Treatment Patterns for Patients with Post-Transplant Lymphoproliferative Disorder Who Fail Rituximab after Allogeneic Hematopoietic Stem Cell Transplantation: Findings from a Systematic Literature Review

Abstract Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized disease after allogeneic hematopoietic stem cell transplantation (HCT) and is one of the most common post-transplant malignancies. In most cases, PTLD is associated with Epstein-Barr Virus (EBV) infection. The management of PTLD remains a challenge, with no approved treatments for patients. Clinical practice treatment guidelines recommend rituximab as first-line therapy for PTLD post-allogeneic HCT; however, treatment options for PTLD patients who fail rituximab are not clearly defined. We conducted a systematic literature review of the published literature to better understand treatment patterns for patients with PTLD who fail rituximab post-allogeneic HCT in a real-world setting. Methods: The systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. Using extensive search terms for the indication and study designs, studies were identified using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. No treatment limitations were imposed to ensure inclusion of all relevant evidence; the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram. Results: A total of 69 studies were identified that described patients with PTLD post-allogeneic HCT. The majority (61 studies) were retrospective chart reviews, of which 54 studies were single-center studies. Forty-eight studies reported data on treatment of patients with PTLD. Among these, 5 studies included data prior to 2000, 33 studies included data from 2000-2010, and 26 studies included data from 2010-2016. The sample size for PTLD patients was between 1 and 144 patients, with only one study of > 100 patients. First-line therapy in PTLD included rituximab (41 studies), various chemotherapy regimens (15 studies), and lymphocyte infusion (10 studies). Nine studies reported treatment for patients who failed first-line rituximab (13-67% of PTLD patients); the number of patients with second-line treatments ranged from 2-10 across studies. Second-line treatments varied greatly across studies and included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP, n=1); rituximab plus CHOP (R-CHOP, n=1-2); cyclophosphamide, etoposide/cytarabine (VP16/ARA-C, n=1); rituximab plus cyclophosphamide (n=1); rituximab plus high-dose cytarabine (n=1); chemotherapy unspecified (n=2-4), and lymphocyte infusion (n=3-5). Only 2 studies reported treatment outcomes in rituximab-refractory patients. One study (N=62, second-line n=10, median age 49 years) reported no complete or partial remission in the chemotherapy group; 60% had complete remission in the lymphocyte infusion group. The second study (N=12, second-line n=3, mean age 5 years) reported complete remission in 1 patient with lymphocyte infusion as second-line treatment. Conclusions: This systematic literature review demonstrates that data on treatment patterns for PTLD patients who failed rituximab post-allogeneic HCT are limited (9 studies with a sample size ≤ 10). Published data suggest that the percentage of patients who fail rituximab vary greatly (13-67%), there is no consistent standard of care for PTLD patients who fail rituximab, and outcomes are poor. There continues to be a significant unmet need among PTLD patients who fail rituximab, and further studies are needed to better understand rituximab response rates in the real-world setting. Disclosures Xu: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

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A Systematic Literature Review of Real-World Evidence in Post-Transplant Lymphoproliferative Disorder

Blood ◽

10.1182/blood-2018-99-113583 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5839-5839 ◽

Cited By ~ 1

Author(s):

Hairong Xu ◽

Anna Forsythe ◽

Arie Barlev ◽

Nazia Rashid ◽

Crystal Watson

Keyword(s):

Literature Review ◽

Systematic Literature Review ◽

Real World ◽

Lymphoproliferative Disorder ◽

Survival Outcomes ◽

Employment Equity ◽

The Real ◽

Post Transplant ◽

Real World Evidence ◽

Equity Ownership

Abstract Introduction: Recipients of solid-organ transplant (SOT) or allogeneic hematopoietic stem cell transplantation (HCT) have an increased risk of cancers from Epstein-Barr virus (EBV), specifically lymphomas due to immunosuppression. Post-transplant lymphoproliferative disorder (PTLD) is a disease with a range of clinical presentations, including that of an aggressive lymphoma, that occurs after transplantation. PTLD occurs rarely after transplantation and is associated with poor survival outcomes. Publications on the clinical evidence for PTLD are scarce; therefore, a systematic literature review (SLR) was conducted to better understand the real-world evidence in PTLD. Methods: An SLR was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with the scope defined in terms of Population, Intervention Comparators, Outcomes and Study design (PICOS) criteria. Studies were identified based on a systematic search using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. To ensure inclusion of all relevant evidence, no treatment limitations were imposed; however, the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram. Results: A total of 447 articles were identified that met the SLR criteria: 350 SOT, 70 HCT, and 27 that included both SOT and HCT. Among 97 studies of PTLD post HCT, 81 involved allogeneic HCT, 2 involved autologous HCT, and 14 did not report the type of HCT. Of the 376 identified studies with PTLD post-SOT, the most prevalent SOTs involved were: kidney (193 studies), heart (126 studies), liver (91 studies), lung (84 studies), pancreas (43 studies), and intestine (25 studies). Data on the risk of PTLD, treatment patterns for PTLD, and utilization and survival outcomes following PTLD were reported in 334, 331, and 210 studies, respectively. There was notable clinical and methodological heterogeneity among studies. For example, there was variability in the study populations: 114 were adult populations, 136 were pediatric populations, and 197 did not specify age. Most of the studies were retrospective (419 studies) versus prospective (28 studies), and most were single-center studies (340 studies) versus multicenter studies/registries (98 studies), limiting the generalizability of the results. In addition, the sample sizes were small among most PTLD studies, with fewer than 50 patients in 376 studies, 50-100 patients in 9 studies, and more than 100 patients in 46 studies. The clinical and methodological heterogeneity noted above may explain the large variations in reported risk of PTLD in both HCT and SOT. Among adult SOT patients, the risk of developing PTLD was 0.2% to 11.5%, while among pediatric SOT patients, the risk was 0.3% to 25.0%. Among adults with HCT, the risk of developing PTLD was 1.0 to 20.0%, while among pediatric patients with HCT, the risk was 1.3% to 23.5%. Conclusions: To the best of our knowledge, this is the first comprehensive SLR to examine the published real-world evidence in patients with PTLD. Our SLR reveals important differences with respect to methodology and reporting of real-world published studies assessing the current landscape in PTLD. Additional large, high-quality studies employing more rigorous study methodology are required to understand the current landscape of PTLD in the real-world setting. Disclosures Xu: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

