scholarly journals Baseline PET-Derived Metabolic Tumor Volume Metrics Did Not Predict Outcomes in Follicular Lymphoma Patients Treated with First-Line Immunochemotherapy and Antibody Maintenance in the Phase III GALLIUM Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2882-2882 ◽  
Author(s):  
Sally F Barrington ◽  
Judith Trotman ◽  
Deniz Sahin ◽  
David Belada ◽  
Andrew Davies ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standardized Uptake Value ◽  
Metabolic Tumor Volume ◽  
Tumor Burden ◽  
Phase Iii ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Evidence suggests that baseline 18fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography-derived parameters, such as metabolic tumor volume (MTV) and maximum standardized uptake value (SUVmax), may predict progression-free survival (PFS) in patients (pts) with follicular lymphoma (FL) treated with first-line R-CHOP immunochemotherapy. However, data from pts routinely treated with bendamustine or antibody maintenance are lacking, and several methods have been used to evaluate PET metrics for tumor burden in pts with lymphoma. This prospective exploratory analysis assessed the prognostic value of baseline MTV, total glycolytic activity (TLG), and SUVmax for PFS and overall survival (OS) in pts with FL treated with first-line obinutuzumab (GA101; G) or rituximab (R) plus chemotherapy (chemo) in the Phase III GALLIUM study (NCT01332968; Marcus et al. N Engl J Med 2017), using two published methods for measuring tumor burden. Methods: Pts ≥18 years with previously untreated FL (grade 1-3a) and advanced disease (Stage III/IV or Stage II with tumor diameter ≥7cm) requiring treatment were randomized 1:1 to receive 6-8 cycles of G (1000mg intravenous [IV] on days [D] 1, 8, and 15 of cycle [C] 1 and D1, C2-6 or 8) or R (375mg/m2 IV on D1) plus standard chemo (CHOP, bendamustine, or CVP). Responding pts received the same antibody as maintenance every 2 months for up to 2 years. After an early protocol amendment, PET imaging at baseline and end of induction (EOI) was mandatory in the first 170 pts and optional thereafter. Independent reviewers segmented FDG-avid tumors applying thresholds of I) standardized uptake value (SUV)max ≥2.5, and II) SUVmax ≥41% of lesional maximum SUV and a minimum volume of 1mL, using MIM software. Results were analyzed for the PET intent-to-treat population. MTV, TLG, and SUVmax were split into quartiles: Q1, <25%; Q2, 25-49%; Q3, 50-74%; and Q4, 75-100%, based on their distribution in the available population. Investigator-assessed PFS and OS were estimated using Kaplan-Meier methods (data cut-off, February 12, 2018). Hazard ratios refer to stratified log-rank tests comparing Q2, Q3, and Q4 with Q1, adjusted for the randomization stratification factors FLIPI score and chemo regimen. Multivariable Cox analyses were also undertaken to investigate whether baseline MTV quartiles and other covariates were prognostic for PFS. Statistical significance at 0.05 was determined using the Wald test. Results: Of 1202 enrolled FL pts, 609 had a baseline PET scan and 521 had baseline PET scans available for all quantitative assessments by central review; 303 pts (58%) received bendamustine, 179 (34%) CHOP, and 39 (8%) CVP. After a median follow-up of 57 months, none of the 3 baseline PET parameters (MTV or TLG measured by either method or SUVmax) significantly predicted PFS (Table). Multivariable analysis, which included baseline pt and disease characteristics, confirmed that MTV did not predict PFS. Consistent with the primary analysis, receipt of G-chemo was an independent predictor of improved PFS. Conclusions: Contrary to previous reports, these prospective data from the Phase III GALLIUM study show that baseline quantitative PET metrics do not predict PFS or OS in FL pts receiving first-line immunochemotherapy (of whom the majority received bendamustine) followed by antibody maintenance treatment, irrespective of the measurement method applied. Conversely, a previously reported analysis from GALLIUM suggests that PET-complete metabolic response at EOI assessed using Lugano 2014 criteria is a strong predictor of long-term outcome in these pts. Table. Table. Disclosures Barrington: EPSRC: Research Funding; Department of Health (England): Research Funding; F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; National Institute of Health Research: Research Funding; MRC: Research Funding; CRUK: Research Funding. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding. Sahin:Roche: Employment, Equity Ownership. Belada:Janssen-Cilag: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Davies:Janssen: Consultancy, Honoraria; GSK: Research Funding; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Pfizer: Research Funding. MacEwan:Consultant Radiologist/ Nuc Med Physician: Consultancy. Owen:Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Honoraria; Janssen: Honoraria, Research Funding; Teva: Honoraria; AbbVie: Research Funding. Ptáčník:F. Hoffman-La Roche: Honoraria. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Mattiello:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

scholarly journals Baseline PET-Derived Metabolic Tumor Volume Metrics Predict Progression-Free and Overall Survival in DLBCL after First-Line Treatment: Results from the Phase 3 GOYA Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 824-824 ◽  
Author(s):  
Lale Kostakoglu ◽  
Maurizio Martelli ◽  
Laurie H. Sehn ◽  
David Belada ◽  
Angelo-Michele Carella ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Predictive Value ◽  
Research Funding ◽  
Metabolic Tumor Volume ◽  
First Line ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, &lt;25%; Q2, 25-50%; Q3, 50-75%; and Q4, 75-100%, which were obtained based on their distribution in the available population. The reported hazard ratios (HRs) refer to stratified log-rank tests comparing Q2, Q3, and Q4 to Q1, adjusted for stratification factors of the study: IPI score (low [0-2], intermediate [3], and high [4-5]) and number of planned CHOP cycles (6 or 8). Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p&lt;0.0001, and HR=1.91, 95% CI 1.28-2.85, p=0.0005, respectively. TMTV was also predictive of overall survival (OS): HR=2.63, 95% CI 1.55-4.46; p&lt;0.0001. However, SUVmax-based prediction of PFS was not statistically significant (HR=0.84, 95% CI 0.57-1.23, p=0.3782). Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Figure 1 Figure 1. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Vitolo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Mundipharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trněný: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

