Arthritis Advisory Committee Meeting\
Briefing Document for ENBREL^^ (etanercept)

March 4, 2003

Amgen Inc.

Table of Contents

[1. Introduction 3](#introduction)

[2. ENBREL Experience 4](#enbrel-experience)

[2.1 Clinical Trials in Patients with Rheumatic Diseases
4](#clinical-trials-in-patients-with-rheumatic-diseases)

[2.2 Post-Marketing Commercial Experience
4](#post-marketing-commercial-experience)

[3. ENBREL Pharmacovigilance Program
5](#enbrel-pharmacovigilance-program)

[3.1 Post-Marketing Safety Surveillance
6](#post-marketing-safety-surveillance)

[3.2 Ongoing Clinical Trials 6](#ongoing-clinical-trials)

[3.3 Registries 7](#registries)

[3.4 Epidemiologic Studies 7](#epidemiologic-studies)

[4. FDA Arthritis Advisory Committee 2001: TNF Antagonists Safety Review
and Recent Safety Update to the Label
7](#fda-arthritis-advisory-committee-2001-tnf-antagonists-safety-review-and-recent-safety-update-to-the-label)

[5. TNF and Carcinogenesis 8](#tnf-and-carcinogenesis)

[6. Lymphoma in Rheumatoid Arthritis
9](#lymphoma-in-rheumatoid-arthritis)

[7. Lymphoma Observations from Pharmacovigilance
10](#lymphoma-observations-from-pharmacovigilance)

[7.1 Clinical Trial Observations 10](#clinical-trial-observations)

[7.2 Post-Marketing Safety Surveillance
11](#post-marketing-safety-surveillance-1)

[7.3 Lymphoma Histopathologic Subtypes Compared to RA and Non-RA
Controls
12](#lymphoma-histopathologic-subtypes-compared-to-ra-and-non-ra-controls)

[8. Communication and Education 13](#communication-and-education)

[9. Summary and Conclusions 14](#summary-and-conclusions)

[10. References 16](#references)

APPENDIX 1. Post-Approval Studies with
ENBREL.....................................................\.......21

**APPENDIX 2. Epidemiologic Studies of Lymphoma in
RA..........................................\........25**

# Introduction

Immunex Corporation, a wholly owned subsidiary of Amgen Inc., developed
ENBREL^^ in partnership with Wyeth and certain predecessors of Wyeth.
In this report, Immunex will be referred to as Amgen.

This Briefing Document is submitted to facilitate discussion regarding
the safety of tumor necrosis factor (TNF) antagonist therapies and
focuses attention on lymphoma. Given limitations in our current
understanding of the natural history of rheumatoid arthritis (RA), the
contributions of RA disease severity, prior and concurrent
immunosuppressive therapies, and the interaction of these elements with
TNF antagonist therapies, Amgen and Wyeth welcome the opportunity for
review and commentary from the Arthritis Advisory Committee.

ENBREL^^ is a protein comprised of the extracellular domains of two
human TNF receptors attached to a portion of a human IgG immunoglobulin
(Mohler et al, 1993). ENBREL^^ acts primarily by binding and
neutralizing both soluble and cell-bound TNF. The conformation and
binding specificity of the human TNF receptor reflect evolutionary
selection and may have distinct advantages over other TNF antagonists.
ENBREL^^ contains an entirely human amino acid sequence and is
therefore only rarely immunogenic. ENBREL^^ does not bind complement
and is not associated with complement-mediated cell lysis. These
product-specific attributes may be relevant to the ENBREL^^ safety
profile.

In November 1998, ENBREL^^ was approved by the Food and Drug
Administration (FDA) for reducing signs and symptoms of moderately to
severely active rheumatoid arthritis (RA), as monotherapy or in
combination with methotrexate, in patients who had an inadequate
response to one or more disease-modifying antirheumatic drugs (DMARDs).
The current label includes information describing the safety and
efficacy in patients with RA treated over the course of 3 years. The
indications for ENBREL^^ have since expanded to include
polyarticular-course juvenile rheumatoid arthritis (JRA, May 1999);
inhibition of structural damage in patients with moderately to severely
active RA, including those who have not previously failed prior DMARD
therapy (June 2000); and reduction of signs and symptoms in psoriatic
arthritis either as monotherapy or in combination with methotrexate
(January 2002). ENBREL^^ is the only TNF antagonist approved as an
initial DMARD in RA, and is approved for application in children with
JRA and in patients with psoriatic arthritis.

The safety information included in this document, unless otherwise
noted, is from the worldwide ENBREL^^ safety database, including
patients who have received ENBREL^^ in clinical trials since 1993 and 4
years of commercial experience with ENBREL^^ through November 2, 2002.

# ENBREL^^ Experience

ENBREL^^ has been the subject of extensive investigation and safety
evaluations since 1991, starting with cell culture toxicity studies,
animal tolerability studies, through studies evaluating safety in normal
human volunteers and patients with a variety of different medical
conditions.

## Clinical Trials in Patients with Rheumatic Diseases

The ENBREL^^ clinical trial database through 2002 includes 3389
patients who have received ENBREL^^ in Amgen- and Wyeth-sponsored
rheumatic disease clinical trials for currently approved indications. In
open-label extension studies, the efficacy and the safety profile
associated with longer-term administration of ENBREL^^ (up to 6 years)
remain stable over time. The following table reflects worldwide trial
experience estimated through December 2002.

