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

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.

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

Blood ◽

10.1182/blood.v120.21.3750.3750 ◽

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.

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Impact Of The Proportion Of Metaphases With Isolated Del(5q) On Clinical Outcomes In Lenalidomide (LEN)-Treated Patients With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) In MDS-003 and MDS-004

Blood ◽

10.1182/blood.v122.21.1538.1538 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1538-1538

Author(s):

Aristoteles Giagounidis ◽

Alan List ◽

Eva Hellström-Lindberg ◽

Mikkael A. Sekeres ◽

Ghulam J. Mufti ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

Log Rank Test ◽

Equity Ownership ◽

Baseline Characteristics ◽

Rbc Transfusion

Abstract Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

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Registry Of Patients Treated With Protein C Concentrate (Human) In The United States and Europe: Interim Results

Blood ◽

10.1182/blood.v122.21.1146.1146 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1146-1146

Author(s):

Marilyn J. Manco-Johnson ◽

Paul Knoebl ◽

Amy D. Shapiro ◽

Maureen Finnerty ◽

Leman Yel ◽

...

Keyword(s):

United States ◽

Board Of Directors ◽

Research Funding ◽

Protein C ◽

The United States ◽

Employment Equity ◽

Advisory Committees ◽

Protein C Concentrate ◽

Concentrate Treatment ◽

Equity Ownership

Abstract Background Protein C (PC) is a naturally occurring, vitamin-K dependent anticoagulant produced by the liver. Deficiency of PC, which can be congenital or acquired, results in a hypercoagulable state. Patients with severe PC deficiency may manifest severe, often life-threatening, disseminated intravascular coagulation (DIC), purpura fulminans (PF), and/or thromboembolism. Highly purified protein C concentrate prepared from human donor plasma (Ceprotin; Baxter Healthcare Corporation, Westlake Village, CA) is an approved therapy for prevention and treatment of venous thrombosis and PF in patients with severe congenital PC deficiency (SCPCD) in the United States. It is indicated in patients with SCPCD for PF and coumarin-induced skin necrosis, and short-term prophylaxis in the European Union and other countries. Use of protein C concentrate (human) has been reported in patients with acquired PC deficiency. The Ceprotin Treatment Registry is a prospective, international, multi-center, open-label, non-interventional, observational study designed to examine the long-term safety and effectiveness of protein C concentrate (human) in the clinical setting. This is the first large, real-world assessment of the treatment of a rare disease with protein C concentrate (human). Here we report data from the first interim analysis in June 2013 covering a 3-year enrollment period. Methods Patients of any age who received, or were initiating/receiving protein C concentrate are included. The study duration is 5 years (3-year enrollment period plus 2 years of follow-up). All study visits/assessments are in accordance with standard of care, with protein C concentrate dose, dose frequency, duration and route of administration determined by the investigator. The study objectives are to determine the most common medical diagnoses associated with protein C concentrate treatment, protein C concentrate treatment regimens, and safety information based on all serious adverse events (SAEs) and rate of treatment-related AE. Other objectives include: an examination of the relationship between protein C concentrate treatment and outcomes in all registry participants, as well as various subgroups. Descriptive statistical analyses are used. Results At the time of data extraction, 34 patients were enrolled from 26 centers; 10 centers in the United States and 16 centers in Europe. Half of the patients were males. The primary diagnosis of PC deficiency was congenital in 25 patients (73.5%) and acquired in 9 patients (26.5%). The median age at diagnosis was 0.03 years (range 0–19.9). Mean plasma PC activity level was 9% (range 1–40.0). The most common (in ≥3 patients) thrombotic disease-associated conditions were PF (50.0%); blindness (44.1%); thromboembolic disease (41.2%), which included deep vein thrombosis, arterial thrombosis and DIC; stroke (32.4%), and renal dysfunction (8.8%). Of the 23 patients being treated with protein C concentrate, 15 were administered protein C concentrate intravenously, and 8 patients received protein C concentrate subcutaneously. The body weights of patients receiving subcutaneous treatment ranged from 10.0 kg to 57.9 kg. A total of 15 patients received an anticoagulant treatment in addition to protein C concentrate. Eight patients reported 23 SAEs, all of which were considered not related to treatment. Eighteen (52.9%) patients reported 72 AEs; only 1 of them, an episode of upper respiratory infection, was considered possibly treatment-related. In 18 patients in whom PC activity recovery was determined after protein C concentrate treatment, there were no patients documented with poor recovery. Protein C concentrate was used during 18 surgeries/invasive procedures and considered effective in all interventions for which data were available. Conclusions Data from the first interim analysis of the Ceprotin Treatment Registry demonstrate that patients with both congenital and acquired severe PC deficiency who are treated with protein C concentrate (human) have a low incidence of treatment related SAEs and AEs, and treatment with protein C concentrate appears to be effective when used during surgery/invasive procedures. Further patient follow up will shed light onto clinical treatment outcomes. Disclosures: Manco-Johnson: CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Research Funding. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Shapiro:Cangene: Research Funding; Biogen Idec: Research Funding; Baxter BioScience: Research Funding; Bayer HealthCare: Research Funding. Finnerty:Baxter: Employment, Equity Ownership. Yel:Baxter: Employment, Equity Ownership. Gelmont:Baxter: Employment, Equity Ownership.