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Characterization of Disease, Treatment Patterns, and Outcomes of Patients with Myelofibrosis: Analysis of 2 United States Commercial Claims Databases

Blood ◽

10.1182/blood.v128.22.4769.4769 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4769-4769 ◽

Cited By ~ 1

Author(s):

Maneesha Mehra ◽

Ravi Potluri ◽

Jianming He ◽

Grace Wang ◽

Suneel Mundle ◽

...

Keyword(s):

Supportive Care ◽

Myeloproliferative Neoplasm ◽

Treatment Patterns ◽

Line Treatment ◽

Second Line ◽

Management Options ◽

Disease Treatment ◽

Employment Equity ◽

Platelet Counts ◽

Equity Ownership

Abstract Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm with profound negative effects on quality of life and survival. MF is characterized by clonal myeloproliferation, ineffective erythropoiesis, bone marrow stromal changes, hepatosplenic extramedullary hematopoiesis, and aberrant cytokine expression. Patients (pts) with MF may present with splenomegaly, constitutional symptoms, anemia, thrombocytopenia, or leukocytosis. Presentation may be primary (PMF), secondary following transformation from polycythemia vera or essential thrombocythemia (post-PV/ET sMF), or secondary from diseases such as myelodysplastic syndrome, leukemia, or lymphoma (Other sMF). Management options include allogeneic stem cell transplantation (the only potentially curative treatment), hydroxyurea, interferon alpha, alkylating agents, splenectomy, splenic radiotherapy, and the JAK1/2 inhibitor ruxolitinib. The present analysis was conducted to characterize disease, treatment patterns, and outcomes in pts with MF using 2 US health insurance claims databases. Methods: The Truven Health Analytics MarketScan® (Commercial Claims and Encounters and Truven Medicare) and Optum™ integrated virtual electronic health records and claims databases were retrospectively analyzed to identify pts with MF diagnosed between 2006 and 2015. Pts aged ≥ 18 years with ≥ 1 month of medical history prior to diagnosis were included. Pts were categorized as PMF, post-PV/ET sMF, or Other sMF based on earliest MF International Classification of Diseases, 9th revision diagnosis code. Demographic characteristics, constitutional symptoms, platelet counts, and treatment patterns were summarized. A treatment line was considered ended if followed by a treatment gap of ≥ 60 days. Kaplan-Meier analysis was performed to determine overall survival (OS). The effects of specific covariates on OS were analyzed using a Cox proportional hazards model. Results: 6,982 pts in the Truven and Optum databases met the inclusion criteria. Median age at diagnosis was 66 years (interquartile range, 58-78 years); 52.3% (n = 3,650) were aged > 65 years. More than half of pts were male (52.6%; n = 3,673). Overall, 23.5% (n = 1,637), 13.7% (n = 956), and 62.9% (n = 4,389) of pts had PMF, post-PV/ET sMF, and Other sMF, respectively. At the time of index diagnosis (± 90 days), 10.7% (n = 749) of pts had splenomegaly; an additional 3.3% (n = 227) developed splenomegaly > 90 days following index diagnosis, and a total of 17.8% (n = 1,239) had splenomegaly at any time. Among 112 pts with available baseline platelet counts (-90 to +180 days of index MF diagnosis) most had > 100,000/μL (77.7%; n = 87); 1.8% (n = 2) had 75,000-100,000/μL, 11.6% (n = 13) had 50,000-75,000/μL, and 8.9% (n = 10) had < 50,000/μL. Overall, 56.6% (n = 3,950) of pts received frontline treatment or supportive care, and 18.7% (n = 1,305) received second-line treatment or supportive care. Among pts receiving frontline and second-line treatment/supportive care, respectively, the most common approaches were steroids alone (26.7% [n = 1,053] and 26.7% [n = 348]) and hydroxyurea alone (20.5% [n = 811] and 21.1% [n = 276]). Ruxolitinib, ± other treatments, was given frontline to 12.4% (n = 488) of pts and second-line to 12.0% (n = 157) of pts. Median OS for pts who received frontline ruxolitinib was 30 months compared with 22 months for pts receiving other treatments (hazard ratio [HR] = 0.7; 95% confidence interval, 0.6-0.8; Figure 1A). Of the 488 pts who received frontline ruxolitinib, 23.0% (n = 112) went on to receive ≥ 1 further treatment; in 43.8% (n = 49) of these pts, the latter regimen also included ruxolitinib. Median OS among pts (n = 430) who failed or discontinued frontline ruxolitinib was 7 months (Figure 1B); this was not affected by sex (HR = 1.03; P = 0.85), age (< 65 vs ≥ 65 years; HR = 0.88; P = 0.50), or the presence of splenomegaly (-90 days before index diagnosis to any point after index diagnosis; HR = 0.87; P = 0.48). Conclusions: Most pts diagnosed with MF were aged ≥ 65 years and had neither splenomegaly nor thrombocytopenia at baseline. In the present database analysis, slightly more than half of pts received any treatment or supportive care. Although only a fraction of pts received ruxolitinib, treatment with ruxolitinib was associated with favorable median OS. However, median OS was greatly reduced once pts failed or discontinued ruxolitinib; additional treatment options for these pts are needed. Disclosures Mehra: Janssen: Employment, Equity Ownership. Potluri:Janssen Research & Development, LLC: Other: Contracted to perform research; SmartAnalyst, Inc.: Employment. He:Janssen Global Services, LLC: Employment, Equity Ownership. Wang:Janssen Research & Development, LLC: Employment, Equity Ownership. Mundle:Janssen Research & Development, LLC: Employment, Equity Ownership. Bussolari:Janssen Research & Development, LLC: Employment, Equity Ownership.