First-Line Treatment and Management of Chronic Myeloid Leukemia (CML) in Clinical Practice: Update of > 1800 Patients (Pts) in the WORLD CML Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3750-3750
Author(s):  
Jorge E. Cortes ◽  
Ricardo Pasquini ◽  
Hagop M. Kantarjian ◽  
David Joske ◽  
Luis A Meillon ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Board Of Directors ◽  
Research Funding ◽  
Disease Status ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Time Points ◽  
The World ◽  
Equity Ownership

Abstract Abstract 3750 Background: The WORLD CML Registry is a multinational, prospective registry established to longitudinally assess global patterns of current and evolving methods for diagnosis, treatment, and clinical outcome measures in pts with CML and to compare clinical practice patterns to management recommendations provided by the European LeukemiaNet (ELN; Baccarani M, et al. J Clin Oncol. 2009;27:6041–6051). Here, we report overall efficacy and safety data from this registry, as well as clinical monitoring practices and outcomes in the subgroup of pts with CML in chronic phase (CP) treated with first-line imatinib. Methods: Pts (≥ 16 y of age) with CML in CP, accelerated phase (AP), or blast crisis (BC) within 6 mo + 2 weeks of confirmed CML diagnosis were enrolled at sites in Latin America, Asia-Pacific, the United States, Russia, Turkey, the Middle East, and Africa. Baseline demographics and medical history were collected at enrollment; disease status and management information were collected at approximate 6-mo intervals or when there was a change in disease status/management. Adverse events (AEs) were collected only if they resulted in a dose/regimen change, nonadherence to treatment, or death. Results: A total of 1837 of the 1889 pts enrolled between February 2008 and December 31, 2010, were evaluable (ie, had confirmed informed consent forms and no protocol deviations) and are the basis for this analysis. Median age was 47 y (range, 16–92 y), and 58% of pts were male. CML diagnosis was established using hematologic (91% of pts), bone marrow (82%), cytogenetic (83%), and molecular (polymerase chain reaction [PCR]; 53%) assessments. Nearly all pts (94%) were initially diagnosed in CP (Table). As of the data cutoff (December 31, 2010), median overall survival (OS) and median event-free survival (EFS) in all pts were not reached. Estimated OS and EFS rates at 3 y were 90.4% and 74.8%, respectively. AEs reported in ≥ 1% of pts were thrombocytopenia (3%) and neutropenia (2%). In the CML-CP subgroup, imatinib (Glivec®/Gleevec®) was administered as first-line therapy (in clinical practice or in a clinical trial) to 63% of pts (n = 1083). Disease burden in CML-CP pts on imatinib over time was most commonly assessed via blood counts (Table). Cytogenetic and molecular assessments were used in a minority of CML-CP pts at most time points. Only 50% of pts had a disease assessment at 3 mo (hematologic, 49%; cytogenetic, 10%; molecular, 15%). Of the pts on first-line imatinib outside of a clinical trial setting (n = 1024), 95 (9%) had their dose increased, 77 (8%) had their dose decreased, and 82 (8%) were switched to nilotinib or dasatinib. In all CML-CP pts treated with first-line imatinib, estimated OS and EFS rates at 3 y were 92.1% and 76.6%, respectively (Table). Estimated OS and EFS rates at 3 y were higher in pts who had higher imatinib exposure (treatment received ≥ 85% of total days) vs pts who received imatinib treatment on < 85% of days. Conclusions: The majority of CML-CP pts treated with first-line imatinib did not have cytogenetic or molecular assessments in accordance with current ELN recommendations, particularly at early time points. Additionally, pts who had higher drug exposure to imatinib had higher estimated OS and EFS rates at 3 y than those who did not. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Piccolo:Novartis Pharma AG: Employment. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Sivarathinasami:Novartis Healthcare Pvt. Ltd,: Employment. Eng:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Kim:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Consultancy, Honoraria, Research Funding. Hughes:Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding.

scholarly journals Systemic Exposure of Rituximab Increased By Ibrutinib: Pharmacokinetic Results from the Helios Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4403-4403
Author(s):  
Paula Cramer ◽  
Fatih Demirkan ◽  
Graeme Fraser ◽  
Alexander Pristupa ◽  
Nancy L Bartlett ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Systemic Exposure ◽  
Tumor Burden ◽  
Time Data ◽  
Employment Equity ◽  
Advisory Committees ◽  
Concentration Time ◽  
Equity Ownership