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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 ◽

10.1182/blood-2018-99-117235 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2882-2882 ◽

Cited By ~ 3

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.

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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 ◽

10.1182/blood.v130.suppl_1.824.824 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 824-824 ◽

Cited By ~ 2

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, <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<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<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.

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Safety and Efficacy of Dasatinib (DAS) Vs. Imatinib (IM) by Baseline Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial.

Blood ◽

10.1182/blood.v116.21.3421.3421 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3421-3421 ◽

Cited By ~ 7

Author(s):

H. Jean Khoury ◽

Jorge E. Cortes ◽

Hagop Kantarjian ◽

Michele Baccarani ◽

Neil P. Shah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Initial Therapy ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Once Daily ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Abstract 3421 Background: BCR-ABL kinase inhibitors DAS, nilotinib and IM have become the primary treatment modality for patients (pts) with CML-CP. Pre-treatment comorbid conditions have been proposed to help select a second-line BCR-ABL inhibitor for IM-resistant CML-CP. The DASISION trial is a large Phase 3 trial comparing DAS with IM as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of DAS 100 mg once daily after a minimum follow-up of 12 months (Kantarjian, H, et al. N Engl J Med 2010;362:2260). This analysis assessed the impact of baseline comorbidities on safety and efficacy of these agents when used as initial therapy for CML-CP. Methods: 519 pts with newly diagnosed CML-CP were randomized to either DAS 100 mg once daily (n = 259) or IM 400 mg once daily (n = 260). Key exclusion criteria included serious uncontrolled medical disorders or active infections; uncontrolled or serious cardiovascular disease; prior or concurrent malignancy; inadequate hepatic or renal function; and ECOG performance status of ≥ 3. Pts were analyzed according to the number (0, ≥ 1 and ≥ 2) and type of baseline comorbidity (allergic, dermatologic, diabetes, endocrine-metabolic, gastrointestinal, hematologic-lymphatic, hepatobiliary, hyperlipidemia, musculoskeletal, renal and respiratory), and age (< 46, 46–65 and > 65 y). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed across these groups. Cardiovascular comorbidities were analyzed separately and are not included here. Results: Across the 2 treatment arms, 74% of the pts had 31 baseline comorbidity and 47% had 32. The distribution of comorbidities including allergic (n = 61), dermatologic (n = 62), diabetes (n = 31), endocrine/metabolic (n = 98), gastrointestinal (n = 176), hematologic/lymphatic (n = 57), hepatobiliary (n = 56), hyperlipidemia (n = 41), musculoskeletal (n = 150), neoplasia (n = 17), renal (n = 33) and respiratory (n = 72) was balanced across the 2 arms. Proportions of pts across 3 Hasford risk groups were similar between pts with baseline comorbidity and those without. Safety profiles of DAS and IM in pts with and without baseline comorbidities were comparable (Table). Proportions of pts with at least 1 dose interruption or dose reduction were also similar with or without any comorbidity (Table). Pts with 32 comorbidities and pt grouped by comorbidity type including diabetes mellitus, hepatobiliary conditions and hyperlipidemia also had generally similar safety profiles. In both arms, the 12-mo rates of CCyR and MMR were similar (Table). In DAS-treated pts with diabetes (n = 18), hepatobiliary conditions (n = 32) and hyperlipidemia (n = 22), CCyR rates were 67, 78 and 96%, respectively; the respective MMR rates were 44, 56 and 59%. IM pts with diabetes (n = 13), hepatobiliary conditions (n = 24) and hyperlipidemia (n = 19) had CCyR rates of 69, 75 and 79%, respectively; and MMR rates of 15, 29 and 32%, respectively. In DAS-treated pts, CCyR rates were 88% for pts aged < 46 y (n = 128), 78% for those aged 46–65 y (n = 111) and 85% for those aged > 65 y (n = 20); the corresponding MMR rates were 45, 47 and 50%, respectively. The corresponding IM age groups (n = 111, 125 and 24, respectively) had CCyR rates of 70, 70 and 83%, respectively; and MMR rates of 26, 30, 29%, respectively. Safety profiles were generally similar across age groups in both treatment arms, except that fluid retention rates in pts aged < 46, 46–65 and > 65 y were 13, 25 and 35%, respectively, for DAS; and 34, 45 and 67%, respectively, for IM. Conclusions: The presence of baseline comorbidities appeared to have no effect on the safety and efficacy of either DAS or IM as initial therapy for CML-CP. Disclosures: Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani:Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin:Bristol-Myers Squibb: Employment, Equity Ownership. Hochhaus:Brostol-Myers Squibb, Novartis: Consultancy, Research Funding.

