scholarly journals Functional Predictors of Chemotherapy Toxicity in Elderly Lymphoma Patients: A Prospective Pilot Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4843-4843
Author(s):  
Anca Prica ◽  
Vinita Dhir ◽  
Manjula Maganti ◽  
Vishal Kukreti ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Grip Strength ◽  
Risk Score ◽  
Older Patients ◽  
Research Funding ◽  
Systemic Chemotherapy ◽  
Performance Tests ◽  
Chemotherapy Toxicity ◽  
Grade 3 ◽  
Over Time ◽  
Frailty Score

Abstract Introduction: Treatment of lymphoma, while subtype specific, often includes curative intent combination chemotherapy. There is little evidence on which to base treatment decisions for older patients, and oncologists often rely on their clinical impression and the patient's chronologic age to make treatment decisions. Objective measures may be more accurate and reproducible in predicting eligibility for combination chemotherapy; however their utility in the clinical setting is still under investigation. Objective: The objectives of this pilot study were to assess the feasibility of applying the Hurria (Hurria et al. JCO 2011) and CRASH (Extermann et al. Cancer 2012) chemotherapy toxicity risk stratification measures, as well as physical performance tests, during busy outpatient clinics, and their ability to potentially predict chemotherapy toxicity. Methods: This is a prospective, single centre pilot feasibility study in patients 70 years of age or older, with lymphoma, planned for definitive systemic chemotherapy. Patients completed geriatric tools (eg. Hurria and CRASH questionnaires, gait speed test and grip strength, CSHA Clinical Frailty Scale and Charlson Comorbidity Index) at baseline. Physical performance tests were repeated with each treatment cycle and data were collected on toxicities, hospital admissions, as well as change in treatment cycles or dosing. Primary outcomes were feasibility and time needed to complete the measures; secondary outcomes were correlation between chemotherapy toxicity and geriatric assessment results, and other patient characteristics (stage and ECOG status). Results: Thirty patients have been enrolled to date (out of a target of 30), and 29 have completed all follow-up assessments, with a median age of 77 yrs (range 69-90) for the whole group, and 59% being male. Diagnosis was diffuse large B cell lymphoma in most (59%), followed by CLL (17%), indolent lymphoma (10%), and other (14%). Chemotherapy treatments most commonly included RCHOP (59%), and bendamustine and rituximab (24%). Aggressive histology pts received G-CSF as 1° prophylaxis. The chemotherapy was dose reduced by the treating physician at cycle 1 in 8 patients (28%), and during the course of treatment in 3 pts (10%). Using the Hurria risk stratification score, 7 pts (24%) were low, 17 (59%) were intermediate and 5 (17%) high risk for chemotherapy toxicity. Similarly, the CRASH scoring identified 2 pts (7%) as low, 11 (38%) as medium-low, 14 (48%) as medium-high and 2 (7%) as high risk. The median amount of time needed to complete the Hurria tool was 2 min (1-5 min) vs. 20 min (5-30min) for the CRASH score. Fourteen pts (48%) experienced CTCAE grade 3-5 toxicity, for a total of 25 severe AEs. The most common gr ≥3 AEs was febrile neutropenia (4 pts), anemia and thrombocytopenia (3pts each); other severe AEs, such as upper GI bleed, PE and DVT, rapid atrial fibrillation, and hyponatremia occurred in one pt each. Dose delays occurred in 9 pts (31%) and 5 pts (17%) required hospitalization due to toxicity. The CSHA frailty score and grip strength worsened throughout treatment and had not recovered by the 1 month visit post-treatment, while the 6 meter walk time did not significantly vary over time during treatment (Figure 1). On univariate analysis, the CSHA frailty score and grip strength changes over time, and the Hurria risk score at baseline were significantly associated with any adverse event, while only the CSHA frailty score and Hurria risk score were associated with Grade 3 or higher events (Tables 1 and 2). On multivariate analysis, the CSHA Frailty score and Hurria risk score retained significance for any AE, however when adjusted for CSHA Frailty, the Hurria score was no longer a significant predictor. Conclusion: When perceived fit older patients are treated with full-dose systemic chemotherapy, the rate of toxicity is high. The Hurria tool, takes a short time to administer, and while not previously tested in lymphoma patients, appears to predict toxicity. The CSHA Frailty was the most robust predictor of chemotherapy toxicity in our patient population, and is a very simple measure to administer. The results of this pilot has led us to recommend routine use of these tools in all older lymphoma patients undergoing systemic chemotherapy at our centre, with the aim of further testing their ability to predict chemotherapy toxicity and treatment outcomes, as well as help plan co-interventions. Disclosures Kuruvilla: Abbvie: Consultancy; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding; Lundbeck: Honoraria; BMS: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; Merck: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria. Crump:Jansen-Ortho: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Servier Canada: Consultancy.

