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

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.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1637-1637 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
Stefan W. Krause ◽  
Stefan Kallert ◽  
...  

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.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  

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.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2071-2071
Author(s):  
Jyotsna Mehta ◽  
Hongwei Wang ◽  
Usman Iqbal ◽  
Ruben A. Mesa

Abstract Abstract 2071 Background: PV and ET are clonal stem cell diseases belonging to the 3 BCR ABL negative myelopoliferative neoplasms. Patients with PV and ET suffer from splenomegaly and disease associated symptoms such as pruritus, night sweats, fatigue, and bone pain. Both diseases, if progressive despite standard therapies, are associated with an increased risk of thrombosis, bleeding, and progression to MF or even acute myeloid leukemia. Literature estimates looking at burden of illness are lacking for these disorders. Hence, real world analyses evaluating economic burden are imperative. The objective of this study was to evaluate the clinical and economic burden of these disorders by describing the patient demographics, prevalence, comorbidities, utilization and costs using large scale databases. Method: The US IMPACT® claims database was used to retrospectively identify unique patients with PV and ET between 1/1/08 and 12/31/10. This database is a fully de-identified, HIPAA compliant national database that captures the complete medical history for over 100M managed care individuals, including patient demographics, disease description, laboratory results, and details of medical, pharmacy, outpatient, and inpatient claims. ICD9 CM codes were used to identify PV and ET. Charlson Comorbidity Index (CCI) was used to assess overall comorbid disease status. Enrollment was restricted to those with a full year of medical and pharmacy benefit. Control group was age and gender matched but without any diagnosis of PV or ET. Medical costs include inpatient, outpatient and ER cost. Result: In 2010, we identified 5752 PV patients from ∼12M enrollees. This corresponds to an age adjusted prevalence of 56.5 cases/100000 patients. Compared with age gender matched control patients, PV patients had higher overall comorbidities (mean CCI 1.2 vs 0.7), were hospitalized more often (16% vs 8%), had higher average number of hospital days spent (1.7 vs 0.8), and had more outpatient visits (31 vs 18). PV patients incurred much higher average annual cost ($14,903 vs $7,913) than age gender matched controls driven by both medical ($12,006 vs $6,188) and pharmacy ($2,897 vs $1,724) cost. In 2010, we identified 5483 ET patients from ∼12M enrollees. This corresponds to an age adjusted prevalence of 56.1 cases/100000 patients. Compared with age gender matched control patients, ET patients had higher overall comorbidities (mean CCI 1.4 vs 0.7), were hospitalized more often (30% vs 9%), had higher average number of hospital days spent (5 vs 0.9 days), and had more outpatient visits (37 vs 19). ET patients incurred much higher average annual cost ($29,553 vs $8,026) than age gender matched controls driven by both medical ($26,287 vs $6,394) and pharmacy ($3,267 vs $1,631) cost. Similar trend was observed in 2008 and 2009. Over a period of 3 years, annual cost of PV ranged from $14,000-$16,000 and those of ET ranged from $29,000-$31,000. The utilization rate and total cost in each of conditions were significantly higher than those of their matched patients in each of the 3 years. Conclusion: PV and ET are associated with significant burden of illness. Healthcare expenditure was twice as higher in PV patients compared with the control group. ET patients incurred more than 3 times the healthcare expenditure than the control group. Our study indicates that PV and ET associated medical resource utilization and the corresponding expenditures for those services are substantive. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed. Disclosures: Mehta: Sanofi: Employment. Wang:Sanofi: Employment, Equity Ownership. Iqbal:Sanofi: Employment, Equity Ownership. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 497-497
Author(s):  
Karynsa Cetin ◽  
Leah J McGrath ◽  
Robert Overman ◽  
Diane Reams ◽  
Anjali Sharma ◽  
...  