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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 ◽

10.1182/blood.v126.23.2510.2510 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2510-2510 ◽

Cited By ~ 6

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.

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Defibrotide for the Treatment of Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with/without Multi-Organ Dysfunction Following Chemotherapy: Results from an Ongoing Expanded Access Program

Blood ◽

10.1182/blood.v126.23.3121.3121 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3121-3121

Author(s):

Nancy A. Kernan ◽

Paul G. Richardson ◽

Angela R. Smith ◽

Brandon M. Triplett ◽

Stephan A. Grupp ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

The United States ◽

Occlusive Disease ◽

Sinusoidal Obstruction Syndrome ◽

Employment Equity ◽

Advisory Committees ◽

Kaplan Meier ◽

Equity Ownership ◽

Chemotherapy Patients

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS. Methods In the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy. Results Out of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, <1 month-58.0 years), and 55 patients (80%) were ≤16 years (39 patients were children aged 2-11); 54% of patients were male. The most common primary diseases were acute lymphocytic leukemia (44%) and acute myelogenous leukemia (10%). Chemotherapeutic agents received by more than 30% of patients were vincristine, cyclophosphamide, cytarabine, doxorubicin, methotrexate and PEG-L-asparaginase. Antibody-drug conjugates linked to ozogamicin that are associated with development of VOD/SOS (gemtuzumab and inotuzumab) were received by 3 and 1 patient, respectively. The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%-85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%-85.7%) and 80.9% (62.3%-90.9%), respectively. Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported. Conclusions Day+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis: Consultancy, Research Funding. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Clinical Outcomes and Health-Related Quality of Life (HRQoL) Among Randomized Clinical Trial (RCT)-Eligible and RCT-Ineligible Patients: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126143 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1843-1843

Author(s):

Lynne I. Wagner ◽

Kathleen Toomey ◽

Sikander Ailawadhi ◽

Sundar Jagannath ◽

Cristina Gasparetto ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Initial Therapy ◽