Maintenance Therapy with Low-Dose Subcutaneous 5-Azacitidine in Older Patients with AML in 1st Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1029-1029
Author(s):  
Jeffrey E Lancet ◽  
Rami S. Komrokji ◽  
HuiYi Lin ◽  
Carlos M. de Castro ◽  
David A. Rizzieri ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Maintenance Therapy ◽  
Older Patients ◽  
Research Funding ◽  
Low Dose ◽  
Disease Free Survival ◽  
Free Survival ◽  
Grade 3 ◽  
Disease Free ◽  
Risk Categories

Abstract Abstract 1029 Poster Board I-51 Background: Elderly patients with AML have a poor outcome, with low complete response (CR) rates and durations of CR that are typically less than 1 year, highlighting the need for more effective post-remission therapy. 5-azacitidine (AZA) is a nucleoside analogue/DNA methyltransferase inhibitor approved for use in all FAB subtypes and risk categories of myelodysplastic syndromes (MDS). In higher-risk patients with MDS, including those with AML (former RAEB-T subtype), AZA improves overall survival and delays the time to leukemia transformation. We undertook a phase 2 pilot study of low-dose subcutaneous (SC) AZA in older adult patients with AML in 1st CR or CR with incomplete platelet recovery (CRp) following standard induction therapy. Methods: Study objectives included the following: 1) determine the one year disease-free survival in elderly patients with acute myeloid leukemia (AML) in first CR/ CRp treated with low-dose SC AZA as post-remission therapy. 2) determine safety and tolerability of SC AZA administered in the post-remission setting. 3) investigate the relationship between bone marrow genomic promoter methylation with 1-year disease-free survival. Eligibility included age ≥ 60 with AML in 1st CR/ CRp following 1-2 cycles of induction chemotherapy and 1-2 cycles of consolidation therapy, ECOG PS 0-2, adequate end-organ function. AZA was administered subcutaneously on 1 of 2 different dosing schedules: A) 50 mg/m2/d x 5d (d 1-5), or B) 50 mg/m2/d x 7d (d 1-5, 8-9). Cycles were repeated every 4 weeks, and up to 12 cycles. Results: As of August 2009, 16 patients have been enrolled on the study and 15 are currently evaluable. Nine patients received dosing schedule A and 6 received schedule B. Median age was 69 years (range 62-81); M/F was 13/2; baseline cytogenetic risk categories at initial diagnoses: poor (6), intermediate (8), and unknown/not done (1). Two of 15 patients had a history of antecedent MDS. Nine of 15 patients (60%) required 2 cycles of induction chemotherapy to achieve CR/CRp. The median time from achievement of CR/CRp to AZA initiation was 13.6 weeks (range 7 – 21.9 weeks). To date, the median number of AZA cycles received was 4, ;5 patients have received ≥ 6 cycles, 2 of whom have received the 12 planned cycles and another who remains on-study after 11 cycles. Median duration of CR/CRp was 54.8 weeks (95% CI: 28.1-96.4 weeks) estimated using the Kaplan-Meier method. Only 2 of 15 (13%) patients developed grade 3-4 non-hematologic adverse events (colitis, headache). Six of 15 (40%) patients developed reversible grade 3-4 neutropenia or thrombocytopenia, but only 3 required dose reduction. No patients discontinued AZA due to toxicity, and there were no deaths that occurred on-study. Criteria for early stoppage, based upon toxicity, have not been reached. Methylation array analyses are ongoing. SC AZA administered as maintenance therapy in older patients with AML in 1st CR/CRp appears feasible and safe. Extended treatment was possible in a high proportion of patients, with encouraging early signs of durable remissions. Accrual to this trial is ongoing and updated results will be presented. Disclosures: Lancet: Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. de Castro:Celgene: Speakers Bureau. Rizzieri:Celgene: Research Funding, Speakers Bureau. List:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Disease Characteristics and Patterns of Care In Elderly Patients (80+ years) with Follicular Lymphoma (FL) In the United States (US); Are Older Patients Treated Differently? Report From the National LymphoCare Study (NLCS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4152-4152
Author(s):  
Chadi Nabhan ◽  
Michelle Byrtek ◽  
Michael Taylor ◽  
Jill Tydell ◽  
Jamie H. Hirata ◽  
...  
Keyword(s):  
Older Patients ◽  
Research Funding ◽  
Age Groups ◽  
Treatment Patterns ◽  
Disease Stage ◽  
Younger Patients ◽  
Disease Characteristics ◽  
Significant Difference ◽  
The Difference ◽  
Grade 3

