Chronic Comorbidities and Chemotherapy-Induced Febrile Neutropenia in Patients with Non-Hodgkin Lymphoma

Abstract Abstract 3671 Background: Chemotherapy induced febrile neutropenia (FN) is a clinically important adverse event as it can impact patient survival by delaying or reducing chemotherapy dose administered. Clinical guidelines recommend granulocyte-colony stimulating factors (G-CSF) be used in cancer patients when febrile neutropenia (FN) risk is >20%. Although the myelotoxicity of the chemotherapy regimen is a key determinant of FN risk, it is now recognized that patient characteristics may increase this risk further. We conducted a retrospective cohort study to evaluate the association of chronic comorbidities to FN in patients with non-Hodgkin lymphoma (NHL). Methods: Incident NHL cases diagnosed between 2000–2009 who received chemotherapy within 12 months of cancer diagnosis were identified from Kaiser Permanente Southern California, a large managed care organization. Those who had prophylactic G-CSFs, dose-dense chemotherapy or bone marrow transplant were excluded. Comorbidities of interest included cardiovascular, liver, renal, metabolic and autoimmune disorders, anemia, previous cancer and HIV infection. History of comorbidity of interest were assessed in the 12 months prior to NHL diagnosis, and identified by ICD-9 codes or disease registries. FN was assessed only in the first chemotherapy cycle, and identified by absolute neutrophil count (ANC), ICD-9 codes for neutropenia and fever, or hospitalization with bacterial/fungal infection. Patients were followed from their first chemotherapy treatment to the start of the second cycle, death or day 28, whichever came first. Logistic regression was used to estimate the propensity score for each comorbidity; these propensity scores included patient characteristics and other comorbidities as covariates. Each comorbidity and propensity score were included in Cox models to determine associations between comorbidities and FN. We also evaluated models that additionally adjusted for cancer stage, baseline ANC, chemotherapy regimen, dose reduction, and radiation treatment prior to chemotherapy. Results: A total of 2,480 NHL patients who received chemotherapy were included. The mean age was 63.3 years. Fifty-five percent of the cases were male, and the majority of the cases were of white race (65.6%). Sixty percent of the cases received CHOP or R-CHOP. There were 236 (9.5%) patients that had FN in the first chemotherapy cycle. Anemia [adjusted hazard ratio adjusted (HR) =1.6, 95% CI, 1.2–2.2], HIV infection [HR=3.0, 95% CI 1.6–5.3], AIDS [HR=2.4, 95% CI 1.2–4.6], and rheumatoid diseases [HR=2.1, 95% CI 1.2–3.6] were all associated with a statistically significantly increased FN risk (Table 1). In addition, peptic ulcer disease, renal disease and connective tissue disease were also associated with risk of FN, although these associations were not statistically significant. HR estimates did not change materially after also adjusting for cancer stage, ANC, chemotherapy regimen, dose reduction and radiation therapy prior to chemotherapy in the Cox model. Conclusions: Our findings suggest that several chronic comorbidities may be associated with increased FN risk in the first chemotherapy cycle among NHL patients not already receiving prophylactic G-CSFs. This information, if confirmed by others, may aid clinical decision making with respect to use of prophylactic G-CSF use during chemotherapy treatment. Disclosures: Chao: Amgen,Inc: Research Funding. Page:Amgen, Inc: Employment, Shareholder Other. Rodriguez:Amgen, Inc: Research Funding. Yang:Amgen, Inc: Research Funding. Huynh:Amgen, Inc: Research Funding. Chia:Amgen, Inc: Employment, Shareholder Other.

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Overuse and underuse of pegfilgrastim for primary prophylaxis of febrile neutropenia

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155218792698 ◽

2018 ◽

Vol 25 (6) ◽

pp. 1357-1365

Author(s):

Andrew R Zullo ◽

Uvette Lou ◽

Sarah E Cabral ◽

Justin Huynh ◽

Christine M Berard-Collins

Keyword(s):

