in the calreticulin gene (CALR) are found in the majority of patients that are negative for mutations in the JAK2 and MPL genes. Patients with mutated CALR have a better prognosis and lower thrombosis risk than those with mutated JAK2. Recently, decreases in the CALR mutant allele burden have been observed with interferon alpha after long-term treatment of two- and four-years, respectively (NEJM 2014, 371;2:188-9, Cassinat B. et al.). From the clinical phase II ET study with imetelstat (IT), a first in class, potent, specific inhibitor of telomerase, we reported a substantial and rapid decrease in the JAK2V617F allele burden. 7/8 patients (88%) reached a partial molecular response (MR: >50% reduction from baseline), 6 within the first 3 months and 1 after 12 months. Aims: We aimed to monitor molecular response to imetelstat therapy in ET patients with CALR mutations by serial measurements of CALR mutant allele burden. Methods: The study enrolled patients with ET who had failed or were intolerant to ≥1 prior therapy, or refused standard therapy. During the induction phase, patients were treated with IT 7.5 mg/kg or 9.4 mg/kg IV weekly until attainment of platelet (plt) count ~250-300x109/L. Maintenance phase was then commenced with dosing titrated to platelet count. CALR mutations were detected by Sanger sequencing and quantification of the allele burden was performed by fragment analysis. Results: 18 patients with ET (10 patients with JAK2V617F, 5 patients with CALR and 2 patients with MPL mutations) were enrolled and were treated in the study. 4 of the 5 CALR positive patients achieved complete hematologic responses (CR: Plts < 400 x109/L for 4 weeks) after a median of 6 weeks (range 5 to 14 weeks) and the 5th patient achieved a partial response after 19 weeks, with weekly imetelstat doses starting at 7.5 mg/kg in 2 patients and 9.4 mg/kg in 3 patients. CALR mutations consisted of three cases with type 1 (52-bp deletion; c.1092_1143del), one with type 2 (5-bp insertion; c.1154_1155insTTGTC) and one unknown mutation type (32-bp deletion; c.1092_1124del). Molecular monitoring of CALR allele burden at cycles 3, 6 and 9 demonstrated a rapid decrease in the CALR-mutated patients. 3 pts had a 35-50% reduction from baseline within 4 months and 1 pt had an 11% decrease within 8 months. One of these patients had a 48% reduction in 2 months and a second one had a deepening of response after 10 months to a 55% reduction. All 3 patients with CALR allele burden reductions of 35% or more also achieved hematologic CR. Conclusions: In 4 of 5 patients with CALR-mutated ET, IT induced a rapid CR and in 3 patients hematologic CR was associated with a substantial decrease in the allele burden of 35-50% after 4 months which is more rapid than what has so far been seen with other treatments for ET. Overall 9/13 patients with JAK2 or CALR mutations reached a >35-50% decrease of the mutant clone within 4 months of treatment with IT, providing clinical confirmation of imetelstat’s inhibition of neoplastic clonogenic cell growth in vivo. This additional evidence of reduction in the clonal burden supports IT’s potential to modify the biology of MPNs long-term. Disclosures Baerlocher: Geron Corporation: Research Funding. Odenike:Incyte Pharmaceuticals, Sanofi Aventis, Suneisis, Algeta, Spectrum Pharaceuticals: Honoraria. Roeth:Geron Corporation: Research Funding. Shih:Geron: Employment, Equity Ownership. Burington:Geron Corporation: Employment, Equity Ownership. Leibundgut:Geron Corporation: Research Funding.