Abstract Abstract 4152 Background: While FL is the most common low-grade lymphoma in the US, median age was less than 60 in patients enrolled on pivotal studies that led to our understanding of disease biology and optimal therapy. It remains unclear whether similar disease characteristics, presentation, prognostic factors, treatment patterns, and outcomes pertain to older patients with FL. No clear guidelines exist on how older patients should be treated and data is lacking as to whether current practice patterns affect their survival and progression. Previous reports on FL in the elderly have been retrospective and single center-based. Methods: The NLCS is a prospective, longitudinal multicenter, observational study that enrolled consecutive newly diagnosed FL patients from 3/2004 through 3/2007 collecting data on disease and patients' characteristics, treatment patterns, and outcome. Using the NLCS data we analyzed information on disease stage, grade, FL International Prognostic Index (FLIPI), B symptoms, and treatment choice for patients <60 years, 60–69 years, 70–79 years, and 80+ years. Either Chi-square or Fisher's exact comparison was used to assess the correlations depending on the sample size of the test. Results: A total of 2,736 pts were enrolled, of which 1,215 (44%) were < 60, 708 (25%) were between 60–69, 549 (20%) were between 70–79, and 264 (9%) were >80. There was a significant difference in grade distribution across the different age groups (p < 0.0001), with 22% of pts 80+ having grade 3 FL vs 17% pts <60. No significant differences across age groups in B symptoms, extra nodal sites, or LDH values were observed. A significant difference in FLIPI score was seen across the age groups (p < 0.0001) where high-score FLIPI was present in 48% of pts 80+ as opposed to 16% of pts <60, although calculating FLIPI might be confounded by the fact that older patients were more likely to not have received a bone marrow (BM) exam with 66% of pts 80+ not having BM exam vs. only 40% of those <60 (p < 0.0001). The difference in FLIPI was mainly due to lower Hgb values as older patients were more likely to have had Hgb < 12 g/dL than younger patients (31% of pts 80+ vs. 15% of pts <60) and to age being a component of the FLIPI index. The difference in FLIPI score across age groups was also observed in patients with grade 3 FL where 53% of pts 80+ had poor FLIPI vs. 15% of pts <60 (p < 0.0001). A statistically significant difference in treatment patterns was found across age groups (p <0.0001). When treatment was implemented, older patients were more likely to have received rituximab (R) monotherapy (37% of 80+ vs. 12% of <60) and less likely to have received R+Chemotherapy (40% of pts 80+ vs. 64% of pts<60). In addition, more pts 80+ were observed compared to those <60 (23% vs. 16%). These differences persisted even in those with advanced stage (III/IV), grade 3 disease, region of diagnosis, and in poor-risk FLIPI. When chemotherapy was used, older patients were less likely than younger patients to receive anthracyclines (p < 0.0001) (31% of pts 80+ vs. 69% of pts<60). Anthracycline use remained significantly different regardless of disease stage, grade, or FLIPI score. Conclusions: To our knowledge, this is the largest prospective data collection available for FL pts 80+ years of age. We demonstrate that these pts have higher FLIPI score and grade 3 disease. When treatment is initiated, these patients receive R monotherapy more often than their younger counterpart. Anthracycline use in this population is also less common regardless of disease stage, grade, or risk profile. Whether these baseline differences translate into different outcomes remains to be seen. Disclosures: Nabhan: genentech: Research Funding, Speakers Bureau. Byrtek:Genentech: Employment. Taylor:Genentech: Employment. Hirata:Genentech: Employment. Flowers:Genentech/Biogen-Idec (unpaid): Consultancy; Celgene, Intellikine: Consultancy; Millennium: Research Funding.