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Assessment of Treatment Patterns and Adverse Events Among Patients with Chronic Myeloid Leukemia Using Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood-2018-99-112695 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3585-3585

Author(s):

Sudeep Karve ◽

Joanna C Huang ◽

Nikhil Ranade ◽

Sanchita Porwal ◽

Monali Desai ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Cardiovascular Events ◽

Kinase Inhibitors ◽

Treatment Patterns ◽

First Line ◽

Employment Equity ◽

Equity Ownership

Abstract INTRODUCTION: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm is primarily treated using tyrosine kinase inhibitors (TKIs). Several next-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib) have been approved since the first approval of imatinib in 2002. With varying safety profiles, data on non-trial long-term TKI use and associated adverse events (AE) can aid in clinical decision making. Using population based data sources the current study assessed treatment patterns and AEs in a non-trial setting among TKI users with CML. METHODS: A retrospective cohort analysis was conducted using MarketScan Commercial, and Supplemental Medicare databases (2012-2016). Data includes details on medical (e.g., date of diagnosis, diagnosis codes, procedures) and pharmacy (e.g., drug dose, duration, strength) utilization for over 90 million individuals enrolled in employer-sponsored health-plans in the US. Patients with a prescription claim for TKI along with at least 2 medical claims on separate dates with a diagnosis code for CML (ICD-9-CM: 205.10 - 205.12; ICD-10: C92.10-C92.12) were selected. Patients were aged ≥18 years at TKI initiation and had continuous health plan enrollment ≥6 months before and ≥6 months after TKI initiation. Patients were followed from TKI initiation until health plan disenrollment or end of database, whichever occurred earlier (defines follow-up period). TKI treatment patterns including initial dose, initial and total TKI treatment duration, treatment switching and discontinuation were assessed. Frequency and proportion for incident (i.e. newly observed conditions) AEs including rash, bleeding, gastrointestinal disorders (nausea, vomiting, diarrhea), tumor lysis syndrome and cardiovascular events (CHF, arrhythmia, peripheral arterial occlusive disease, cerebrovascular events) and post-AE outcomes (switching, discontinuation, dose reduction) were assessed. AE list was developed based on commonly reported events in clinical trials involving TKIs for CML and clinical judgement. All analyses were descriptive in nature. RESULTS: Study included 2,213 CML patients with mean age (standard deviation [SD]) of 55 (15) years, of which 55% were male and 55% had ≥2 co-morbid conditions. Post CML diagnosis, first-line of TKI initiated was imatinib (41%), dasatinib (36%), nilotinib (22%), and bosutinib and ponatinib (1% each). The average (SD) follow-up duration post TKI initiation was 607 (442) days. Mean (SD) duration of first-line TKI prescription was 392 (383) days. 61% of patients continued initial TKI during the follow-up period, 7% discontinued and 32% switched/re-initiated TKI (Figure 1). 39.2% patients had at least 1 incident AE while on index TKI therapy. GI disorders (20.4%) were the most commonly observed AE, followed by cardiovascular events (14.6%), rash (8.4%), bleeding (8.0%), and TLS (0.2%). The average (SD) time to GI disorders, bleeding, cardiovascular event, rash, and TLS was 242 (274) days, 238 (272) days, 219 (261) days, 222 (255) days, and 223 (285) days, respectively. The rates of discontinuation, treatment switch or dose reduction were largely similar across all AEs (Figure 2). The mean duration on any TKI (all-lines of therapy) was 561 (438) days. The most commonly observed AEs on while of TKI therapy (irrespective of line of therapy) were GI disorders (24.7%), followed by cardiovascular events (17.3%), rash (11.5%), bleeding (10.1%) and TLS (0.5%). CONCLUSIONS: The study helps address the current literature gap of long-term treatment patterns and AE among patients with CML using TKIs in a non-clinical trial setting. During follow-up 46% patients experienced at least 1 incident AE while on TKI therapy. Majority of patients (61%) continued same TKI therapy following AE. The type and rate of AE were similar following first-line therapy and anytime on TKI (any-line) during the follow-up period. Study results may not be comparable to clinical trial findings due to certain limitations; e.g., this study did not capture all adverse events but assessed incident AE based on a pre-specified list. Also, due to limitations of administrative claims data, assessment of AE grade was not feasible. However, findings from this study can complement clinical trial data in selection of TKIs for long-term use in real-world setting and can also be of value in selecting TKIs for future clinical studies involving novel combinations in CML. Disclosures Karve: AbbVie: Employment, Equity Ownership. Huang:ZS Associates: Employment; Novo Nordisk Inc: Equity Ownership; AstraZeneca: Research Funding. Ranade:ZS Associates: Employment. Porwal:ZS Associates: Employment. Desai:AbbVie: Employment, Equity Ownership. Rosenberg:AbbVie: Employment, Equity Ownership.