World Population ◽

Employment Equity ◽

Eligibility Criteria ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps

Background: MM clinical trials often have stringent eligibility criteria that limit the enrollment of patients (pts) reflective of the general patient population (Shah, Clin Lymphoma Myeloma Leuk 2017). The Connect® MM Registry, a prospective observational study of pts with newly diagnosed MM (NDMM) in the US, provided the opportunity to examine differences between pts with MM who were identified as RCT-eligible vs -ineligible, to observe the generalizability of clinical trial results to real-world clinical settings. Differences in baseline characteristics, treatment, clinical outcomes, and HRQoL were examined in RCT-eligible and -ineligible pts from this registry, which represents an unselected, broad real-world population. Methods: Pts with NDMM were enrolled at 250 community, academic, and government sites. Eligible pts were ≥18 y of age with symptomatic MM diagnosed ≤2 months preenrollment per the International Myeloma Working Group (IMWG) criteria. For this analysis, pts were considered ineligible for RCT per the following key exclusion criteria previously described: absolute neutrophil count ≤1.5 × 109/L, platelet count ≤75 × 109/L, creatinine >2.5 mg/dL, AST/ALT >3 times the ULN, peripheral neuropathy grade >2; ECOG PS 3/4; history of myelodysplastic syndromes/other hematologic malignancies, or solid tumors (Shah 2017). Sites administered pt HRQoL questionnaires and provided clinical data at baseline and quarterly during follow-up until death or study discontinuation. Differences in HRQoL at baseline, changes from baseline to 1 and 2 years, and survival outcomes, adjusted for covariates via propensity score, were compared between RCT-eligible/-ineligible pts. Results: Of the 3011 pts enrolled, 2873 pts met the CRAB (hyperCalcemia, Renal failure, Anemia, and Bone disease) criteria per IMWG at enrollment. Of these, 1622 (56.5%) were identified as RCT-eligible and 1251 (43.5%) as RCT-ineligible (data cut-off February 7, 2019). Both groups were similar in median age, sex, race, and ethnicity distribution, although the RCT-ineligible group had more pts aged ≥75 y (26.3% vs 23.2%) and more pts with ECOG PS 3/4 (6.2% vs none). Overall, 34.5% of RCT-ineligible pts received a transplant vs 42.8% of RCT-eligible pts. More RCT-ineligible pts had ISS stage III disease (39.4% vs 19.8%), elevated calcium (≥11.5 mg/dL; 12.7% vs 6.8%), elevated creatinine (>2.0 mg/dL; 40.3% vs 6.5%), and low hemoglobin (<10 g/dL or >2 g/dL <LLN; 60.8% vs 40.3%). Use of triplet treatment (54.2% vs 56.2%) and alkylator (24.9% vs 20.1%) was similar between the RCT-ineligible/-eligible groups. Lenalidomide + bortezomib + dexamethasone (RVd) was the most common initial therapy, and R was the most common maintenance therapy in both groups, but fewer RCT-ineligible pts received RVd as initial therapy (23.9% vs 31.0%) and R as first maintenance regimen (18.1% vs 22.7%). Absolute baseline HRQoL scores were significantly higher, indicating better HRQoL, in RCT-eligible (115.9) vs -ineligible (111.5) pts on the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM) Total score (P=0.007), FACT-MM Trial Outcome Index (74.3 vs 70.3, P=0.002), and FACT-MM Subscale (37.3 vs 35.5, P=0.003). Scores were similar for EuroQol-5D Overall Index (0.73 vs 0.72, P=0.5) and Brief Pain Inventory (3.42 vs 3.43, P=0.9). Both RCT-eligible and -ineligible pts showed significant improvement in HRQoL from baseline at years 1 and 2, although the magnitude of improvement was similar between both groups (Fig. 1a and b). RCT-ineligible pts showed significantly shorter median PFS and OS vs RCT-eligible pts (Fig. 2 & 3, respectively). Conclusions: The CONNECT MM registry provided the opportunity to examine key differences between RCT-eligible and -ineligible pts. By applying common RCT eligibility criteria, a substantial proportion of MM pts (43.5%) in this real-world population may have been ineligible to participate in a RCT. RCT-ineligible pts had advanced disease, poor performance status, and poor laboratory parameters at baseline vs RCT-eligible pts, which could affect PFS and OS. These findings enhance our understanding of HRQoL among MM pts, which at present, is largely based on RCT participants. A similar magnitude of HRQoL improvement in both groups at 1 and 2 years suggests the need to evaluate RCT eligibility criteria in MM to help broaden enrollment and maximize external validity. Disclosures Wagner: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Toomey:Celgene: Consultancy. Ailawadhi:Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Jagannath:Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Rifkin:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline plc: Research Funding; Amgen: Consultancy, Research Funding. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Catamero:Celgene: Employment, Equity Ownership. Abonour:BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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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 ◽

10.1182/blood.v128.22.613.613 ◽

2016 ◽

Vol 128 (22) ◽

pp. 613-613 ◽

Cited By ~ 20

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.

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