Changes in Annualized Bleeding Rate over Time and Relationship with Dosing of Turoctocog Alfa during the guardian™ Program

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2850-2850
Author(s):  
Margareth Ozelo ◽  
Dragana Janic ◽  
Irina Matytsina ◽  
Andrea Landorph ◽  
Niels Zeuthan ◽  
...  
Keyword(s):  
Older Patients ◽  
Research Funding ◽  
Initial Period ◽  
Clear Correlation ◽  
Weekly Dose ◽  
Bleeding Rate ◽  
Younger Patients ◽  
Time Period ◽  
The Guardian ◽  
Over Time

Abstract Introduction: The guardian™ program is a large, multinational trial program designed to support the registration of turoctocog alfa (NovoEight®), a new B-domain–truncated recombinant Factor VIII (FVIII) molecule. A total of 214 patients with severe hemophilia A without inhibitors were enrolled in the guardian™ program as of 1 Sept 2012. Two open-label, non-controlled, phase 3a trials assessing the efficacy, safety, and pharmacokinetics of turoctocog alfa in previously treated patients (PTPs) ≥12 years old (guardian™1) or PTPs <12 years old (guardian™3) were conducted; upon completion, participants could enter an extension trial (guardian™2) that is ongoing. Patients received turoctocog alfa as prophylaxis and to treat bleeds. The primary endpoint was incidence of FVIII inhibitors (≥0.6 Bethesda Units) and a key efficacy endpoint was the annualized bleeding rate (ABR). Methods: For inclusion in this post-hoc analysis, PTPs must have participated in guardian™2 and either guardian™1 or 3, had ≤1 week of surgery treatment in guardian™1/guardian™3 (initial period), and had ≥3 months of exposure to turoctocog alfa prophylaxis during a selected time period (1 January 2012 – 30 June 2013) in guardian™2. This guardian™2 time period was selected to obtain a group of patients who had participated in the trial for an adequate duration to enable comparison over time. Starting dose of turoctocog alfa was 20 IU/kg in guardian™1 and was determined by the investigator in guardian™3; doses were adjusted based upon clinical criteria, at the discretion of the physician. This analysis investigated the relationship between change in ABR from guardian™1/guardian™3 to guardian™2 and average ABR during these periods. Change in ABR was defined as the change in number of bleeds per year and average ABR was defined as (ABR [guardian™1/guardian™3] + ABR [guardian™2]) /2 for each patient. Change in ABR versus the ratio of mean weekly preventive dose was also investigated, with ratio defined as (mean weekly dose [guardian™ 2] / [mean weekly dose [guardian™1/guardian™3]) for each patient. Analyses were descriptive; statistical analyses were not conducted. Results: A total of 166 patients met inclusion criteria for this analysis (111 from guardian™1 [21 adolescents 12–17 years old and 90 adults ≥18 years old] and 55 from guardian™3 [27 children ≤5 years old and 28 children 6–11 years old]). For this subgroup of patients with prolonged extension study exposure, overall median ABR in guardian™1 was 4.0 bleeds/patient/year (range: 0.0–38.4), and in guardian™3 was 3.8 bleeds/patient/year (range: 0.0–34.7); overall median ABR during guardian™2 was 1.6 bleeds/patient/year (range: 0.0-18.8). ABR by age is shown in table 1. Table 1: Median annualized bleeding rate and reduction over time Abstract 2850. Tableguardian™1/ guardian™3guardian™2% reduction during extensionAdults4.21.369%Adolescents4.01.563%Children 6–11 years3.62.336%Children ≤5 years3.82.047% The majority of patients had a reduction in ABR during the trials (Fig. 1). The patients with the highest ABR during the initial period were those with the largest reduction in ABR. When the change in ABR was examined by age, older patients tended to have a larger reduction in ABR than younger patients. For some patients, ABR in guardian™2 was higher than in the initial period. There was no clear correlation between dose and ABR (figure not shown in abstract). Within age groups, weekly doses were highly variable. The majority of patients showed an increase in dose over the analyzed period, most by approximately 20% compared with the initial dose (figure not shown). Fig. 1: Change in ABR versus average ABR for guardian™1/guardian™3 and guardian™2. Fig. 1:. Change in ABR versus average ABR for guardian™1/guardian™3 and guardian™2. Conclusions: For PTPs on long-term prophylaxis with turoctocog alfa, change in ABR over time may be correlated with initial ABR levels. Patients who initiated with high ABR levels (and therefore likely poor joint status) tended to have the most pronounced reduction in ABR while, for others, low ABR was maintained. Older patients likewise tended to have a larger reduction in ABR than younger patients. No clear correlation was found between dose and ABR, indicating that dose changes may occur due to considerations other than bleeding frequency. Slight increases in dose over time likely represent individualized dose adjustments by physicians aimed to optimize treatment outcomes. Disclosures Ozelo: Novo Nordisk, Baxter and Bayer: Consultancy, Speakers Bureau; Bayer, CSL Behring and Novo Nordisk: Research Funding. Janic:Novo Nordisk, Baxter, Bayer, Pfizer and Octafarma: Honoraria; Novo Nordisk, Baxter and Bayer: Speakers Bureau; Novo Nordisk, Baxter, Bayer and Pfizer: Research Funding. Matytsina:Novo Nordisk A/S: Employment. Landorph:Novo Nordisk A/S: Employment. Zeuthan:Novo Nordisk A/S: Employment. Santagostino:Pfizer: Research Funding; Bayer, Pfizer, Baxter, CSL Behring, Novo Nordisk and Grifols: Consultancy; Biotest, Kedrion and Octapharma: Speakers Bureau.