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Trends in the Multiple Myeloma Treatment Landscape: A United States Analysis of Oscer Electronic Health Record Data 2011-2019

Blood ◽

10.1182/blood-2019-125972 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4722-4722

Author(s):

Megan Braunlin ◽

Rajesh Belani ◽

Jacqueline Buchanan ◽

John Travis Wheeling ◽

Christopher Kim

Keyword(s):

Multiple Myeloma ◽

Second Line ◽

Front Line ◽

First Line ◽

Electronic Health Record Data ◽

Employment Equity ◽

The Us ◽

Equity Ownership ◽

Electronic Health

Introduction The treatment (tmt) for multiple myeloma (MM) is evolving with the introduction of novel immunomodulatory drugs (IMiD), monoclonal antibodies (MoAB), and proteasome inhibitors (PI). As new efficacious therapies are approved, the prevalence of MM continues to increase and remains an incurable disease. There is limited real-world evidence describing these temporal changes (Song 2016, Curr Med Res Opin; Fonseca 2017, Leukemia). This study characterizes trends in MM tmts and patient (pt) survival from 2011-19 in the US-based Flatiron electronic health records (EHR) database. Methods Data analyzed were from an enhanced database of oncology EHR contained in the Oncology Services Comprehensive Electronic Records (OSCER), generated by Flatiron Health that includes additional unstructured data processing (New York, NY, March 31, 2019). OSCER represents a longitudinal, demographically and geographically diverse database with data from over 265 cancer clinics representing over 2 million active pts treated at primarily community-based hematology/oncology practices in the US. Inclusion criteria included adult pts ≥18 years (yrs) with a diagnosis of MM (ICD9: 203.x; ICD-10: C90.x) and at least two clinic visits after 2011. Pt and disease characteristics were characterized; line of therapy (LOT) (1-5), year of therapy initiation, and all tmt regimens received. Follow-up time was measured from tmt index until death or last follow-up. Kaplan-Meier overall survival (OS) proportions were estimated from LOT tmt index. Results A total of 9289 pts were identified. At diagnosis the median age was 69 yrs, with 54% of pts male and 68% white. The majority of pts were treated in the community setting (89%) and 11.5% presented with high risk cytogenetics (del17p, t(4;14), t(14;16)). International Staging System (ISS) data was available in 49.2% of subjects, with 16.6%, 16.1% and 16.3% stage 1, 2, and 3 respectively. Among the 91% of pts who received tmt for newly diagnosed MM, median time to tmt was 30 days. In 2017-18, triplet combination (comb) PI-IMiD-dexamethasone (dex) was the most common front (48%) and second line regimen (27%); and the use of this comb increased in both first and second lines over the study period. In contrast, the use of IMiD or PI -dex doublet regimens decreased. In third line setting, PI-IMiD-dex remained the most common comb in 2017-18 (21%) but gradually decreased over the study period with a dip in 2013-14 while MoAB-IMiD-dex combs increased from 3% to 12% (2015/16-2017/18). In second, third, and fourth line MoAB-IMiD-dex comb increased to 8%, 12%, and 14% respectively beginning in 2015 (Table 1). MM tmt regimens changed over the study period, most notably in the first and second LOTs. By 2017-18, triplets replaced doublets as the most common front line (58%) and second line (45%) therapies over the study period. Across all LOTs, triplets were the most prescribed comb in 2017-18 with 42%, 42% and 30% in third, fourth, and fifth lines. Over the study period, monotherapies decreased to 12% in frontline, but their use has remained constant in later lines (Table 2). Overall, 26% of pts received a transplant during follow-up. Approximately 34% of pts survived until the end of follow-up. With each LOT, OS deceased. Median OS of pts treated in first line was 57 months and decreased to 44 months, 32 months, and 25 months in second, third, and fourth lines respectively (Figure 1). OS of MM pts who received first line tmt appears to increase the more recently they were diagnosed. Median OS of MM pts diagnosed in 2013-14 was slightly longer compared to pts diagnosed in earlier yrs (2011-12); 60 months compared to 56 months. Median OS was not reached in 2015-16 (Figure 2). Conclusion Triplet therapies have replaced doublet therapies over time as more options became available to MM pts, especially in frontline setting; frontline monotherapies have nearly halved since the beginning of the study period. In 2015, tmt patterns begin to shift as MoAB based triplets were approved and comprised a higher proportion of the regimens in the relapsed and refractory population. Yet, the majority of pts are still receiving PI-IMiD-dex triplets. OS estimates suggest survival in front line treated pts is slowly increasing in recent yrs. These data illustrate the current tmt landscape of MM and the changes that have occurred since the introduction of novel therapies over the past 8 yrs. MM disease management continues to evolve. Disclosures Braunlin: Amgen, Inc.: Employment. Belani:Amgen, Inc: Employment, Equity Ownership. Buchanan:Amgen Inc.: Employment, Other: Owns Amgen stock, Research Funding. Kim:Amgen, Inc.: Employment, Equity Ownership.

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Systematic Literature Review on Global Real-World Treatment Patterns of Mantle Cell Lymphoma (MCL)

Blood ◽

10.1182/blood-2019-130896 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5881-5881

Author(s):

Keri Keri Yang ◽

Beth Lesher ◽

Eleanor Lucas ◽

Tony Caver ◽

Boxiong Tang

Keyword(s):