Febrile Neutropenia ◽

Palliative Chemotherapy ◽

Chemotherapy Regimen ◽

Multivariable Analysis ◽

Patient Characteristics ◽

Primary Prophylaxis ◽

Cancer Center ◽

Cancer Type ◽

Prescribing Practices ◽

Physician Characteristics

Introduction Guidelines recommend pegfilgrastim for primary prophylaxis of febrile neutropenia after highly myelosuppressive chemotherapy. While deviations from guidelines could result in overuse and increased costs, underuse is also a concern and could compromise quality of care. Our objectives were to evaluate guideline adherence and quantify the extent to which physician heterogeneity may influence pegfilgrastim use. Methods We randomly sampled 550 patients from a retrospective cohort of those who received infusions at an academic cancer center between 1 September 2013 and 1 September 2014. Electronic medical and drug dispensing records provided information on patient characteristics, chemotherapy characteristics, prescribing physician, and pegfilgrastim administration. Results We included 154 patients treated by 25 physicians. About half of patients were male and mean age was 61.3 years. Forty (26.1%) patients had no febrile neutropenia risk factors, 62 (40.5%) had one, and 51 (33.3%) had two or more. Thirty patients (19.5%) received pegfilgrastim, of which 12 (40%) received palliative chemotherapy. Nine (60%) of 15 patients on a regimen with a febrile neutropenia risk ≥ 20% received pegfilgrastim. Pegfilgrastim use significantly varied by cancer type (p < 0.01), chemotherapy regimen (p < 0.001), and regimen febrile neutropenia risk (p < 0.001). Multivariable analysis reaffirmed the association between chemotherapy regimen febrile neutropenia risk ≥ 20% and pegfilgrastim use (odds ratio (OR) = 10.1, 95% confidence interval (CI): 1.6–62.7) and suggested that 31% (95% CI: 8%–71%) of the variation in use was attributable to physician characteristics. Conclusion Pegfilgrastim was potentially overused for palliative chemotherapy and underused for chemotherapy regimens with febrile neutropenia risk ≥ 20%. Successful interventions to modify prescribing practices likely require an understanding of the relationship between specific physician characteristics and pegfilgrastim use.

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Personalizing Cancer Supportive Care: Predicting Neutropenic Complications in Patients Receiving Intermediate Risk Cancer Chemotherapy

Blood ◽

10.1182/blood.v118.21.1022.1022 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1022-1022 ◽

Cited By ~ 1

Author(s):

Gary H. Lyman ◽

Eva Culakova ◽

Marek S. Poniewierski ◽

Jeffrey Crawford ◽

David C. Dale ◽

...

Keyword(s):

High Risk ◽

Febrile Neutropenia ◽

Cancer Chemotherapy ◽

Research Funding ◽

Risk Model ◽

Chemotherapy Regimen ◽

Risk Group ◽

Low Risk ◽

Severe Neutropenia ◽

Intermediate Risk

Abstract Abstract 1022 Background: Neutropenic complications represent important dose-limiting toxicities of cancer chemotherapy. We recently developed and validated a risk model for neutropenic complications in patients with solid tumors or lymphoma receiving cancer chemotherapy (Lyman et al. Cancer 2011). While practice guidelines recommend primary colony-stimulating factor (CSF) prophylaxis for patients at >20% risk of febrile neutropenia (FN), many patients receive chemotherapy regimens associated with an intermediate risk (10–20%) of FN. For these patients, the decision to give or withhold primary CSF prophylaxis is based on clinical judgment. We report here the ability of the risk model to identify patients with individual characteristics placing them at high risk for neutropenic complications among patients receiving intermediate risk chemotherapy regimens. Methods: A prospective cohort study was conducted of consenting patients initiating a new chemotherapy regimen at 115 randomly selected US oncology practices between 2002–2006. The risk of cycle 1 severe or febrile neutropenia was estimated [95% CI] utilizing logistic regression analysis adjusting for key clinical factors including: planned chemotherapy, prior chemotherapy, age, abnormal hepatic or renal function, low pretreatment white blood count, and immunosuppressive medications. The cumulative incidence of severe neutropenia and FN across 4 cycles was estimated by the product limit method of Kaplan and Meier. Results: Among 3,760 patients with cancers of breast, lung, ovary, colon, or lymphoma, 2,270 received an intermediate risk chemotherapy regimen based on NCCN guidelines. Overall, in the subpopulation receiving intermediate risk regimens, severe or febrile neutropenia occurred in cycle 1 in 21.4% while FN over 4 cycles was observed in 11%, and primary CSF prophylaxis was utilized in 16.4%. The performance of the risk model was good in this subgroup with a c-statistic of 0.82 [0.80–0.84]. Among the half of patients classified as high risk based on the model despite receiving an intermediate risk chemotherapy regimen, cycle 1 severe or febrile neutropenia occurred in 38% [35%–41%] compared to 5% [4%–6%] of patients classified as low risk based on the model receiving such regimens. Model sensitivity and specificity were 89% and 61%, respectively. The cumulative risk of FN over 4 cycles of chemotherapy was 20% in predicted high risk group versus 5% in the low risk group (Figure). The majority of severe or febrile neutropenia events (67%) and FN events (55%) were observed in cycle 1. One-half of high risk patients who did not receive primary CSF prophylaxis in cycle 1 received CSF during subsequent cycles following a neutropenic event. Conclusions: Our model for predicting neutropenic complications can identify patients at high individual risk for severe neutropenia in cycle 1 or FN in the first 4 cycles of chemotherapy when receiving intermediate risk chemotherapy. This analysis emphasizes the potential value of determining an individual patient's risk of chemotherapy complications based on a validated risk model. Disclosures: Lyman: Amgen: Research Funding. Crawford:Amgen: Consultancy, Honoraria, Research Funding. Dale:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuderer:Amgen: Research Funding.