Abstract Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of several B-cell malignancies. In the phase 3 HELIOS trial, the addition of ibrutinib to a bendamustine plus rituximab regimen significantly improved patient outcomes, including quality of life, overall response, and progression-free survival, in patients with relapsed/refractory chronic lymphocytic leukemia (CLL; Chanan-Khan, Lancet Oncol 2016; 17:200-211). Here we report the results from analyses exploring the pharmacokinetic (PK) interactions between ibrutinib, bendamustine, and rituximab from the HELIOS trial. Methods: In total, 578 patients were randomized to 420 mg ibrutinib (n = 289) or placebo (n = 289) in combination with 6 cycles of bendamustine and rituximab until disease progression or unacceptable toxicity. The bendamustine intravenous (IV) dose was 70 mg/m2 on days 2-3 of cycle 1 and days 1-2 of cycles 2-6; the rituximab IV dose was 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 in cycles 2-6. Infusion durations were typically 30 min for bendamustine and varied based on tolerability and infusion rates for rituximab. Ibrutinib PK samples were collected from all patients at predose, 1, 2, and 4 hr on day 1 of cycles 1 and 2. In a subset of patients, bendamustine PK samples were collected on day 2 of cycles 1 and 2 at predose, end of infusion, and at 1, 2, and 4 hr. Rituximab PK samples were collected on days 1 (predose) and 15 of cycle 1, day 1 (predose) of cycles 2-6, and on day 1 of cycles 7-9. Dose-normalized bendamustine and rituximab concentration-time data were stratified by treatment to evaluate the effect of ibrutinib on the PK of these drugs. Descriptive statistics were calculated using R (www.R-project.org). Results:PK samples from 178 patients were analyzed; 84 patients from the placebo arm and 94 patients from the ibrutinib arm. The mean dose ± standard deviation (SD) of bendamustine was 68.2 ± 6.3 mg/m2 and 68.9 ± 4.7 mg/m2 in patients receiving ibrutinib and placebo, respectively; the doses of rituximab were 468.1 ± 55.3 mg/m2 and 465.2 ± 65.0 mg/m2, respectively. The dose-normalized plasma concentration-time data of bendamustine (a cytochrome P450 1A2 substrate) from both arms were comparable, indicating that ibrutinib did not alter bendamustine PK. In contrast, systemic exposure of rituximab was higher in patients coadministered with ibrutinib than in patients who received placebo; mean predose serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher in subsequent cycles (Figure). The systemic exposure of ibrutinib (n = 280; mean area under the plasma drug concentration-time curve at steady state ± SD = 447.5 ± 298.2 ng•h/mL) in patients receiving the 420 mg dose was comparable to exposures observed in studies of single agent ibrutinib (Marostica, Cancer Chemother Pharmacol 2015; 75:111-121), indicating that bendamustine and rituximab did not impact the PK of ibrutinib. No relevant differences in safety profile were observed between the ibrutinib and placebo arm with the increase in systemic exposure of rituximab. All-grade infusion-related reactions were more frequent with placebo than with ibrutinib (22% vs. 16.7%, respectively), and the incidence of chills was comparable (~11%). Dose interruptions, dose reductions, and discontinuations due to infusion-related reaction were more frequent in the placebo arm (34.8% vs. 27.9%). Additional analyses to model the rituximab PK data using metrics of tumor burden as covariates (e.g., sum of the products of diameters) are currently ongoing and will be presented. Conclusions:Coadministration of ibrutinib with bendamustine and rituximab did not affect the PK of bendamustine or ibrutinib but led to greater dose-normalized systemic exposure of rituximab when compared to patients who received placebo. Rituximab has been reported to be characterized by target-mediated drug disposition (TMDD; Li, J Clin Pharmacol 2012; 52:1918-1926), which may describe many rituximab PK features, such as PK differences in CLL, non-Hodgkin's lymphoma, and rheumatoid arthritis and the dependency of PK behavior on baseline tumor burden. TMDD may account for the rituximab PK findings from this study, with the early decreased tumor burden following ibrutinib resulting in decreased rituximab clearance and hence higher systemic exposure. The clinical significance of this finding needs additional exploration. Disclosures Cramer: Mundipharma: Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Demirkan:Amgen: Consultancy. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Bartlett:Pharmacyclics: Research Funding; Janssen: Research Funding. Dilhuydy:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Loscertales:Roche: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goy:Genentech: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ganguly:Seattle Genetics: Speakers Bureau; Janssen: Research Funding; Onyx: Speakers Bureau. Poggesi:Janssen: Employment, Equity Ownership. de Jong:Janssen: Employment. Neyens:Janssen: Employment. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Howes:Janssen Research & Development: Employment. Mahler:Janssen Research & Development: Employment.

Bortezomib Plus Melphalan–Prednisone Continues to Demonstrate a Survival Benefit Vs Melphalan–Prednisone in the Phase III VISTA Trial in Previously Untreated Multiple Myeloma After 3 Years' Follow-up and Extensive Subsequent Therapy Use.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3859-3859 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Paul G Richardson ◽  
Rudolf Schlag ◽  
Nuriet K Khuageva ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Ortho Biotech ◽  
Equity Ownership