Literature Review ◽

Adverse Events ◽

Real World ◽

Treatment Options ◽

Treatment Patterns ◽

Second Line ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Third Line

Introduction: MCL is an aggressive type of non-Hodgkin's lymphoma, and was reported associated with early relapse and poor long-term survival. Treatment options include chemotherapy, immunotherapy, and molecular targeted therapies. As of 2019, molecular targeted therapies available in the United States indicated for the treatment of MCL include the proteasome inhibitor bortezomib, the immunomodulatory drug lenalidomide (following two previous lines of therapy), and the Burton's tyrosine kinase inhibitors (BTKIs) ibrutinib and acalabrutinib (following at least one previous line of therapy). Objective/Methods: To examine the real-world treatment patterns of patients with MCL globally, a systematic literature review was performed (2010-2019) with predefined methodology and inclusion and exclusion criteria. Embase and Medline were searched via ProQuest and the Cochrane Controlled Register of Trials (CENTRAL) via the Cochrane Library. Results: Of the 2207 publications identified, 6 publications (US, n = 4; EU, n = 2) provided information on the first-line treatment of MCL (Table). The most commonly administered first-line treatments were bendamustine-rituximab; high dose cytarabine ± rituximab; and cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) ± rituximab although differences were noted across studies. Most patients received rituximab first-line either in combination with chemotherapy (54.2%-87.5%) or as monotherapy (12.9%-28.9%); although in some studies, rituximab maintenance therapy could not be excluded. The most commonly administered second-line therapies were cytarabine, rituximab monotherapy, and ibrutinib while third-line therapies were rituximab monotherapy, ibrutinib, and temsirolimus. Nine studies provided data on the real-world treatment of MCL with the BTKI ibrutinib (EU, n = 3; US, n = 5; EU/US, n = 1; Table); no real-world studies were identified for acalabrutinib. Six studies enrolled patients only with relapsed or remitting MCL; 3 studies enrolled patients (≤7.5%) who received ibrutinib as first-line therapy. Ibrutinib second-line therapy was administered to 13%-20% of patients and third-line therapy to 21% of patients. Ibrutinib discontinuation rates in 7 studies varied from 38.7%-83.6%. Non-response, including relapse or progression (34.6%-100%), was the main cause of discontinuation, followed by toxicity/adverse events (8.1%-25.6%). Across studies, toxicity/adverse events causing ibrutinib discontinuation included atrial fibrillation, bleeding/hemorrhage, chronic obstructive pulmonary disease, diarrhea, herpes zoster, infection, leukocytosis/ lymphocytosis, lung cancer, myelodysplastic syndrome, and thrombocytopenia. Two studies provided information on ibrutinib dose reductions (16.4% of patients) and ibrutinib dose interruptions (7.8%-30.2% of patients). Treatment options administered post-ibrutinib included rituximab (52.7%), hyper-CVAD + rituximab (16.7%-25.8%), lenalidomide-based regimens (9.7%-41.5%), and bortezomib-based regimens (8.4%-34.4%). Conclusion: Our analyses showed that most patients with MCL received first-line chemoimmunotherapy, although regimens varied across studies. Approximately 13%-21% of patients received ibrutinib following first-line therapy. Most ibrutinib discontinuation was due to progression followed by toxicity/adverse events. Upon discontinuation of ibrutinib, considerable variation in treatments was seen and no standard therapy identified. Given the limitations of current therapies, there is a need for additional second- and third-line treatments for patients with MCL. Quantitative assessments of clinical endpoints from real-world studies evaluating BTKI therapies are also warranted. Disclosures Yang: BeiGene, Ltd.: Employment. Lesher:Pharmerit: Employment. Lucas:Pharmerit: Employment. Caver:BeiGene, Ltd.: Employment. Tang:BeiGene, Ltd.: Employment.

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Risk of Patients Developing Post-Transplant Lymphoproliferative Disorder within the First Year after an Allogeneic Hemopoietic Stem Cell Transplant, 2011 to 2016: A US Claims Database Analysis

Blood ◽

10.1182/blood-2018-99-113598 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5840-5840

Author(s):

Arie Barlev ◽

Hairong Xu ◽

Nicole Fulcher ◽

Crystal Watson ◽

Ila Sruti ◽

...

Keyword(s):

Large Scale ◽

Hemopoietic Stem Cell ◽

First Year ◽

Cell Transplant ◽

Employment Equity ◽

Claims Database ◽

Post Transplant ◽

Allogeneic Hct ◽

Equity Ownership ◽

The Mean

Abstract Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a heterogenous disease that can develop after solid organ or allogeneic hemopoietic stem cell transplant (HCT). PTLD after HCT is primarily of the monomorphic subtype and driven by the Epstein-Barr Virus. It is an ultra-rare disease that follows an aggressive clinical course with poor outcomes and for which there is no approved standard treatment. The risk of PTLD after HCT in the current clinical setting is insufficiently quantified, and large-scale data from the US are lacking. The objective of this study was to estimate the incidence of PTLD after allogeneic HCT using a large US claims database. Methods: A retrospective cohort study using the MarketScan Commercial and Medicare Supplemental database was conducted. Patients who received an allogeneic HCT between January 1, 2011 and December 31, 2016 with at least 6 months of continuous enrollment prior to allogeneic HCT were included in the analysis. PTLD cases were identified as having a diagnosis of PTLD (ICD-9 code 238.77 or ICD-10 code D47Z1) or one inpatient or two outpatient claims for preselected, clinically relevant lymphoma codes within 1-year post-transplant. Patients with a clinically relevant lymphoma diagnosis in the 6 months prior to HCT were excluded. The percentage of patients who developed PTLD during the first year after allogeneic HCT was calculated, the average time to PTLD diagnosis was estimated, and patient characteristics at PTLD diagnosis were described. Results: A total of 2,735 eligible patients were included in the analysis; the mean (range) post-transplant follow-up time was 576 (1-2555) days. Overall, 103 patients (3.8%; 95% CI: 3.1%-4.6%) developed PTLD during the first year after allogeneic HCT, and the median (range) time from allogeneic HCT to PTLD diagnosis was 90 (0-364) days. The mean (SD) age at time of first PTLD diagnosis was 46.8 (17.2) years, with 84.5% of patients 18 to < 65 years old, 8.7% of patients < 18 years old, and 6.8% of patients ≥ 65 years old. There was a higher percentage of male versus female PTLD patients: 55.3% versus 44.7%. Conclusions: This analysis of a large-scale US claims database showed that 3.8% (95%CI: 3.1%-4.6%) of post-allogeneic HCT patients had PTLD within the first year after transplant. Most patients impacted by PTLD were younger than 65 (93.2%), and a substantial proportion were pediatric patients (8.7%). Future studies are needed to better understand the disease state and burden of PTLD as well as the unmet medical need for this patient population. Disclosures Barlev: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Xu:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Fulcher:IBM Watson Health: Employment. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Sruti:IBM Watson Health: Employment. Sudhindra:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