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A Phase 1b Dose Escalation Trial of Carfilzomib in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-123279 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2828-2828

Author(s):

Swetha Kambhampati ◽

Bita Fakhri ◽

Weiyun Ai ◽

Lawrence D Kaplan ◽

Joseph Tuscano ◽

...

Keyword(s):

Febrile Neutropenia ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Level 3 ◽

Phase 1B ◽

Equity Ownership ◽

Level 2

Background Despite advances in therapy, relapsed or refractory (RR) non-Hodgkin lymphoma (NHL) remains a major treatment challenge. Preclinical data support the activity of proteasome inhibitors against lymphoma through multiple mechanisms including activation of the endoplasmic reticulum (ER) stress response and reduction in the threshold for apoptosis in response to chemotherapy. Clinically, proteasome inhibiton with bortezomib added to bendamustine yielded promising results in patients (pts) with indolent NHL with limited additional toxicity. Compared to bortezomib, carfilzomib is a more target specific and potent proteasome inhibitor with less neurotoxicity. We embarked on a multicenter, phase 1b dose escalation trial to assess the combination of carfilzomib with bendamustine and rituximab in pts with RR aggressive or indolent NHL. Methods The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended phase II dose of carfilzomib when combined with bendamustine and rituximab. The secondary objective is to evaluate the preliminary antitumor activity of the combination in select NHL histologies. Correlative studies examine markers of ER stress and apoptosis in response to treatment. Here we report the preliminary results of the dose escalation phase expected to be completed in Fall 2019. We followed a standard 3+3 design with escalation of the carfilzomib dose in 4 dose level cohorts combined with bendamustine dosed at 90 mg/m2 IV on Days 1 and 2 and Rituximab dosed at 375 mg/m2 IV on Day 9 of cycle 1 and Day 1 of subsequent cycles. Initially, carfilzomib was dosed twice a week with dose level 1 at 15 mg/m2 IV on days 1,2,8,9, 15, and 16. Subsequently, we explored weekly dosing schedules with carfilzomib at 36 mg/m2 (dose level 2), 56 mg/m2 (dose level 3), and 70 mg/m2 (dose level 4) on days 9 and 16 with a 20 mg/m2 starting dose on day 2. Dose limiting toxicity (DLT) was defined as Gr4 or specific Gr3 events attributable to the combination. Pts are treated for up to 6 cycles with an interim PET/CT after cycle 3. Results To date, 10 pts have been treated on the dose escalation phase with one patient currently on study treatment. Overall, 5 pts had diffuse large B-cell lymphoma (DLBCL), 3 mantle cell lymphoma (MCL), 1 follicular lymphoma (FL), and 1 marginal zone lymphoma (MZL). Pts received a median of 3 prior lines of therapy. Four pts were treated on dose level 1, 3 on dose level 2, and 3 on dose level 3. Treatment-emergent Grade 2-4 adverse events included thrombocytopenia in 1 pt (Gr 4), neutropenia in 1 pt (Gr 4), febrile neutropenia in 1 pt (Gr 3), culture negative fevers in 1 pt (Gr 3), nausea/vomiting in 2 pts (Gr 2 and 3), other GI toxicities in 1 pt (Gr 2), lower back pain in 1 pt (Gr 2), arthralgias in 1 pt (Gr 2), and cerebrevoascular ischemia in 1 pt (Gr 2). Two pts had treatment related-SAEs (Gr3 culture negative fevers; Gr 3 febrile neutropenia and Gr 3 vomiting) at dose level 2 and 3 respectively. One patient experienced DLT (Gr 3 febrile neutropenia) at dose level 3. There were no treatment related deaths. Of 10 evaluable pts to date, the overall response rate (ORR) is 40% with 3 pts achieving complete remission (one with FL, one with DLBCL and one with MCL) and one pt with MCL achieving a partial remission. The responder with FL had relapsed disease after achieving prior complete remission with rituximab and bendamustine alone. For the 9 pts who completed study treatment, median duration of treatment was 2.4 months, median progression free survival was 1.9 months and median overall survival was 11.6 months. The median duration of response for the 3 responders who completed therapy was 21.8 months. Conclusion Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for pts with RR NHL. The MTD has not been reached and enrollmemt continues, with dose escalation phase anticipated to complete in Fall 2019. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options. Disclosure: This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program with general research support provided by Amgen. Disclosures Tuscano: Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria; Amgen: Honoraria; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy.