Abstract Abstract 3859 Poster Board III-795 The initial results of the pivotal, international, phase III VISTA trial demonstrated the superiority of bortezomib (Velcade®) plus melphalan–prednisone (VMP) versus MP alone across all efficacy end points, including overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008). We conducted a planned updated survival analysis of VISTA after a median >3 years of follow-up and with the majority of patients having received subsequent therapy. We confirmed the previously demonstrated OS benefit of VMP versus MP, examined the use of subsequent therapy and its efficacy following VMP and MP, and evaluated the survival of patients who had received subsequent therapy. Patients were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, all cycles) or MP (N=338) alone. Response was assessed using EBMT criteria with central laboratory M-protein analysis. After disease progression, patients were followed for survival and subsequent therapy, including investigator-assessed best response to subsequent therapies. The median age of patients was 71 years, 30% were aged ≥75 years, 34% had ISS stage III MM, and 33% had β2-microglobulin >5.5 mg/L. After median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP vs MP (hazard ratio [HR] 0.653, p=0.0008); median OS was not estimable vs 43.1 months, and 3-year OS rates were 68.5% vs 54.0% with VMP vs MP, respectively. This OS benefit was seen consistently across patient subgroups predefined by baseline characteristics. Within the VMP arm, OS was longer among patients aged <75 vs ≥75 years (HR 1.664, p=0.011; 3-year OS: 74.1% vs 55.5%); by contrast, there were no significant differences, although there were trends to longer OS among patients with creatinine clearance ≥60 versus <60 mL/min (HR 1.291, p=0.238; 3-year OS: 74.5% vs 63.1%) and patients with standard- vs high-risk cytogenetics (HR 1.346, p=0.399; 3-year OS 71.6% vs 56.1%). At data cut-off (16 March 2009), 178 (52%) VMP and 233 (69%) MP patients had received subsequent therapy; median time to subsequent therapy (28.1 vs 19.2 months, HR 0.527, p<0.0001) and median treatment-free interval (17.6 vs 8.4 months, HR 0.543, p<0.0001) were superior with VMP vs MP. Receipt of and response to subsequent bortezomib-, thalidomide-, and lenalidomide-based therapy are summarized in the Table. Median survival from start of subsequent therapy following VMP and MP was 30.2 vs 21.9 months (HR 0.815, p=0.21) among all patients receiving subsequent therapy. This updated analysis of VISTA confirms that VMP results in significantly longer OS compared with MP, despite 50% of MP patients being rescued with bortezomib-based therapy in the relapsed setting. VMP treatment used upfront appears more beneficial than treating with conventional agents and saving bortezomib- and other novel-agent-based treatment until relapse. Subsequent therapies appeared similarly effective in the VMP and MP arms, with our analysis also demonstrating the benefit of retreatment with bortezomib-based therapies following VMP. In addition, post-relapse survival among all patients receiving subsequent therapy appeared longer following VMP, indicating that frontline bortezomib use does not induce more resistant relapses. Table Response among patients who received subsequent therapy VMP (N=178) MP (N=233) Received subsequent therapy containing:*     Bortezomib, n (%) 43 (24) 116 (50)     Thalidomide, n (%) 81 (46) 110 (47)     Lenalidomide, n (%) 57 (32) 30 (13) Overall response rate (%) to subsequent therapy:     Bortezomib-based 47 59     Thalidomide-based 41 53     Lenalidomide-based 59 52 * Patients could have received >1 agent, either in combination or separately in different subsequent lines of therapy Disclosures: Mateos: Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Kropff:Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Millennium: Research Funding. Schots:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esseltine:Millennium: Employment, Equity Ownership. Liu:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Patterns of Care of Aged Chronic Lymphocytic Leukemia Patients in the United States: Systematic Analysis of 457 Patients in the Connect CLL Registry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4672-4672
Author(s):  
Chadi Nabhan ◽  
Natalie Galanina ◽  
Neil E. Kay ◽  
Anthony R. Mato ◽  
David L. Grinblatt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
The United States ◽  
Initial Therapy ◽  
Patterns Of Care ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Baseline Characteristics

Abstract Introduction: The median age at diagnosis for CLL pts in the US is 72 years. As clinical trials in CLL have largely enrolled younger pt populations, data on disease and pts' characteristics, patterns of care, prognosis, and molecular features in aged CLL pts are limited. With this in mind, we conducted a prospective study to update critical demographic data and patterns of care for aged CLL pt. Patients and Methods: Connect®-CLL is a US-based prospective, longitudinal, multi-center, observational registry that is aimed at understanding patterns of CLL management without a study-specific intervention. We enrolled pts treated at an academic (n=155) or community (n=1340) setting between 2010 and 2014. Eligible pts were adults with a clinical diagnosis of CLL who required therapy 2 or less months after enrollment. Data on demographics, baseline characteristics, and treatment selection are presented here using descriptive statistics. Continuous variables are reported using appropriate measures of dispersion and central tendency (means, medians, ranges and standard deviations) while categorical variables are summarized as number and percentage of the analysis population. Results: Of 1495 enrolled pts, 457 (30.5%) were ≥75 years (57.3% males, 94.2% white). Rai stage III/IV was noted in 33% and B symptoms (predominantly fatigue (58.4%)) were observed in 68.1%. These and other clinical baseline characteristics appeared similar to pts younger than 75 years except that older pts had more prior malignancies (33.5% vs. 19.8%) and co-morbidities (69.3% vs. 53.6%). Cardiac, neurologic, and renal disorders were the most common morbidities in pts ≥75 years (11.5%, 8.8%, and 4.6% respectively). Imaging studies were performed in 157 (60.2%) older pts and in 416 (65.7%) pts less than 75 years prior to initial therapy. Percentage of pts with bulky nodes (> 5 cm) by imaging was similar in the two groups, 19.3% overall. Prognostic biomarker data were available on 247 pts (178 (72%) <75 years; 69 (28%) ≥75 years). While a higher proportion of older pts had CD38+ CLL (55.1% vs. 40.5%, P=0.038), the proportions of patients with ZAP-70+ CLL were similar between the two groups. In total, 137 (9%) older and 378 (25%) younger pts had 17p and 11q analysis by FISH at enrollment prior to first-line therapy. Of these, 27.0% of pts ≥75 years and 20.6% of pts <75 years had a deletion of either 17p or 11q (P=0.125). Out of all pts enrolled in the registry, 894 (60%) received first-line treatment (261 (29%) pts ≥75 years and 633 (71%) <75 years) as their indication for study entry. Amongst these treated pts, interim analysis shows (data cutoff date: 25 June 2014) progressive marrow failure was more commonly used as the indication for therapy in older pts compared to younger pts (52.1% vs. 38.5%; P<0.001), while splenomegaly was a more common cause for therapy in younger pts (16% vs. 9%; P<0.01). Rai stage III/IV at time of first therapy was 46% and 49% for younger and older pts, respectively. Progressive lymphocytosis was used as the indication for therapy in one third of pts regardless of age. Seventy-four percent of older CLL pts received first-line therapies containing rituximab (R) vs. 85% in pts <75 years (P<0.0001). R-bendamustine was the most common first-line regimen for CLL pts ≥75 (23.4%) while FCR was more commonly given to pts <75 years (32.5%). R-monotherapy was used in 18.8% of older pts versus 9.5% in pts <75 years (P<0.0001). Of note, approximately 25% of CLL pts ≥75 years did not receive R-based regimens for initial therapy. Conclusions: Connect®-CLL is the largest prospective, multicenter CLL registry in the United States. CLL Pts ≥75 years more frequently overexpress CD38 and may more commonly demonstrate high risk cytogenetics by FISH, although the difference did not reach statistical significance. Pts ≥75 years also more commonly had co-morbid diseases, and surprisingly 25% did not receive first-line R-based therapy. CLL pts are rarely included in front-line clinical trials (<3%). Given that novel therapies are increasingly available for CLL patients a continued analysis is warranted to determine their use in elderly vs younger patients as well. A longer follow up is needed to evaluate the impact of these findings on outcomes. Disclosures Nabhan: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Kay:Celgene: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Flinn:Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Kristen:Celgene: Employment, Equity Ownership. Flowers:Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy; Gilead, Spectrum, Millennium, Janssen: Research Funding.

CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2510-2510 ◽  
Author(s):  
Tara L. Lin ◽  
Laura F. Newell ◽  
Robert K. Stuart ◽  
Laura C. Michaelis ◽  
Stephen E. Rubenstein ◽  
...  
Keyword(s):  
Renal Function ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Dose Adjustment ◽  
Cardiac Repolarization ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar ratio. It is highly effective in patients with high-risk acute myeloid leukemia (AML). This study evaluated the impact of CPX-351 (100 units/m2) on cardiac repolarization. Methods: This open-label, Phase II, pharmacokinetic (PK) and pharmacodynamic (PD) study entered AML and acute lymphocytic leukemia (ALL) patients with good risk hepatic function (Child-Pugh scores <7), and normal cardiac function (LVEF≥50%, QTcF<470 ms). Cardiac repolarization changes were assessed using conventional ECG and Holter monitor recordings. PK was assessed during the first 21 days for total cytarabine, daunorubicin, Ara-U and daunorubicinol. The relationship between CPX-351 PK, QTcF, and renal function using the equation to calculate the estimated glomerular filtration rate (eGFR) was evaluated. Results: Twenty-six patients entered the study and 21 were evaluable for QT interval change from baseline. Evidence that CPX-351 prolongs the QTcF interval was not observed. The largest absolute and mean change from time-matched baseline was 12.56 and 8.03 ms, respectively (Day 1, hour 4). Mean QTcF change on Day 5 was unchanged from baseline. QTcF intervals >480 ms were never observed and no consistent QTcF intervals >450 ms were noted. Absolute QTcF increases between 30 and 60 ms were present in 4 of 25 patients and no changes >60 ms were observed. CPX-351 plasma concentration vs. time curves for day 1 and 5 exhibited a volume of distribution approximately equal to the plasma volume with prolonged single-exponential elimination half-lives for cytarabine and daunorubicin of ≥24 hours. The PK of CPX-351 was independent of renal function. Patients with moderately impaired (eGFR=30-59 mL/min/1.73m2) renal function exhibited similar drug exposure as those with mild and normal renal function. Table 1. Impact of renal function impairment on Day 5 CPX-351 PK parameters (mean, %CV): Analyte Renal Function Cmax (ng/mL) AUClast (ng*hr/mL) AUCinf (ng*hr/mL) T1/2 (hr) Cytarabine Normal (n=3) Mean 59333 2893146 2902641 42.5 %CV 28.7 68.8 69 34.1 Mild (n=7) Mean 58071 3599512 3606695 41.0 %CV 31.9 52.4 52.4 21.8 Moderate (n=3) Mean 57333 3149303 3156738 38.0 %CV 46.6 50.7 50.6 21.9 Daunorubicin Normal (n=3) Mean 25967 754646 870861 24.9 %CV 23.1 63 65.3 56.0 Mild (n=7) Mean 28686 865034 1021420 30.5 %CV 43.9 43.5 43.6 25.3 Moderate (n=3) Mean 21933 671542 814732 35.4 %CV 50.9 35.9 33.5 31.2 Table 2 summarizes response and transplant outcomes. One of two ALL patients achieved CR and was transplanted. Among AML patients there were 7 CR and 2 CRi of which three went on to transplant. An additional four patients became morphologically leukemia free (MLF) and were transplanted before full documentation of CR was achieved. A large majority of patients given first-line treatment with CPX-351 responded or became suitable for transplant (10/13, 77%). Table 2. 206 Study Efficacy Diagnosis n ResponseCR/CRi Transplanted in CR/CRi Induced MLF and Transplanted No Response ALL-Relapsed 2 1/0 1/0 0 1 AML-First Line de novo 8 5/0 0 1 2 AML-First Line sAML 5 1/2 1/1 1 1 AML-Salvage 11 1/0 1/0 2 8 Conclusions: Clinically relevant prolongation of QTcF is not a feature of CPX-351 treatment. CPX-351 exposure was independent of renal function, indicating no need for dose adjustment when renal function is impaired. The high rate of complete remission and referral for transplant corroborate the high level of efficacy observed in earlier studies with CPX-351. Disclosures Stuart: Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Pentikis:Celator Pharmaceuticals: Consultancy. Alvarez:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Mayer:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership.