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Younger Patients Are Impacted By Post-Transplant Lymphoproliferative Disorder: Findings from a Systematic Literature Review of Real-World Evidence

Blood ◽

10.1182/blood-2018-99-113622 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5841-5841

Author(s):

Crystal Watson ◽

Hairong Xu ◽

Anna Forsythe ◽

Shan Ashton Garib ◽

Arie Barlev

Keyword(s):

Literature Review ◽

Sample Size ◽

Study Design ◽

Real World ◽

Lymphoproliferative Disorder ◽

Pediatric Patients ◽

Employment Equity ◽

Younger Patients ◽

Cancer Statistics ◽

Equity Ownership

Abstract Introduction: Transplant recipients younger than 18 years old are believed to have a 2- to 4-fold higher risk of developing post-transplant lymphoproliferative disorder (PTLD) than adult transplant patients. Within the pediatric group, there is evidence to suggest an increased risk of PTLD in younger children. We conducted a systematic literature review (SLR) to estimate the weighted mean age (WMA) at PTLD diagnosis and describe patient demographics in the real-world setting. Methods: An SLR was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. Studies were identified based on a systematic search using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. To ensure inclusion of all relevant evidence, no treatment limitations were imposed; however, the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram. Using the sample size from the selected studies, the WMA for each relevant subgroup was determined and was compared to the average age at the time of diagnosis for other cancers reported in SEER Cancer Statistics (2011-2015; https://seer.cancer.gov/csr/). Results: A total of 447 studies fulfilled the search criteria: 114 adult studies, 136 pediatric studies with varied definitions (< 16, < 18 or < 21 years old), and 197 that did not specify inclusion by age. Seventy studies enrolled only PTLD patients after allogeneic hematopoietic stem cell transplantation (HCT). Among these studies, 17 included pediatric patients with a WMA of 12.5 years, 10 included adult patients with a WMA of 40.2 years, and 41 had no age restriction with a WMA of 34.4 years. For pediatric patients, the risk of post-HCT PTLD was 1.3-23.5% and the time from transplant to PTLD was 0.9-6.0 months. There was only one pediatric HCT study (N=4; mean age, 9 years), which reported median survival of 27.6 months. A total of 350 studies only enrolled PTLD patients after solid-organ transplant (SOT). Among these studies, 115 included pediatric patients with a WMA of 6.6 years, 98 included adult patients with a WMA of 46.9 years, and 136 had no age restriction with a WMA of 38.6 years. Among the pediatric SOT studies, the risk of PTLD was 0.3-25.0%, the time from transplant to PTLD was 1.4-92.8 months, and the reported survival was 0.9-37.2 months. The average age of lymphoma patients at cancer diagnosis according to the SEER Cancer Statistics database was 65 years. Conclusions: This SLR of published real-world studies demonstrates that the WMA at PTLD diagnosis (for studies with no age restrictions: 34.4 years for HCT and 38.6 years for SOT) is substantially lower than the reported average age at diagnosis for lymphomas (65 years), irrespective of study design and inclusion criteria. PTLD greatly impacts the pediatric population, with a quarter of HCT studies and a third of SOT studies focusing on this population. Currently, there is no indicated treatment for this ultra-rare disease with poor prognosis, indicating a clear unmet need for patients with PTLD that disproportionately affects younger patients. Disclosures Watson: Atara Biotherapeutics, Inc: Employment, Equity Ownership. Xu:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

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Incidence of Post-Transplant Lymphoproliferative Disease: A Systematic Literature Review

Blood ◽

10.1182/blood-2021-147715 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4564-4564

Author(s):

Dhanalakshmi Thirumalai ◽

Crystal Watson ◽

Pengcheng Xun ◽

Natalia Sadetsky ◽

Kassandra Schaible ◽

...

Keyword(s):