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Medicare Patients Receiving Chimeric Antigen Receptor T-Cell Therapy for Non-Hodgkin Lymphoma: A First Real-World Look at Patient Characteristics, Healthcare Utilization and Costs

Blood ◽

10.1182/blood-2019-124364 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 793-793 ◽

Cited By ~ 4

Author(s):

Karl M. Kilgore ◽

Iman Mohammadi ◽

Amy Schroeder ◽

Christie Teigland ◽

Anna Purdum ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Patient Characteristics ◽

Non Hodgkin Lymphoma ◽

Episode Of Care ◽

Car T ◽

History Of ◽

Medicare Patients

Introduction: Approximately 74,000 Americans are diagnosed with Non-Hodgkin Lymphoma (NHL) each year, approximately one-third of whom have diffuse large B-cell lymphoma (DLBCL). Historically, there have been limited curative treatment options for most patients with DLBCL who relapse or have refractory disease. Recently, autologous anti-CD19 chimeric antigen receptor T-Cell (CAR T) therapies were approved for the treatment of patients with relapsed or refractory large B cell lymphoma with ≥ 2 prior systemic therapies. Objectives: To describe the demographic and clinical characteristics of Medicare patients receiving CAR T therapy (axicabtagene ciloleucel or tisagenlecleucel), and compare healthcare utilization, costs, and outcomes pre- and post-CAR T therapy. Methods: The study utilized a single-group pre-test/post-test design. Data were derived from the Center for Medicare and Medicaid Services (CMS) 100% Medicare Fee-for-Service (FFS) Part A and B claims data. Part D data for the study period were not yet available, so pharmacy claims for oral medications were not evaluated. Patients were included in the study if they had an indicated lymphoma diagnosis and received CAR T therapy between 10/1/2017 and 9/30/2018. The index episode of care was defined as the initial CAR T infusion and associated inpatient stay, if any. To allow for evaluation of patient characteristics and treatments pre- and post-CAR T, patients must have been continuously enrolled in Medicare FFS for 6 months prior to and 100 days after the index date. Baseline demographic and clinical characteristics included age, gender, census region, dual eligibility status, original reason for entitlement to Medicare, specific B-cell lymphoma diagnosis, comorbidities, and prior history of certain conditions. Measures of utilization and cost pre- and post-CAR T (standardized as per patient per month to account for different follow-up durations) included hospitalizations, intensive care unit (ICU) transfers, and emergency department (ED) visits. Pre- and post-CAR T statistical analyses excluded the index episode of care itself. Results: 177 patients met all inclusion criteria. Data are summarized in Table 1. The average age was 70 years, 58.8% were male, and 87.6% were white. The vast majority were non-dual-eligible (91.5%) and qualified for Medicare because of age (87.6%) rather than disability. Clinically, 91.5% had a primary diagnosis of DLBCL. Patients had multiple co-morbidities and 74.6% had a Charlson Comorbidity Index score ≥ 3. Fewer than 5% of patients had a previous autologous stem cell transplant. Forty-three percent of patients had one or more comorbidities that would have disqualified them from CAR T clinical trials (e.g. renal failure, heart failure, recent history of DVT/PE.) Over half of all patients (52%) received intravenous chemotherapy (CTX) in the 6 months prior to CAR T, and 60% received outpatient lymphodepletion. Patients spent a median of 16 days (IQR = 10) in the hospital during their index episode of care for CAR T infusion and nearly half (45.5%) were transferred to the ICU during their post-CAR T infusion stay. During the 6-month pre-index period, over half the patients had ≥ 1 hospitalization, and nearly 20% had ≥ 3. Of these, 27.1% were re-admitted during the post-index period. For those hospitalized, the median length of stay (LOS) pre- and post-index was 7 and 5 days, respectively. The number of patients with an ED visit was reduced by one-half during post- vs. pre-index (15.8% vs. 29.9%). None of the patients expired during the post-index period, but a small percentage (<5%) were admitted to hospice care. There was no clear evidence of subsequent CTX use during the 100-day post-index period (which would suggest disease progression) although claims for the period may lag for some patients. Exclusive of index episode of care costs, median total healthcare costs during the pre-index period were $51,999 (mean=58,820, SD=45,701) and $14,014 post-index (mean=23,738, SD=29,698), which translates into $9,749 pre- vs. $7,121 post-index per patient per month, a 27% decrease. Conclusions: The results of this real-world study indicate that older patients with multiple comorbidities can be treated successfully with CAR T therapy, and that post-index care was associated with lower hospitalization rates, bed days, ED visits, and lower total costs during this period. Disclosures Kilgore: Kite Pharma: Research Funding. Mohammadi:Kite Pharma: Research Funding. Schroeder:Kite Pharma: Research Funding. Teigland:Kite Pharma: Research Funding. Purdum:Kite Pharma: Employment. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding.