scholarly journals Minimal Residual Disease in Patients with Follicular Lymphoma Treated with Obinutuzumab or Rituximab As First-Line Induction Immunochemotherapy and Maintenance in the Phase 3 GALLIUM Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 613-613 ◽  
Author(s):  
Christiane Pott ◽  
Eva Hoster ◽  
Britta Kehden ◽  
Michael Unterhalt ◽  
Michael Herold ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Residual Disease ◽  
First Line ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Background: Minimal residual disease (MRD) status reflects treatment efficacy and may predict prognosis after first-line therapy in patients (pts) with follicular lymphoma (FL). GALLIUM (NCT01332968) is an ongoing, randomized global Phase 3 study evaluating the efficacy and safety of obinutuzumab (GA101; GAZYVA/GAZYVARO; G) vs rituximab (R) as induction (with chemotherapy [chemo]; bendamustine, CHOP or CVP) and maintenance (in responders) in previously untreated pts with indolent non-Hodgkin lymphoma. In GALLIUM, the primary endpoint of investigator-assessed PFS in pts with FL was significantly improved with G- vs R-based treatment. We report the results of MRD assessment at mid induction (MI) and end of induction (EOI) in FL pts in GALLIUM. Methods: Diagnostic peripheral blood (PB) and bone marrow (BM) samples from FL pts were screened by consensus PCR to detect a t(14;18) translocation and/or clonal Ig variable domain rearrangement suitable for MRD assessment. In pts with a detectable clonal marker, allele- or translocation-specific real-time quantitative (RQ)-PCR assays were designed with a sensitivity ≤10-4. RQ-PCR data were evaluated by European Study Group criteria for MRD detection (van der Velden, Leukemia 2007). MRD status was assessed at MI in PB, and at EOI in PB and BM, and defined as negative (MRD response) if RQ-PCR and subsequent nested PCR were negative in all samples analyzed at the respective time point. Results: Of the 1202 FL pts enrolled in GALLIUM, 1138 provided consent for MRD analyses. Baseline PB or BM samples were available for 1101 pts; a clonal marker was detected in 968 (88%) of these pts and 815 (74%) had an RQ-PCR assay fulfilling sensitivity criteria. Pts with a detectable clonal marker had baseline characteristics comparable to pts without a marker, with the exception of higher-stage disease (61% vs 34% Ann Arbor stage IV), reflecting increased BM involvement. Among 696 pts with an available PB or BM sample at EOI, MRD response was significantly higher in the G-chemo arm than the R-chemo arm (92% vs 85%; p=0.0041; Table 1). BM clearance of residual tumor cells at EOI was higher in the G-chemo vs R-chemo arm (93% [199/214] vs 83% [165/200]; p=0.0014), whereas PB clearance at EOI was similarly high in both arms (96% [323/336] vs 94% [320/341]; p=0.22). MRD clearance occurred early during treatment: at MI, 94% of pts in the G-chemo arm achieved MRD-negative status in PB compared with 89% in the R-chemo arm (p=0.013; Table 2). The anti-lymphoma activity of G-chemo induction was confirmed by analyzing quantitative MRD data in PB at MI: all 20 (100%) pts who remained MRD-positive at MI in the G-chemo arm had low-level MRD (below the limit of quantification) compared with 24/38 (63%) pts in the R-chemo arm. The chemo backbone in the R-chemo arm affected MRD status in PB at EOI giving an MRD response rate of 96% (201/209) after R-bendamustine (B), 93% (100/108) after R-CHOP, and 79% (19/24) after R-CVP. No such effect was seen in the G-chemo arm, where MRD response rates in PB at EOI were high and similar with all three chemo regimens: 96% (187/194), 96% (105/109), and 94% (31/33), respectively. Similarly, in BM, chemo had a large influence on MRD-negative status at EOI in the R-chemo arm (87% [100/115] after R-B, 74% [55/74] after R-CHOP), but negligible impact in the G-chemo arm (93% [109/117] after G-B, 93% [76/82] after G-CHOP). Achievement of MRD negativity at EOI in PB/BM for pts with CR/PR at EOI was associated with longer subsequent PFS, with a hazard ratio of 0.35 (95% CI, 0.22, 0.56; p<0.0001; Figure 1), and comparable effects in both treatment arms. Conclusions: Data from this exploratory analysis support the potential prognostic value of MRD assessment after EOI in FL pts treated with immunochemotherapy. The higher proportion of pts achieving MRD-negative status at MI and EOI, and of pts with low-level MRD among MRD-positives at MI, in the G-chemo arm suggests that G-based induction induces rapid and more effective tumor cell clearance than R-containing therapy. G was more effective than R at enhancing the depth of response to induction therapy in PB and BM, potentially leading to a compensation of differential chemo activity. Future analyses of MRD kinetics during maintenance/follow-up will investigate the pattern and prognostic value of changes in MRD status before relapse, and further evaluate the impact of different chemo regimens. Figure 1. PFS from date of EOI sample by MRD status in PB and/or BM Figure 1. PFS from date of EOI sample by MRD status in PB and/or BM Disclosures Herold: Roche: Honoraria, Other: Grants; Genentech: Other: Grants; Celgene: Honoraria; Gilead: Other: Personal fees from member advisory board. Kneba:AbbVie: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Research Funding; Glaxo-SmithKline: Other: Travel grants. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Danesi:F. Hoffmann-La Roche Ltd: Employment. Fingerle-Rowson:Roche: Employment, Equity Ownership. Harbron:Roche: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Mundt:Roche: Employment. Marcus:Takeda: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Hiddemann:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

Effect of Ruxolitinib On the Incidence of Splenectomy in Patients with Myelofibrosis: A Retrospective Analysis of Data From Ruxolitinib Clinical Trials.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2847-2847
Author(s):  
Srdan Verstovsek ◽  
Jean-Jacques Kiladjian ◽  
Ruben A. Mesa ◽  
Alessandro M. Vannucchi ◽  
Jason Gotlib ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Employment Equity ◽  
Massive Splenomegaly ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Phase Iii Studies