Literature Review ◽

Sample Size ◽

Systematic Literature Review ◽

Organ Transplant ◽

Lymphoproliferative Disease ◽

First Year ◽

Transplant Recipients ◽

Post Transplant ◽

Over Time

Abstract Introduction: Post-transplant lymphoproliferative disease (PTLD) is an ultra-rare lymphoma following allogeneic hematopoietic stem cell transplant (HCT) or solid organ transplant (SOT). Incidence of PTLD varies over time after transplant with majority of cases occurring within the first year (yr) after HCT (Garcia-Cadenas, Eur J Haematol. 2019). In the SOT setting, PTLD can occur up to 30 yrs post-transplant and is largely dependent on the transplanted organ, the type and degree of immunosuppression, and transplant recipient characteristics (Dierickx, N Eng J Med. 2018; Trappe, J Clin Oncol. 2017). Published literature reports wide ranges of epidemiological estimates due to variation in the follow-up time, transplant type and sample size. We conducted a systematic literature review (SLR) to summarize the incidence of PTLD to better understand the reasons for such variation. Methods: A SLR on the burden of PTLD was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes and Study design (PICOS) criteria. Pertinent literature on epidemiology of PTLD published between January 2010 to February 2020 and relevant conference abstracts published between January 2018 to February 2020 were identified. Comprehensive literature searches were performed using the Ovid platform to identify articles indexed in PubMed, Embase, PsycINFO, and the National Health Service Economic Evaluation Database. Study designs were limited to population/registry-based studies, observational cohort studies (prospective/retrospective), and cross-sectional studies. Studies reporting incidence of PTLD were limited to those with at least 1000 total transplant recipients. All titles and abstracts were reviewed by two independent researchers with any discrepancies resolved by a third researcher. Incidence estimates were calculated by data extractors when it was not directly reported in the literature. Results: A total of 177 studies reporting epidemiological data on PTLD were identified using pre-specified SLR criteria. Most of the studies (n=150) were retrospective in design. Incidence was reported in 114 studies. Majority of the studies reported cumulative incidence (CI) over specified times such as 5-yr or 10-yr incidence or proportion of patients (pts) with PTLD out of a sample of transplanted pts. In the HCT setting, only CI was reported; twelve studies reported CI ranging from 0.1% among 15094 pts receiving autologous HCT over a 19-yr period to 4% in a cohort of 1021 pts receiving allogeneic HCT over a 16-yr period. A total of 100 studies reported incidence of PTLD in SOT pts which was highly influenced by the study population, EBV status at the time of transplant and follow-up time. Of these, 12 reported incidence rates ranging from 24 EBV negative PTLD cases per 100,000 person-years (PY) within 1-5 yrs post-transplant to 3460 PTLD cases per 100,000 PY at 20 yrs post-transplant. Eighty studies reported CI, 19 of which reported CI for various timepoints. In a group of 23171 heart transplant pts CI was 1% during a median follow-up of 4.3 yrs, while in a subgroup of four pediatric multi-organ transplant recipients followed from 2003 to 2011 CI was 25%. Across studies, CI at 1-yr post-transplant ranged from 0.1% to 4.9% and 5-yr CI ranged from 0.7% to 12.1% in select group of transplant pts. Twenty-four studies reported CI by transplant organ type ranging from 0.2% in kidney transplant pts within the first year to 12.1% in lung transplant pts over 7.5 yrs, with higher estimates reported in studies with smaller sample sizes. Conclusions: Our SLR shows large variation in the reported incidence of PTLD due to heterogeneity in the methodology and the study populations in both HCT and SOT settings. Published literature lacks the granularity to correctly interpret the incidence of PTLD in the general transplant population. Thus, additional methods and data considerations such as population type (HCT/SOT transplants, adult/pediatric pts, etc.), representativeness (single institutional data/multi-center/country level registry), unit of measurement of risk (CI/incidence rate, etc.), type of study (retrospective/prospective), length of follow-up, sample size, trends in transplant and treatment landscape over time are needed to ensure accuracy in the estimation of incidence of PTLD. Disclosures Thirumalai: Atara Biotherapeutics: Current Employment. Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Xun: Atara Biotherapeutics: Current Employment. Sadetsky: Atara Biotherapeutics: Current Employment. Schaible: Evidera: Current Employment. Barlev: Atara Biotherapeutics: Current Employment.

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Patterns of Total Costs of Care over Time for Patients with Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v126.23.3294.3294 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3294-3294

Author(s):

Steven R Arikian ◽

Gary Binder ◽

Craig Gibson ◽

X Henry Hu ◽

Yasir Nagarwala ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Research Funding ◽

Second Line ◽

First Line ◽

Employment Equity ◽

Monthly Total ◽

Equity Ownership ◽

Line Of Therapy ◽

Over Time

Abstract Introduction. A previous study of patients (pts) with newly-diagnosed multiple myeloma (NDMM) showed that initial high monthly total costs declined over time until returning near initial levels upon pts advancing to later lines of treatment (Tx) at disease progression (Arikian, CMRO 2015). However, the longer-term economic implications of the choice of first-line Tx, regardless of subsequent Tx regimens, have not been described. We utilized an intent-to-treat approach to further evaluate and compare the total costs of NDMM patient cohorts initiated on Lenalidomide (LEN) or Bortezomib (BORT)-based Tx and followed these patients over 54 months. Methods: A retrospective analysis was performed using a large US medical and pharmacy claims database, covering > 25 million commercial and Medicare lives annually. NDMM patients were defined as having ≥ 2 outpatient claims or ≥ 1 inpatient medical claim with a diagnosis of MM (ICD-9-CM code 203.0X), with the first such claim used to define the index date. Inclusion criteria required ≥ 12 months' pre-index and ≥ 6 months' post-index continuous enrollment from 2006 - 2013, and evidence of initiation of a subsequent line of therapy. Pts with claims for stem cell transplantation (SCT) or receiving concurrent LEN plus BORT as first-line Tx were excluded. The analysis focused on cohorts of NDMM pts receiving LEN or BORT-based first line Tx, who progressed to one or more subsequent lines of Tx, using time to next therapy (TTNT) as a proxy for progression. Pts receiving LEN or BORT-based first line Tx were randomly matched 1:1 on age (+/- 3 years at index), sex, baseline Charlson comorbidity score (+/- 1), and presence of renal disease. Using methods similar to those described by Gaultney(J Clin Pharm Ther, 2013), pts' average monthly costs and standard errors were determined, including medical and pharmacy costs, and total cost patterns were calculated from first line Tx initiation until the end of patient eligibility or 54 months. Results: 1,181 NDMM pts receiving LEN (N=444) or BORT-based (N=737) first line Tx with complete data available through initiation of subsequent line of Tx were identified. After matching, 856 NDMM patients remained (428 LEN, 428 BORT). Monthly total direct medical plus pharmacy costs for these pts were in excess of $12,000 at initiation. Total monthly costs declined quarterly for each cohort until the median TTNT was reached (20 months for BORT; 37 months for LEN). As increasing numbers of pts in each cohort then advanced to subsequent lines of therapy, costs of those patients began to offset continued cost declines for pts still on first line of therapy. Over the full 54 month follow-up period, total monthly costs averaged $8,324 (SE = $370.30) for pts initiated on LEN vs. $10,728 (SE = $500.55) for pts initiated on BORT (p-value <0.001). Medical costs represented 54-57% of total monthly costs for each cohort. In each cohort, the most common Tx option upon disease progression was to switch to the other regimen. Conclusions: For a matched population of NDMM pts followed continuously for 54 months, initiation on LEN- versus BORT-based Tx without SCT was associated with an average of $2,404 lower monthly direct total costs. Following initiation of first-line therapy, total monthly costs per pt declined quarterly until initiation of the next line of Tx. Cumulative costs over the 54-month period were over $120,000 lower per pt in favor of the LEN cohort, influenced by more rapid advancement to subsequent Tx in the BORT cohort, and the associated higher costs. Based on second-line Tx patterns, this analysis also suggests that a sequence of LEN in first line followed by BORT in second line is associated with lower costs over time compared to the reverse sequence. Due to the nature of retrospective claims, some underlying differences may remain between the two cohorts even after matching. Figure 1. Direct monthly costs (medical and pharmacy) for LEN- and BORT-initiated patients and savings attributed to LEN-initiated patients Figure 1. Direct monthly costs (medical and pharmacy) for LEN- and BORT-initiated patients and savings attributed to LEN-initiated patients Disclosures Arikian: Genesis Research: Consultancy. Binder:Celgene Corporation: Employment, Equity Ownership. Gibson:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Nagarwala:Celgene Corporation: Employment. Hussein:Celgene Corporation: Employment, Equity Ownership. Corvino:Genesis Research LLC: Consultancy. Lee:Genesis Research LLC: Consultancy. Surinach:Genesis Research LLC: Consultancy. Kaura:Celgene Corporation: Employment. Usmani:Onyx: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria; Janssen: Research Funding.