Idelalisib Treatment Is Associated with Improved Cytopenias in Patients with Relapsed/Refractory iNHL and CLL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1747-1747
Author(s):  
Susan O'Brien ◽  
Andrew John Davies ◽  
Ian W. Flinn ◽  
Ajay K Gopal ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Advisory Committees ◽  
Time To Peak ◽  
Non Hodgkin Lymphoma ◽  
Pharmaceutical Industries ◽  
Grade 3 ◽  
Over Time

Abstract BACKGROUND Chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) are B-cell malignancies associated with neutropenia, anemia and thrombocytopenia.The etiology of impaired hematopoiesis is not well understood, however the bone marrow leukemia/lymphoma cell infiltrates that often occur with these diseases is thought to contribute. In studies evaluating the selective PI3Kd inhibitor idelalisib (IDL) in B-cell malignancies, hematologic responses across all 3 lineages were observed in a majority of patients (pts) with baseline (BL) cytopenias. This post hoc analysis reports hemogram changes in pts with relapsed or refractory (R/R) CLL/iNHL treated with IDL in two pivotal studies and describes trends in hematologic parameters over time during IDL treatment in pts with or without BL cytopenias. METHODS In phase 3 study 312-0116 (NCT01539512), frail pts with R/R CLL were randomized to receive a combination of 8 doses of rituximab (R) with IDL 150 mg BID or placebo (P). In phase 2 study 101-09 (NCT01282424), pts with refractory iNHL received IDL 150 mg BID. In both studies, IDL was continued until disease progression (PD) or unacceptable toxicity. Trial inclusion criteria allowed enrollment of pts with BL cytopenias of any grade (CLL) or grade ˂3 (iNHL). Hematologic profiles for pts in each study were categorized as normal or abnormal (any grade of cytopenia) at BL. In the iNHL study, pts with PD at the first assessment were excluded from this analysis to avoid confounding by underlying uncontrolled disease. RESULTS A total of 345 pts participated in the 2 trials. The overall response rates of IDL-treated patients in the CLL and iNHL studies were 81% and 57%, respectively. For pts with CLL on IDL+R (n=110), BL cytopenias (grade ≥1) included anemia (76%), thrombocytopenia (62%), and neutropenia (34%). For pts with iNHL on IDL-mono (n=115), BL cytopenias included anemia (50.4%), thrombocytopenia (64.3%), and neutropenia (75.7%). We present changes in hemoglobin (Hgb), platelet (PLT), or neutrophil (ANC) counts over time (BL, peak, and time to peak) in pts with an abnormal BL hemogram in Table 1. Median hematologic lab values over time were unchanged in pts with normal hemograms at BL. Among patients with BL cytopenia, anemia and thrombocytopenia improved over time in pts with CLL and iNHL while on treatment with IDL. For pts with CLL, the magnitude of improvement was larger for pts in the IDL+R arm compared to those in the P+R arm. For pts in the IDL+R arm, median peak values of Hgb and PLT were observed within 6 months of IDL initiation. For pts with iNHL, median peak values for Hgb and PLT were observed within 3 months. ANC remained stable over time in CLL, and increased in iNHL. CONCLUSIONS Idelalisib treatment was associated with improvement in Hgb and PLT counts in this population of pts with R/R CLL or iNHL. In those pts with BL anemia or thrombocytopenia, peak improvement in Hgb or PLT values occurred early in treatment (≤3 months for iNHL and ≤6 months for CLL). Disclosures O'Brien: Gilead: Research Funding. Davies:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Gopal:Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. Newcomb:Gilead: Employment. Waldapfel:Gilead: Employment. Zhang:Gilead: Employment. Stilgenbauer:Gilead: Honoraria, Research Funding.

Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 233-233 ◽  
Author(s):  
Susan M. O'Brien ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Ian W. Flinn ◽  
Jan Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

scholarly journals Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1611-1611 ◽  
Author(s):  
Maro Ohanian ◽  
Guillermo Garcia-Manero ◽  
Elias J. Jabbour ◽  
Naval Daver ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cell Transplant ◽  
Overall Response ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Detailed Safety Analysis of Venetoclax Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2033-2033 ◽  
Author(s):  
Danielle M. Brander ◽  
Michael Y. Choi ◽  
Andrew W. Roberts ◽  
Shuo Ma ◽  
L. Leanne Lash ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Grade 3 ◽  
Over Time

Abstract Background: Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor FDA-approved for patients with del(17p) chronic lymphocytic leukemia (CLL) and who have received ≥1 prior therapy. Based on preclinical evidence of synergy, VEN plus rituximab is being assessed in an ongoing Phase 1b study. Methods: Patients with relapsed/refractory (R/R) CLL received daily VEN with stepwise ramp-up over 3-4 weeks to reach daily doses of 200-600mg. After 1 week at the target dose, monthly rituximab was added for 6 doses. Responses and progression were assessed by iwCLL criteria with CT scan and bone marrow biopsy. Bone marrow assessments were done at screening, completion of combination therapy (month 7), and 2 months after clinical/radiologic criteria of iwCLL response were met. Minimal residual disease (MRD) was assessed in peripheral blood and marrow aspirates using ≥4 color flow cytometry (min sensitivity: 0.01%). Data cutoff was 04March2016, with analysis focusing on updated safety of cytopenias experienced on the course of treatment. Results: Forty-ninepatients enrolled (48 CLL/1 SLL). Patients had received a median of 2 prior therapies (range: 1-5) and disease in 25 (51%) was considered refractory to the most recent therapy. Median time on study was 28 (<1-42) months, with 31 patients active on study. Eighteen patients discontinued: 11 due to disease progression, 3 due to toxicity (peripheral neuropathy [1], MDS [1], and death due to TLS [1]), 3 withdrew consent, and 1 was lost to follow up. Across all doses, the most common AEs of any grade were diarrhea (57%), neutropenia (55%), upper respiratory tract infection (55%), and nausea (51%). Peripheral blood cytopenias were the most common Grade 3/4 AEs (neutropenia [53%], thrombocytopenia [16%], anemia [14%], febrile neutropenia [12%], and leukopenia [12%]). Twenty-seven (55%) patients had a history of neutropenia, of whom 6 were receiving G-CSF support prior to starting VEN. Overall, in the first month of therapy, 15 (31%) experienced an AE of neutropenia (any grade). Thereafter, the rate of new AEs of neutropenia decreased over time. While there was individual patient variability, mean ANC was stable over time. Overall, 26 (53%) patients had Grade 3/4 neutropenia. Neutropenia was generally well tolerated and managed by G-CSF support in 24 patients, in addition to ≥1 dose modification in 11 of the 24 patients. Of 8 (16%) patients who experienced grade 3 infections, 2 were while neutropenic. There were no grade 4 infections. Among the 11 (22%) patients who developed any-grade thrombocytopenia, none occurred within 2 weeks of a reported bleeding-related AE. One patient had thrombocytopenia overlapping with disease progression on therapy. Objective response rate for all patients was 86% (n=42), with 51% (n=25) who had complete response (CR/CRi; 12 achieved CR/CRi by month 7). At the completion of combination therapy (month 7), 39 patients had evaluable bone marrow assessments. Thirty (77%) had no histologic evidence of CLL in the bone marrow and 22 patients (56%) had attained bone marrow MRD-negativity. In longer follow up at any point during treatment for all 49 patients, 37 (75%) patients achieved complete marrow clearance and 28 (57%) achieved marrow MRD-negativity. Conclusions: Transient manageable neutropenia was the most common AE, with first onset usually seen within the first month of treatment and the onset of new neutropenia AEs decreased over time. No patients discontinued the study due to cytopenias. Patients were able to continue on study and high rates of response to treatment were observed. VEN given with rituximab achieved rapid and profound reductions in disease burden in peripheral blood and bone marrow. 77% of evaluable patients achieved morphologic clearance by month 7, and 57% were MRD-negative at any point on study. Figure 1 Figure 1. Disclosures Brander: TG Therapeutics: Research Funding; Gilead: Honoraria. Roberts:AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Lash:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Predicting Chemotherapy Toxicity in Older Adults With Cancer: A Prospective Multicenter Study