Abstract Introduction: Immune thrombocytopenia (ITP) is a rare platelet disorder that can lead to an increased tendency to bleed. Recommended first-line therapies include corticosteroids, intravenous immunoglobulin (IVIg) and intravenous (IV) anti-D. An estimated two-thirds of adult patients with ITP will develop persistent or chronic disease (ITP lasting 3-12 months or >12 months, respectively). Several evidence-based options for second-line treatment exist, but no randomized trials have directly compared one therapy to another. Patterns of treatment in routine clinical practice therefore vary. There is a paucity of data on current real-world treatment dynamics in ITP, and such data could help identify gaps in care and inform future studies of real-world comparative effectiveness and safety. We described the types of treatments administered following an ITP diagnosis, as well as the subsequent occurrence of bleeding and requirement for rescue therapy among adults being managed in routine practice in the United States (US). Methods: We used electronic health record data from hematology clinics across the US (Flatiron Health, Inc.) linked to MarketScan® employer-based and Medicare Supplemental administrative health insurance claims databases (Truven Health Analytics, Inc.). We included patients aged 18 years or older with a new ITP diagnosis from January 1, 2011 through June 30, 2016, continuous enrollment in MarketScan prior to diagnosis, and no previous diagnosis of a secondary cause of thrombocytopenia. The cumulative incidence of each ITP treatment after diagnosis was estimated using competing risk models to account for deaths occurring before initiation. Estimates were provided specifically for 90 days and 1 year following diagnosis to describe treatment uptake in the newly diagnosed and persistent phases, respectively. The incidence of bleeding events and rescue therapy was quantified after the start of the more prevalent second-line therapies: rituximab, splenectomy, and thrombopoietin receptor agonists (TPO RAs) - eltrombopag and romiplostim. Rescue therapies (those that rapidly increase platelet counts in the setting of severe thrombocytopenia or active bleeding) included IV anti-D, IVIg, IV steroids, and platelet transfusions. Results: Among the cohort of 447 adults diagnosed with primary ITP, 47% were male, 61% were white, 32% were 65 years or older, and the median lowest platelet count in the 60 days prior to diagnosis was 85x109/L (IQR: 39, 125). Use of each ITP therapy by 90 days and 12 months post-diagnosis are provided in the Table. Oral corticosteroids were the most commonly used; the cumulative incidence of initiation was 41% by 90 days and 50% by 1 year following ITP diagnosis. IV steroids and rituximab were the next most frequently used medications (16% and 11% at 90 days; and 26% and 16% by 1 year, respectively). The cumulative incidence of the TPO RAs, eltrombopag and romiplostim, by 90 days was 3% and 7%, respectively, and by 1 year was 5% and 9%, respectively. Splenectomy was relatively rare (<4% by 1 year) as was use of all other non-rescue ITP medications (≤1% by 1 year). At 180 days post-ITP treatment initiation, rituximab initiators (N = 84) had a slightly lower incidence of bleeding overall (12% [6, 20]) than the other treatment groups (17% [6, 33] among 31 eltrombopag initiators; 19% [9, 31] among 49 romiplostim initiators; and 19% [6, 38] among 21 splenectomized patients). However, rituximab initiators had the highest cumulative incidence of rescue therapy use (48% [36, 58] compared with 29% [14, 46] for eltrombopag, 26% [14, 39] for romiplostim, and 19% [6, 39] for splenectomized patients). Subsequent oral steroid use was less frequent among TPO RA initiators than rituximab initiators or patients who underwent splenectomy. Conclusions: In this descriptive study of patients with primary ITP receiving care in the US, oral steroids were the most commonly used medication after diagnosis, reflecting their continued role as a frontline therapy. By 1 year after diagnosis, approximately 15% received rituximab, nearly 10% received romiplostim, and 5% received eltrombopag. Splenectomy was less common. Among the medical treatments, although bleeding risk overall appeared lowest in rituximab patients, oral steroid and rescue therapy use were lowest among the patients who initiated TPO RAs. Table. Table. Disclosures Cetin: Amgen Inc: Employment, Equity Ownership. Sharma:Amgen: Employment, Equity Ownership. Brookhart:Amgen Inc: Consultancy, Research Funding; NoviSci: Equity Ownership; Union Chimique Belge: Consultancy; GlaxoSmithKline: Consultancy; Merck: Consultancy; Genentech: Consultancy; TargetPharma: Consultancy; RxAnte: Consultancy; AstraZeneca: Research Funding. Altomare:Genentech: Consultancy; Ipsen: Other: Advisory Board Member; Amgen: Consultancy; Celgene: Other: Advisory Board Member; Novartis: Consultancy; Bayer: Consultancy; Incyte: Consultancy. Wasser:Amgen Inc: Consultancy; Novartis: Consultancy; Becton Dickinson: Equity Ownership; Abbott Labs: Equity Ownership; Biogen: Equity Ownership; Allergan: Equity Ownership; Eli Lilly: Equity Ownership; Incyte: Research Funding; Merck: Equity Ownership, Research Funding; Pfizer: Equity Ownership, Research Funding; Guardant: Research Funding.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 208-208 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Dong-Wook Kim ◽  
Hagop M. Kantarjian ◽  
Tim H. Brummendorf ◽  
Irina Dyagil ◽  
...  

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.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2778-2778
Author(s):  
Azra Raza ◽  
Naomi Galili ◽  
Deborah Mulford ◽  
Scott E. Smith ◽  
Gail Brown ◽  
...  

Abstract Abstract 2778 Introduction: Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide's efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures: Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4422-4422 ◽  
Author(s):  
Jeffrey H. Lipton ◽  
Michael J. Mauro ◽  
Sikander Ailawadhi ◽  
Carole B. Miller ◽  
Lambert Busque ◽  
...  

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.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3782-3782 ◽  
Author(s):  
Jorge E. Cortes ◽  
Jeffrey H. Lipton ◽  
Carole B. Miller ◽  
Sikander Ailawadhi ◽  
Luke Akard ◽  
...  

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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1661-1661 ◽  
Author(s):  
Moshe Mittelman ◽  
Uwe Platzbecker ◽  
Boris V Afanasyev ◽  
Sebastian Grosicki ◽  
Raymond SM Wong ◽  
...  

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.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2880-2880 ◽  
Author(s):  
Antonio Almeida ◽  
Valeria Santini ◽  
Stefanie Gröpper ◽  
Anna Jonasova ◽  
Norbert Vey ◽  
...  

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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