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Phase 1b/2 Study of Vipor (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide) in Relapsed/Refractory B-Cell Lymphoma: Safety, Efficacy and Molecular Analysis

Blood ◽

10.1182/blood-2020-141447 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 44-45 ◽

Cited By ~ 2

Author(s):

Christopher Melani ◽

Rahul Lakhotia ◽

Stefania Pittaluga ◽

Milos D. Miljkovic ◽

James D. Phelan ◽

...

Keyword(s):

Febrile Neutropenia ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

B Cell Lymphoma ◽

Fixed Dose ◽

Targeted Agents ◽

Non Hodgkin Lymphoma ◽

Survival Pathways ◽

Car T

Background: Aggressive B-cell non-Hodgkin lymphoma (NHL) can be cured with chemoimmunotherapy; however, those who fail primary therapy and those with indolent NHL are rarely curable. Targeted agents can disrupt key survival pathways in NHL such as regulation of apoptosis (BCL2: venetoclax), B-cell receptor signaling (BTK: ibrutinib), and NF-κB survival pathways (IRF4/SPIB: lenalidomide). These agents are active as monotherapy but fail to induce deep responses and require continuous therapy. Also, genetically defined subtypes of NHL that best respond to these targeted agents are undefined. Synergistic cytotoxicity has been shown with these targeted therapies and corticosteroids in DLBCL cell lines. We hypothesized that combining agents that target multiple survival pathways will leverage efficacy and time-limited, cyclic dosing will limit toxicities. Methods: Relapsed/refractory (R/R) B-cell NHL pts, excluding MCL and CLL/SLL, with adequate organ function were eligible. A phase I "3+3" design was used to determine the maximum tolerated dose (MTD) of 4 dose-levels (DLs) of dose-escalated venetoclax (200mg, 400mg, 600mg, and 800mg) PO D2-14 (starts cycle 2 for DL1) in combination with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. A phase II expansion in R/R DLBCL and FL was included at the MTD. Up to 6 cycles of ViPOR every 21-days was given without maintenance. TLS and PCP prophylaxis was given to all pts and VTE prophylaxis and G-CSF use was per investigator discretion. Baseline CT, PET, BM and tumor biopsy was performed with CT scans after cycles 1, 2, 4, and 6 and PET after cycle 6 or at time of suspected CR. Surveillance CT was performed q3m for 1y, q4m x 1y, q6m x 1y, then annually x 2y. Results: 53 pts were enrolled and treated; 17 in dose-escalation and 36 in dose-expansion. NHL subtypes included DLBCL (23), FL (19), HGBCL "double-hit" (9), and MZL (2). Of 32 aggressive pts, 34% transformed from indolent NHL. Median age was 57y (range 29-83) with stage III/IV disease in 89%, elevated LDH in 68%, and >2 EN sites in 57%. Median prior therapies was 3 (range 1-9) with 45% of pts refractory (i.e. <PR) to last therapy. A single dose-limiting toxicity (DLT) of G3 intracranial hemorrhage occurred at DL1 with concomitant enoxaparin and ASA. No other DLTs occurred and venetoclax 