2011 ◽  
Vol 29 (25) ◽  
pp. 3457-3465 ◽  
Author(s):  
Arti Hurria ◽  
Kayo Togawa ◽  
Supriya G. Mohile ◽  
Cynthia Owusu ◽  
Heidi D. Klepin ◽  
...  
Keyword(s):  
Older Adults ◽  
Risk Stratification ◽  
Laboratory Test ◽  
Geriatric Assessment ◽  
Risk Score ◽  
Psychological State ◽  
Chemotherapy Toxicity ◽  
Grade 5 ◽  
Laboratory Test Results ◽  
Grade 3

Purpose Older adults are vulnerable to chemotherapy toxicity; however, there are limited data to identify those at risk. The goals of this study are to identify risk factors for chemotherapy toxicity in older adults and develop a risk stratification schema for chemotherapy toxicity. Patients and Methods Patients age ≥ 65 years with cancer from seven institutions completed a prechemotherapy assessment that captured sociodemographics, tumor/treatment variables, laboratory test results, and geriatric assessment variables (function, comorbidity, cognition, psychological state, social activity/support, and nutritional status). Patients were followed through the chemotherapy course to capture grade 3 (severe), grade 4 (life-threatening or disabling), and grade 5 (death) as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events. Results In total, 500 patients with a mean age of 73 years (range, 65 to 91 years) with stage I to IV lung (29%), GI (27%), gynecologic (17%), breast (11%), genitourinary (10%), or other (6%) cancer joined this prospective study. Grade 3 to 5 toxicity occurred in 53% of the patients (39% grade 3, 12% grade 4, 2% grade 5). A predictive model for grade 3 to 5 toxicity was developed that consisted of geriatric assessment variables, laboratory test values, and patient, tumor, and treatment characteristics. A scoring system in which the median risk score was 7 (range, 0 to 19) and risk stratification schema (risk score: percent incidence of grade 3 to 5 toxicity) identified older adults at low (0 to 5 points; 30%), intermediate (6 to 9 points; 52%), or high risk (10 to 19 points; 83%) of chemotherapy toxicity (P < .001). Conclusion A risk stratification schema can establish the risk of chemotherapy toxicity in older adults. Geriatric assessment variables independently predicted the risk of toxicity.

scholarly journals The Impact of Age on the Outcome of Primary Treatment for Classical Hodgkin's Lymphoma: 70 Years of Age Is a Clinical Relevant Cutpoint and the Most Important Predictor of Overall Survival

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1559-1559
Author(s):  
Lourdes Calvente ◽  
Manjula Maganti ◽  
Mary Gospodarowicz ◽  
David C. Hodgson ◽  
Danielle Rodin ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Treatment Outcomes ◽  
Older Patients ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Advanced Stage ◽  
Age Group ◽  
Grade 3 ◽  
The Impact