Phase 3, Placebo-Controlled, ASPIRE Study (TRC114968) of Eltrombopag (EPAG) Treatment of Thrombocytopenia (TCP) in Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Assessment of Clinical Benefit, Safety, and Tolerability

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1661-1661 ◽  
Author(s):  
Moshe Mittelman ◽  
Uwe Platzbecker ◽  
Boris V Afanasyev ◽  
Sebastian Grosicki ◽  
Raymond SM Wong ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Research Funding ◽  
Open Label ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Thrombopoietin Receptor ◽  
Open Label Extension ◽  
Equity Ownership

Abstract Introduction: Thrombocytopenia (TCP) is a serious and life-threatening complication of advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is approved for treatment of chronic immune thrombocytopenic purpura and severe aplastic anemia. Preclinical studies showed that EPAG has potential antileukemic effects. A phase 1 study in advanced MDS/AML demonstrated an acceptable safety profile at doses up to 300 mg, with no worsening of leukemia, and it also showed a trend towards efficacy. Eltrombopag as monotherapy in MDS/AML has not been studied in a randomized fashion. Methods: In Study TRC114968 (ASPIRE), after 8 weeks of open-label, dose-defining EPAG treatment (Study Part 1), patients with highly advanced MDS or AML were randomized 2:1 to EPAG 100-300 mg or placebo (PBO) once daily for 12 weeks (Part 2), then entered a 6-month, open-label extension (Part 3). Patients were stratified by baseline platelet count (<10 Gi/L vs ≥10 Gi/L), and by MDS vs AML. Eligibility included 10-50% baseline bone marrow blasts and a baseline platelet count of <25 Gi/L. The primary endpoint was improvement in the clinically relevant thrombocytopenic event (CRTE) rate during the 12-week double-blind period. CRTE was a composite of a platelet transfusion requirement, significant bleeding event, or platelet count <10 Gi/L. Part 1 results have been presented previously. Blinded results for patients randomized in Part 2 of the study are presented below. Analyses of results by treatment arm, including those for the primary endpoint of CRTE, are ongoing and will be presented at the meeting. Results: A total of 145 patients were enrolled and randomized. According to WHO criteria, 72 (50%) had MDS and 73 (50%) had AML. See Table 1 for baseline characteristics. The majority of patients (n=91, 63%) were escalated to 300 mg (150 mg for East Asians) once daily. 70 patients (48%) completed the randomized portion of the study, and 58 (40%) entered the open-label extension. Patient disposition is described in Table 2. Out of the 144 treated patients, 97 patients (67%) have died (67 patients in Part 2 and 30 patients in Part 3). The main reasons for withdrawal from the study were adverse events (49 patients, 34%) and progressive disease (39 patients, 27%). The most common adverse events in Part 2 were petechiae, epistaxis, fatigue, pyrexia, and diarrhea. The main serious adverse events in Part 2 were pneumonia, sepsis, and febrile neutropenia. Liver test abnormality occurred in 1 (<1%). The median number of platelet transfusions for both groups was 10. Conclusions: This is the first study to evaluate EPAG as monotherapy in a randomized fashion in patients with advanced MDS or AML and severe thrombocytopenia. Overall safety was as expected for this patient population with no unexpected adverse events. This study provides evidence for the safety of EPAG in this mostly heavily pretreated patient population. An Independent Response Committee (IRC) is currently assessing responses and disease progression centrally by arm, and final data will be presented at the meeting. Funding: This study was sponsored by GlaxoSmithKline; eltrombopag is an asset of Novartis AG as of March 2, 2015. Disclosures Mittelman: Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Novartis Pharmaceuticals Corporation: Research Funding; Roche: Research Funding; Amgen: Research Funding. Off Label Use: Eltrombopag is a once daily oral thrombopoietin receptor agonist approved for treatment of chronic ITP, hepatitis C associated thrombocytopenia, severe aplastic anemia, and pediatric cITP. Data will be presented on use in myeloid malignancies for which eltrombopag is not approved.. Platzbecker:Novartis: Honoraria; Celgene: Honoraria; Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Wong:Johnson & Johnson: Research Funding; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Anagnostopoulos:GlaxoSmithKline: Research Funding. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Mannino:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Stone:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Chan:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Mostafa Kamel:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau.

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