800mg was used in expansion. Heme AEs (% cycles) were most common and included thrombocytopenia (23%), neutropenia (23%) and anemia (7%). G-CSF was used in 92% of pts and 89% of cycles with only 3 (6%) cases of febrile neutropenia. Non-heme AEs (% pts) were mainly G1-2 and included diarrhea (67%), hypokalemia (56%), nausea (52%), and rash (42%). Most common G3-4 non-heme AEs included hypokalemia (19%), diarrhea (8%), and a.fib/flutter (6%). G4 TLS occurred in 1 pt with HGBCL after the first venetoclax dose and was successfully treated without further TLS upon continued treatment. Dose reductions and delays occurred in 8% and 9% of cycles, respectively. Of 53 total patients, 51 completed 1C of therapy with restaging CT and tumor reduction occurred in 90% of pts overall (Fig 1A). Of 44 pts who are now off therapy, 43 were evaluable for response with an ORR of 70% and 49% CR, with responses across all DLs and NHL subtypes. In 27 pts with aggressive NHL, ORR was 56% with 37% CR. Based on DLBCL subtype by IHC, ORR and CR rate was 62% (8/13) and 54% (7/13) in non-GCB and 50% (7/14) and 21% (3/14) in GCB DLBCL, respectively. In 16 pts with indolent NHL, ORR was 94% with 69% CR. ORR and CR rate was 52% (11/21) and 29% (6/21) in refractory pts and 86% (19/22) and 68% (15/22) in relapsed pts, respectively. ORR was 40% with 30% CR in 10 patients who failed prior CAR-T and completed ViPOR therapy. With a median potential f/u of 13m, median TTR and DOR was 0.8m and NR, respectively, with 25 (69%) of 36 responses ongoing. 5 pts relapsed after CR, including 2 non-GCB at 3m and 6m, 1 HGBCL at 5m, 1 FL at 6m, and 1 MZL at 16m. Median PFS and OS was 9m and NR, respectively; 20m and NR in indolent NHL, 3m and 13m in GCB, and 7m and 13m in non-GCB DLBCL (Fig 1B). Conclusions: ViPOR is safe without unexpected toxicities observed. Most common AEs were hematologic with rare febrile neutropenia and no severe infections observed when given with G-CSF prophylaxis. ViPOR induces durable CRs without maintenance therapy, including refractory and post CAR-T pts. Molecular analyses are ongoing and will be presented at the meeting. Disclosures Portell: Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. OffLabel Disclosure: Off-label use of the combination of venetoclax, ibrutinib, prednisone, obinutuzumab and lenalidomide in relapsed/refractory B-cell non-Hodgkin lymphoma.

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Phase I Study Of Inotuzumab Ozogamicin (InO) Combined With R-GDP For Relapsed/Refractory CD22+ B-Cell Non-Hodgkin Lymphoma (B-NHL)

Blood ◽

10.1182/blood.v122.21.1821.1821 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1821-1821

Author(s):

Randeep Sangha ◽

Andrew Davies ◽

Nam H. Dang ◽

Michinori Ogura ◽

David A. MacDonald ◽

...

Keyword(s):

Febrile Neutropenia ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Inotuzumab Ozogamicin ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Expansion Cohort ◽