Introduction: Classical Hodgkin lymphoma (cHL) typically affects younger patients but 15-35% are &gt;60 years. The age used to define an elderly population has varied but age 60 is frequently used. A clinically relevant definition of older age could be based on the use of alternate treatments due to different efficacy and/or toxicity. Treatment outcomes may also be influenced by tumor biology and patient comorbidity that vary with age. We evaluated the effect of age on treatment outcomes in cHL. Methods: All cHL patients treated at our centre between Jan 1999 and Dec 2015 were retrospectively analyzed. Clinical data were obtained from prospectively collected Lymphoma database and additional data was manually retrieved. Treatment for localized disease was combined modality (2-4 cycles of ABVD and potentially 6 cycles for bulk disease &gt; 10 cm; radiation doses 20-35 Gy) with advanced disease typically receiving chemotherapy alone (ABVD 6-8 cycles). Older patients received individualized treatment. We used the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), (Sorror Blood 2005) as the elements can be abstracted retrospectively. Results: 607 patients were identified; 14% were &gt;60 years and 6% were age &gt;70. Baseline characteristics are outlined in table 1. Patients &gt;70 presented more frequently with high-risk HCT-CI and worse ECOG PS. Patients &gt; 60 presented more frequently with advanced stage (61-70 age group: 40%; &gt;70 years: 46%). 65% of the patients age &gt;70 presented with an IPS of &gt;3. Chemotherapy alone approaches were used more commonly in older patients (age 61-70: 40%; age 70+: 51%) than in those &lt;60 years (25%). Within the whole cohort 12 patients received non-anthracycline based treatment (&lt;60: n=4; 61-70: n=1; and &gt;70: n=7).For patients &lt;60 and &gt;70 this decision was made due to prior comorbidities that precluded the use of standard treatment, and for the patient in the 61-70 was because of acute toxicity with ABVD-based chemotherapy. Treatment was discontinued in 33% of the patients &gt; 70 (77% due to toxicity), 21% in the 61-70 years group (30% toxicity) and 6% in patients &lt;60 (29% toxicity). Patients &gt; 70 had higher rates of grade 3-5 febrile neutropenia (28% versus 15% [age 61-70] and 7% [age &lt;60]). Bleomycin toxicity was more common in older patients (age &gt;70: grade 3-4 events 12% of the patients with discontinuation in 66%; age 61-70: 13% with discontinuation rate of 20%) compared to a 1% rate of grade 3-5 events in age &lt;60. There was a grade 5 episode of febrile neutropenia in &gt;70 group and 1 death related to bleomycin in age &lt;60. With a median follow up of 8.6 years, the 10-year OS and PFS were 80.5% and 71.2%, respectively. By age-group, the 10-year OS was 88% (&lt;60 years), 57% (61-70 years) and 15% (age &gt;70 years); (p&lt;0.001) (Figure 1a-b). In multivariable analysis for OS, age 61-70 (HR 2.44, p=0.002) and age &gt;70 (HR 5.72, p=0.001), non-anthracycline based chemotherapy (HR 3.69, p&lt;0.001), high-risk HCT-CI (HR 3.03, p=0.001) and ECOG 2-4 (HR 1.8, p=0.017), were significant. Age &gt;70, type of chemotherapy, high-risk HCT-CI, and advanced stage were significant for PFS in the multivariable analysis (Table 2a-b). Death due to disease or toxicity at 10 years was 13.6% (age &lt;60: 9.7%, 61-70 years: 23.2%; and for age &gt; 70: 50.7%; [p=&lt;0.001]) (Figure 2a-b). Multivariable analysis for cause-specific survival identified age &gt;70 years (HR 4.04, p=&lt;0.001), extranodal disease (HR 2.57, p=0.001) and ECOG 2-4 (HR 2.10, p=0.010) as significant predictors(Table 3). Conclusions: Age &gt;70 years is a clinically relevant age cutoff as it has additional prognostic significance and greater rates of treatment discontinuation and toxicity compared to age 60. The HCT-CI is a useful predictor of outcome in cHL and should be validated prospectively. In multivariable analysis, age, type of treatment, comorbidity and ECOG performance status are independent predictors of OS. Further studies are ongoing to validate these findings and assess biologic differences in older versus younger cHL patients. Disclosures Tsang: Nordic Nanovector: Research Funding. Kridel:Gilead Sciences: Research Funding. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Kuruvilla:Janssen: Research Funding; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Gilead: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Celgene: Honoraria; BMS: Honoraria; BMS: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Astra Zeneca: Honoraria; Janssen: Honoraria; Roche: Research Funding; Amgen: Honoraria; Seattle Genetics: Honoraria; Karyopharm: Honoraria.

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