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A Systematic Literature Review (SLR) of Clinical Outcomes after Stem Cell Transplantation (SCT) in Adult Acute Lymphoblastic Leukemia (ALL) Patients with or without Minimal Residual Disease (MRD)

Blood ◽

10.1182/blood-2018-99-112981 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5292-5292

Author(s):

Monica Turner ◽

Shweta Shah ◽

Amber Martin ◽

Ze Cong ◽

Anthony S. Stein

Keyword(s):

Literature Review ◽

Clinical Outcomes ◽

Median Survival ◽

Systematic Literature Review ◽

Lymphoblastic Leukemia ◽

Employment Equity ◽

Free Survival ◽

Significant Difference ◽

Equity Ownership ◽

Reported Data

Abstract Background: Most adult patients with ALL will achieve a complete hematologic remission following frontline therapy, but approximately 40% of patients will subsequently have evidence of MRD. This status describes the presence of leukemia cells in the bone marrow, which cannot be detected by conventional methods and is recognized as an independent negative prognostic factor for disease relapse and survival. An SLR was conducted to evaluate evidence comparing clinical outcomes following SCT among patients who are MRD+ vs. MRD- prior to transplant. Methods: Medline, Embase, and Central databases were systematically searched with keywords for ALL and MRD to identify relevant literature on adults undergoing transplants according to MRD status published through 5/8/2018. Oncology conferences were also searched for relevant data presented between 2014─2018. Results: 30 primary studies were identified that reported outcomes following SCT in ALL patients with MRD results available prior to transplant. Clinical outcome comparisons between MRD+ and MRD- patients were most commonly reported (27/30 studies). Comparisons between MRD+ and MRD- patients universally suggested that those with MRD+ status prior to SCT had lower survival rates at all time points reported relative to patients who were MRD- with an exception of one study, evaluating patients treated with salvage therapy, which favored MRD+ in survival gains with a non-significant difference between MRD+ and MRD- groups (Table 1). The available hazard ratio (HR) on overall survival consistently indicated that patients with MRD+ status before transplant were more likely to die after SCT as patients who are MRD- (HRs for OS: 1.51-2.646) (Figure 1). MRD+ status was also associated with higher likelihood of disease progression, (HRs for PFS: 2.15 to 2.8). Six studies reported data on mean or median survival; median OS after SCT ranged from 1.98 months to 17 months among MRD+ patients compared with 17 months to 67 months among those with MRD- status. This translated to median OS difference ranging from -8 to -50 months for the MRD+ vs. MRD- patients. Data indicated that patients who are MRD- at time of transplant also experienced longer median event-free survival (EFS) (median EFS difference was -8 months for MRD+ vs. MRD- in two studies) and longer median relapse-free survival (RFS) (median RFS MRD+ vs. MRD- of -40.5 months in one study). While 12 studies reported data on the proportion of patients who relapsed after SCT, timepoints were not consistently reported and population sizes varied widely. Among all studies reporting this data, 16% to 100% of MRD+ patients relapsed after SCT, while 0% to 50% of MRD- patients experienced a relapse after SCT. Only four studies reported complete remission (CR); 35.6% to 86%of MRD+ patients achieved CR after SCT, while 100% of MRD- patients maintained CR after SCT based on one study. Conclusion: This systematic literature review found consistent evidence of markedly worse transplant outcomes among patients with MRD+ vs. MRD-, including shorter median survival (OS, RFS and EFS), higher risks of death and relapse events and lower likelihood to achieve hematologic remission. Therapies that can eradicate MRD among adult ALL patients can potentially improve the outcomes of SCT in these critically ill patients. Disclosures Turner: Evidera: Employment. Shah:Amgen, Inc.: Employment, Equity Ownership. Martin:Evidera: Employment. Cong:Amgen, Inc.: Employment, Equity Ownership. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau.

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