Number Of Cycles

Abstract Background CD22 is expressed on most B-NHL. Inotuzumab ozogamicin (InO) is a humanized anti-CD22 antibody conjugated with calicheamicin, a potent cytotoxic antitumor antibiotic with activity in relapsed/refractory B-NHL. This study explored the safety, tolerability and preliminary efficacy of InO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for subjects with CD22+ B-NHL. Methods Part 1 (dose escalation phase, n = 27) enrolled patients (pts) with relapsed or refractory CD22+ B-NHL treated with ≥1 prior R-chemo regimen using an up-and-down independent dose-escalation schema for G and P. InO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-day cycle for up to 6 cycles. R-GDP (R 375 mg/m2 day 1; G 1000 mg/m2 days 1 and 8; D 40 mg days 1-4; P 75 mg/m2 day 1) is a regimen used in some patients with relapsed/refractory B-NHL. Part 2 (MTD confirmation cohort, n = 10) enrolled additional pts to further evaluate the safety and tolerability of the MTD determined in Part 1. Confirmation of the MTD required a dose-limiting toxicity (DLT) rate of < 33% in Cycle 1 and < 4 pts discontinuing prior to Cycle 3 due to adverse event (AE). Part 3 (MTD expansion cohort, n = 18) enrolled additional pts to further evaluate the preliminary efficacy of InO when given in combination with R-GDP. Results Fifty-five pts were treated: 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL. Characteristics: aged 25 to 81 y (median 65 y); 51 with ECOG PS ≤1; median of 2 prior chemo regimens (range 1-6); 8 refractory to prior therapy. The dose-escalation phase (Part 1) identified the MTD as InO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2 (day 1 only), D 40 mg, P 50 mg/m2. This MTD was confirmed in Part 2, in which 3 pts had DLTs (2 with grade 4 platelets, 1 with febrile neutropenia). The most common treatment-related grade ≥3 AEs included thrombocytopenia (69%), neutropenia (56%), lymphopenia (22%), leukopenia (18%), anemia (16%), and febrile neutropenia (11%). Twenty-one pts completed all 6 treatment cycles; the median number of cycles completed was 4 (range 1-6). The most common AEs leading to dose reductions and temporary dose delays included thrombocytopenia, febrile neutropenia, and neutropenia. For the 55 pts enrolled, the overall response rate (ORR) was 45% (n = 25), including 22% of pts (n = 12) who achieved a complete response (CR). Of the 55 pts enrolled, 46 had both a baseline and at least 1 post-baseline assessment reported. In this population to date, the ORR was 54%, including 26% who achieved a CR. 2 pts remain on treatment at the time of data collection. Additional efficacy data are summarized in Table 1 . Pharmacokinetic samples were collected for pts enrolled in the MTD confirmation and expansion cohorts. Fifty-three pts have discontinued treatment, including 21 who completed the planned number of cycles, 12 due to AE (including 8 pts with grade 2/3 thrombocytopenia that did not resolve to grade 1 or better within the 28-day dose delay window allowed per protocol, and 1 each grade 5 oesophageal obstruction, grade 2 skin lesion and grade 4 tumor lysis syndrome) and 12 due to PD. Fifteen deaths have been reported, 12 due to disease progression and 3 due to other causes, including graft-versus-host disease, toxicity after allograft, and sequelae of subdural hematoma not related to study drug (n = 1 each). Conclusions InO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2 day 1 only) and P (50 mg/m2). Preliminary efficacy in the MTD expansion cohort is encouraging. Follow-up for PFS and OS is currently ongoing. Disclosures: Sangha: Boehringer Ingelheim: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Pfizer: Honoraria. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma; this drug is investigational and is not approved for use in any indication in any country. Davies:Pfizer: Research Funding; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ogura:Eli Lilly: Research Funding. Volkert:Pfizer Inc: Employment. Ananthakrishnan:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Goh:Gilead Scienes: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Jannsen: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Hospira: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Hospitalized with stroke at the weekend: Higher cost and risk of early death?

International Journal of Stroke ◽

10.1177/1747493021992597 ◽

2021 ◽

pp. 174749302199259

Author(s):

Marco Ghiani ◽

Sabrina Mueller ◽

Ulf Maywald ◽

Thomas Wilke

Keyword(s):