Abstract Abstract 2847 Background and Purpose: Myelofibrosis (MF) is a progressive Philadelphia-negative myeloproliferative neoplasm characterized by debilitating symptoms, massive splenomegaly, and anemia, which severely impairs quality of life. When medical therapy is not effective or tolerated, splenectomy may be required to ease symptoms in patients with symptomatic portal hypertension, massive splenomegaly, and/or frequent red blood cell transfusions (Barbui et al. J Clin Oncol. 2011;29:761–770). In a recent study (Tefferi et al. Mayo Clin Proc. 2012;87:25–33) up to 27% of patients diagnosed with MF eventually underwent splenectomy. However, splenectomy is associated with limited duration of symptom response, high rates of perioperative morbidity and mortality, and acceleration of hepatomegaly. Clinical studies in patients with MF have demonstrated that ruxolitinib, an oral JAK1/JAK2 inhibitor, provides significant and durable reductions in splenomegaly, the burden of MF-associated symptoms, and also improved quality of life. In this post hoc analysis of pooled data from these studies, we determined the incidence of splenectomy in patients treated with ruxolitinib and those who received placebo or best available therapy (BAT) to evaluate whether ruxolitinib therapy may affect the need for splenectomy. Methods: This analysis included patients who participated in the ruxolitinib phase I/II trial (N=153; Verstovsek et al. N Engl J Med. 2010;363:1117–1127); COMFORT-I, a phase III, 24-month placebo-controlled trial of ruxolitinib (N=309; Verstovsek et al. N Engl J Med. 2012;366:799–807); and COMFORT-II, a phase III, 48-month randomized trial comparing the effects of ruxolitinib and BAT (N=219; Harrison et al. N Engl J Med. 2012;366:787–798). Incidence of splenectomy while on treatment or during the protocol-specified follow-up period, adjusted for differences in the duration of follow up, was calculated for patients on ruxolitinib, placebo, or BAT. Results: As a result of the crossover rules and a higher discontinuation rate on the comparator arms in the phase III studies, mean follow-up duration for placebo (0.67 years) or BAT (0.95 years) overall was substantially shorter than mean follow-up duration for ruxolitinib (1.78 years). Baseline characteristics of the 14 patients who underwent splenectomy were as follows: median age=63 years; median time since initial diagnosis=7.8 years; median spleen length (n=13): 17.0 cm (range: 0–28.0 cm); median spleen volume (in those with measurement, n=11)=2924 cm3 (range: 1203–6807 cm3); IPSS high risk=50%, intermediate-2 risk=43%, intermediate-1=7%. Among patients originally randomized and treated with ruxolitinib, the incidence of splenectomy was 1.1 events per 100 patient years (Table). For patients treated with placebo or BAT in the phase III studies, the incidence of splenectomy was approximately three times higher at 2.9 events per 100 patient years, despite the fact that patients on placebo or BAT were allowed to crossover to ruxolitinib if they had worsening symptomatic splenomegaly. Conclusions: Although limited by small numbers, results of this analysis suggest that ruxolitinib reduces the need for splenectomy in patients with MF. Because of crossover to ruxolitinib and higher discontinuation rates in placebo and BAT, follow-up duration was shorter in these treatment arms compared with ruxolitinib. Further, ruxolitinib treatment in crossover patients may have prevented progression of symptomatic splenomegaly in some patients who may have otherwise become candidates for splenectomy. Our analysis may underestimate the true incidence of splenectomy among patients not receiving ruxolitinib therapy and therefore, the relative reduction in splenectomy rate in patients receiving this therapy. Longer-term follow up will better define the splenectomy rate in ruxolitinib-treated patients. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other. Kantarjian:Incyte: grant support Other. Sirulnik:Novartis: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: An employee of Incyte and receiving stock options as part of his compensation Other, Employment. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding.

scholarly journals Disease Characteristics, Treatment Patterns, and Outcomes of Follicular Lymphoma in Patients 40 Years of Age and Younger: An Analysis from the National LymphoCare Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3044-3044 ◽  
Author(s):  
Carla Casulo ◽  
Michelle Byrtek ◽  
Keith L Dawson ◽  
Xiaolei Zhou ◽  
Christopher R. Flowers ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Watchful Waiting ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Disease Characteristics ◽  
Equity Ownership

Abstract Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the world and has a median age at diagnosis in the seventh decade. FL in young adults (YA; 40 years old or younger) is extremely rare. Currently, there are no standard approaches guiding treatment of YA patients with FL, and very little is known about disease characteristics and outcomes of YA patients with FL given limited research conducted in this vulnerable population. To gain further insight into FL in YA, we analyzed the National LymphoCare Study (NLCS) to describe disease and patient characteristics, as well as features of treatment in YA patients with FL. We previously reported that 2-year progression-free survival (PFS) is an important survival endpoint in patients with FL undergoing chemo-immunotherapy. Hence, we also sought to characterize 2-year PFS in this age group and compare it to older cohorts. Methods: Evaluablepatients were identified in the NLCS, and those between 18–40 years of age with newly diagnosed FL at any stage were classified as YA patients. Patients with mixed histology or transformed disease were excluded, as were patients with progression of disease prior to beginning first-line treatment. Survival probability was estimated by the Kaplan-Meier method. We estimated the association of age group with PFS using hazard ratios (HR) and 95% confidence intervals (CI) from multivariable Cox models. Results: A total of164 YA patients with FL were analyzed, representing 6.2% of the NLCS population, similar to the observed frequency in the Surveillance, Epidemiology, and End Results (SEER) Program data (4.8% of all FL). Sixty nine percent of YA patients had advanced stage disease. The majority of patients (80%) had low-grade histology, and 50% had good risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent of patients (31/164) underwent watchful waiting, 12% received rituximab monotherapy, and 47% received chemo-immunotherapy (61% of whom received R-CHOP [rituximab, doxorubicin, vincristine, prednisone]). There was no significant difference in FLIPI score or other baseline disease characteristics compared to adult patients aged 41–60 years. Eleven deaths occurred among YA with FL; only 5 of these were lymphoma related. Overall survival (OS) at 2 years was 97.4% (95% CI 93.3%, 99.0%), and at 5 years, 93.7% (88.3%, 96.7%), which was similar to patients aged 41–60 (97.2% [96.0%, 98.0%] at 2 years, and 92.0% [90.1%, 93.5%] at 5 years). After a median follow-up of 7.1 years, OS in YA FL was 92%. Through follow-up, there were 64 PFS events. The estimated 2-year PFS (95% CI) for YA and adults 41–60 was 75.9% (67.1%, 82.6%) and 80.9% (78.1%, 83.4%), respectively. After adjusting for FLIPI score, there was no difference in PFS for YA with FL requiring first-line treatment (excluding watchful waiting) compared to adults aged 41–60 years (HR=0.93; 95% CI 0.69, 1.25), and no difference in OS compared to adults aged 41–60 years (HR=1.19; 95% CI 0.64, 2.23). Conclusions: In the largest cohort of YA patients with FL to date, we found few differences in outcomes compared to patients aged 41–60. FLIPI and other disease characteristics were similar to adults aged 41–60 years. There were no differences between YA FL and adults aged 41–60 in PFS for all treated patients. OS in the YA group of patients with FL was outstanding. YA patients with FL have reassuringly similar outcomes to patients aged 41–60. Fertility preservation and survivorship issues should be taken into consideration when defining management strategies, but otherwise these data support that YA patients with FL should not be approached differently from older adults with the same disease. Disclosures Byrtek: Genentech, Inc.: Employment, Equity Ownership. Dawson:Genentech, Inc.: Employment, Equity Ownership. Zhou:RTI-HS: Employee of RTI-HS, which has research contracts with Genentech Other. Flowers:Seattle Genetics: Consultancy; Spectrum: Consultancy, Research Funding; Sanofi: Research Funding; Abbott: Research Funding; Novartis: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Allos: Consultancy. Farber:Gilead: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Speakers Bureau, Stock ownership Other. Cerhan:Genentech, Inc.: LymphoCare Scientific Advisory Board Other. Link:Genentech, Inc.: Consultancy, Scientific Advisory Board for Genentech Other.

Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100 × 109/L): A Comparison to Patients with Normal or High Starting Platelet Counts

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 176-176 ◽  
Author(s):  
Moshe Talpaz ◽  
Ronald Paquette ◽  
Lawrence Afrin ◽  
Solomon Hamburg ◽  
Katarzyna Jamieson ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Equity Ownership ◽  
Eortc Qlq

Abstract Abstract 176 Background: Ruxolitinib (RUX) has demonstrated clinical benefit for patients with myelofibrosis (MF) with or without the JAK2V617F mutation at starting doses of 15 or 20 mg PO BID by alleviating symptoms, improving quality of life measures, reducing spleen volume and exhibiting an apparent increase in overall survival in the phase III placebo (PBO)-controlled COMFORT-I study. Reversible declines in platelet count and hemoglobin (Hgb) can occur with ruxolitinib but are rarely treatment-limiting. Patients with MF who have low platelet counts represent an important subset of MF patients; given the potential risk of bleeding complications, a dosing strategy for such patients is needed. We assessed an alternative strategy using lower starting doses of ruxolitinib with subsequent dose escalation in patients with MF who have platelet counts of 50–100 × 109/L (Study INCB018424-258; NCT01348490). Methods: RUX dosing started at 5 mg BID. With adequate platelet count, doses could increase by 5 mg once daily every 4 weeks to 10 mg BID. Further increases required evidence of suboptimal efficacy. Assessments include measurement of MF symptoms (MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]); Patient Global Impression of Change (PGIC); EORTC QLQ-C30, measurement of spleen volume by MRI, and safety/tolerability. Results: A total of 50 patients have enrolled, with data available for 41 patients. Nineteen have completed 24 weeks of treatment; >70% of these patients attained a final dose of ≥10 mg BID of RUX. Treatment was generally well tolerated in this study population with no withdrawals for thrombocytopenia or bleeding events. Based on analysis of adverse events, no new safety signals were observed in this population of MF patients with low platelet counts. Data for efficacy parameters, including spleen volume reduction, TSS reduction, and improvement in EORTC-QLQ-C30 subscales and PGIC were consistent with RUX treatment in the COMFORT-I study, and demonstrated clinically meaningful efficacy compared with the COMFORT-I PBO arm (Table). Of 19 patients with platelet count data through Week 24, 5 showed increased platelet count over the duration of the study (range of increase: 20 to 95 x109/L); all 5 patients had optimized dosing to ≥10 mg BID. Compared with the 14 patients showing smaller increases or modest decreases in platelet count, these 5 patients were younger (mean age: 63 years vs. 71 years), had been diagnosed with MF more recently (2.2 years vs. 5.2 years) and had lower DIPSS scores (60% Intermediate-1; 20% Intermediate-2; 20% High vs. 0% Intermediate-1; 79% Intermediate-2; 21% High). Four patients (9.8%) reported adverse events of bleeding (excluding events related to bruising) of any grade (all events were Grade 1 except one Grade 2 hematochezia), consistent with previously reported hemorrhage frequency in the COMFORT-I study (16.8%, RUX; 12.6%, PBO). Conclusions: These preliminary findings suggest that a dosing strategy of a low starting dose of RUX with escalation to 10 mg BID may be appropriate in MF patients who have low platelet counts. Most patients were able to titrate to a dose of ≥10 mg BID of RUX, a dose showing efficacy for both spleen volume and patient-reported outcomes generally consistent with previously reported data from Phase III trials. An increase in platelet counts was observed in approximately one-fourth of patients who completed 24 weeks of RUX treatment. Escalation to, and subsequent maintenance of, a 10 mg BID dose of RUX also preserves both Hgb and platelet count which may be beneficial for MF patients with anemia or thrombocytopenia. Disclosures: Talpaz: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paquette:Incyte: Consultancy. Jamieson:Sunesis: Membership on an entity's Board of Directors or advisory committees; Blue Distinction Centers for Transplants BlueCross BlueShield Association: Consultancy. Lyons:Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Research Funding. Tiu:Incyte: Honoraria, Speakers Bureau. Winton:Incyte Corporation: Consultancy, Honoraria. Odenike:Incyte: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis:Membership on an entity's Board of Directors or advisory committees. Peng:Incyte: Employment, Equity Ownership. Sandor:Incyte: Employment, Equity Ownership. O'Neill:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Leopold:Incyte: Employment, Equity Ownership. Levy:Incyte: Employment, Equity Ownership. Kantarjian:Incyte Corporation: grant support Other. Verstovsek:Incyte Corporation: Research Funding.

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