Propensity Score ◽

Cerebral Infarction ◽

Propensity Score Matching ◽

Disease Severity ◽

Patient Characteristics ◽

Weekend Effect ◽

Health Claims ◽

Hospital Death ◽

Stroke Severity ◽

Baseline Characteristics

Objectives Previous studies have shown that weekend hospitalizations are associated with poorer health outcomes and higher mortality (“weekend effect”). However, few of these studies have adjusted for disease severity and little is known about the effect on costs. This work investigates the weekend effect and its costs for patients with cerebral infarction in Germany, adjusting for patient characteristics and proxies of stroke severity. Methods Adult patients with a cerebral infarction hospitalization 10th revision of the International statistical classification of diseases and related health problems (ICD-10: I63) between 01 January 2014 and 30 June 2017 were included from German health claims (AOK PLUS dataset). Propensity score matching was used to match patients hospitalized on weekends or on public holidays (weekend group) with patients hospitalized during the working week (workday group), based on baseline characteristics and proxies for disease severity such as concomitant diagnoses of aphasia, ataxia, and coma, or peg tube at index hospitalization. Matched cohorts were compared in terms of in-hospital, 7-day, and 30-day mortality, as well as risk and costs of stroke and rehabilitation stays in the year after first stroke. Results Of 32,311 patients hospitalized with cerebral infarction between 01 January 2014 and 30 June 2017, 8409 were in the weekend group and 23,902 in the workday group. After propensity score matching, 16,730 patients were included in our study (8365 per group). Matched cohorts did not differ in baseline characteristics or stroke severity. In the weekend group, the risk of in-hospital death (11.2%) and the seven-day mortality rate (6.8%) were 13.1% and 17.2% higher than in the workday group, respectively (both p < 0.01). The hazard ratio for death in the weekend group was 1.1 ( p = 0.043). The risks of subsequent stroke hospitalization and rehabilitation stays for a stroke were 8.4% higher and 5.5% higher in the weekend group (both p = 0.02). As a result, the stroke-related hospitalization and rehabilitation costs per patient year were, respectively, 5.6% and 8.0% higher in the weekend group (both p = 0.01). Conclusions A significant weekend effect emerged after controlling for observable patient characteristics and proxies of stroke severity. This effect also resulted in higher costs for patients admitted on weekends.

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Timing of Pegfilgrastim: Association with Febrile Neutropenia in a Pediatric Solid and CNS Tumor Population

Journal of Pediatric Oncology Nursing ◽

10.1177/10434542211037729 ◽

2021 ◽

Vol 38 (6) ◽

pp. 375-384

Author(s):

Laura Schlenker ◽

Renee C.B. Manworren

Keyword(s):

Febrile Neutropenia ◽

Mixed Model ◽

Random Effect ◽

Retrospective Chart Review ◽

Patient Characteristics ◽

Secondary Outcome ◽

Pharmacokinetic Data ◽

Risk Patients ◽

Independent Variable ◽

Dichotomous Outcomes

Background: While recommended timing of pegfilgrastim administration is ≥24 h after chemotherapy, patient barriers to next day administration, available adult evidence, and pharmacokinetic data have led to earlier administration in some pediatric patients with solid and central nervous system tumors. The purpose of this study was to compare patient outcomes by timing of pegfilgrastim after chemotherapy. Methods: A retrospective chart review examined timing of 932 pegfilgrastim administrations to 182 patients, 0–29 years of age. The primary outcome was febrile neutropenia (FN); the secondary outcome was neutropenic delays (ND) ≥7 days to next chemotherapy cycle. To account for multiple pegfilgrastim administrations per patient, a generalized mixed model was used with a logit link for the dichotomous outcomes (FN & ND), timing as the dichotomous independent variable, and random effect for patient. Results: FN occurred in 196 of 916 cycles (21.4%); and ND in 19 of 805 cycles (2.4%). The fixed effect of pegfilgrastim administration < or ≥24 h after chemotherapy was not significant, p = .50; however, earlier or later than 20 h was significant, p = .005. FN odds were significantly higher when pegfilgrastim was given <20 h (OR 1.78, 95% CI: 1.19–2.65) after chemotherapy, which may be attributable to differences in chemotherapy toxicity regardless of pegfilgrastim timing. Discussion: While attempts should be made to administer pegfilgrastim ≥24 h after chemotherapy, if barriers exist, modified timing based on individual patient characteristics should be considered. Prospective randomized trials are needed to identify lower risk patients for early pegfilgrastim administration.

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ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-135941 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14 ◽

Cited By ~ 1

Author(s):

Tae Min Kim ◽

Nehal Lakhani ◽

Justin Gainor ◽

Manali Kamdar ◽

Philip Fanning ◽

...

Keyword(s):

Immune Response ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Tolerability Profile ◽

Low Grade ◽

Publicly Traded ◽

Private Company ◽

Non Hodgkin Lymphoma ◽

Time Of Presentation

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.

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Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood-2019-125449 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2609-2609

Author(s):

Muhned Alhumaid ◽

Georgina S Daher-Reyes ◽

Wilson Lam ◽

Arjun Law ◽

Tracy Murphy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Treatment Strategies ◽

Patient Characteristics ◽

Cancer Center ◽

Advisory Committees ◽

Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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