Table 2- . Clinical Trial Experience Worldwide

  --------------------------- ------------------- -----------------------
                              Patients (n)        Patient-years

  North America               2119                5444

  Ex-North America            1270                2851

  Total                       3389                8295
  --------------------------- ------------------- -----------------------

## Post-Marketing Commercial Experience

The post-marketing worldwide commercial experience with ENBREL^^
through December 2002 includes greater than 150,000 patients treated,
representing over 230,000 patient-years of therapy, depicted in Figure
2- below. The numbers of patients treated have recently increased
substantially with the approval of the new ENBREL^^ manufacturing
facility in Rhode Island.

Figure 2-. Patients and Patient-Years of ENBREL^^ Therapy Over Time

![](media/image1.wmf)

# ENBREL^^ Pharmacovigilance Program

Establishing the safety profile for a new therapeutic requires analysis
and interpretation of safety observations from multiple settings,
including controlled clinical trials and longer-term extension studies,
surveillance of post-marketing spontaneous (or facilitated) reports,
observational registries, epidemiologic studies, and the medical
literature.

Because ENBREL^^ was the first TNF antagonist approved for chronic
therapy in patients with RA (1998), Amgen and Wyeth jointly established
a comprehensive pharmacovigilance program at the time of approval to
advance the following objectives:

-   Understand the natural history of treated populations (RA, JRA, and
    psoriatic arthritis) in patients receiving conventional DMARDs
    compared to those receiving ENBREL^^, and understand the impact of
    disease severity on health outcomes.

-   Determine the relative risk and incidence of adverse events, as
    power considerations permit, by conducting prospective and
    retrospective population-based studies in large and diverse patient
    populations.

-   Assess potential adverse events of long latency by performing
    studies with long-term follow-up.

-   Assess potential risks to special patient subpopulations, including
    children, geriatric patients, and those with comorbidities.

## Post-Marketing Safety Surveillance

The ENBREL^^ pharmacovigilance program includes evaluation and
follow-up of reported adverse events and ongoing surveillance of safety
information from the medical literature. Analyses are performed both at
the individual case level as well as at the aggregate population level.
Although retrospective, anecdotal, and frequently incomplete,
post-marketing reports can provide insights into product impact in a
broader patient population than clinical trials, including patients with
multiple comorbidities and concomitant medications. Amgen believes that
post-marketing safety surveillance provides an important window on the
\"real world\" patient and prescriber experience with ENBREL^^ therapy,
and has shared observations from this experience as part of proactive
risk communication (Holman et al, 2002; Sabath et al, 2002a), including
the post-marketing experience with lymphoma (Sabath et al, 2002b). These
authors have also demonstrated that extensive communication with
ENBREL^^ patients facilitates adverse event reporting and when
communication increases, adverse event reporting increases in parallel
(Sabath et al, 2002c). Amgen and Wyeth believe that facilitated
reporting has supported improved collection of adverse events from
clinical practice and more rapid characterization of the ENBREL^^
safety profile.

## Ongoing Clinical Trials

In cooperation with the FDA and the European Agency for the Evaluation
of Medicinal Products (EMEA), a significant number of prospective safety
studies have been initiated that advance the pharmacovigilance
objectives outlined above. Brief descriptions of these multiple safety
studies are included in Appendix 1. These programs effectively monitor
ENBREL^^ safety in special subpopulations, including RA patients
receiving concomitant methotrexate, sulfasalazine, hydroxychloroquine,
or parenteral gold; RA patients with significant concurrent medical
problems; elderly RA patients; and children with JRA and systemic onset
JRA. In addition, Amgen and Wyeth have initiated multiple RA
observational studies, including a 10,000-patient North American study
(RADIUS) which provides additional perspective on clinical practice
experience from both patients and physicians.

## Registries

National observational RA registries evaluating the safety and
effectiveness of ENBREL^^ are ongoing in the United Kingdom, Germany,
and Sweden (Moreland et al, 2002).

## Epidemiologic Studies

Amgen has initiated a retrospective epidemiologic study with Drs.
Alexander Walker and Catherine Johannes of the UnitedHealth Group to
assess the incidence of adverse events, including lymphoma, in patients
from the general population as well as patients with RA, psoriatic
arthritis, and ankylosing spondylitis. This ongoing study includes over
49,000 patients with rheumatic diseases out of more than 9.7 million
patients in the general population. Medical records will be reviewed to
validate observations, and analyses will be performed to determine if
prior exposure to medications are associated with any of the predefined
adverse events of interest.

# FDA Arthritis Advisory Committee 2001: TNF Antagonists Safety Review and Recent Safety Update to the Label

Safety reports of serious infections, tuberculosis, neurological
disorders, hematological events, and rashes in conjunction with
autoantibodies (lupus-like conditions) have been incorporated into the
prescribing information for all approved TNF antagonists. Details
regarding these safety issues in patients treated with ENBREL^^ were
presented to the FDA Arthritis Advisory Committee, August 17, 2001 (FDA,
2001). Since that time, ENBREL^^ pharmacovigilance has continued and
the reporting rates for these types of events have been stable over
time.

Subsequent to the 2001 meeting, a precaution was added to the product
labeling based upon the results of two large clinical trials with
ENBREL^^ in patients with congestive heart failure as well as rare
post-marketing reports. The studies were stopped after an independent
data monitoring committee indicated that they would be unlikely to
demonstrate benefit, even if carried to completion. One of the two
trials revealed a trend toward worse heart failure outcomes in the
ENBREL^^-treated patients, while the other did not (Coletta et al,
2002). Meanwhile, the results from a controlled trial with another
marketed TNF antagonist showed a significant dose-related increase in
mortality (Coletta et al, 2002). Because of these observations, language
regarding heart failure experience with ENBREL^^ was added to the
prescribing information.

As the events leading to the 2001 FDA Arthritis Advisory Committee TNF
Antagonists Safety Review have already been extensively reviewed, and
Amgen was asked at this time to focus on the issue of lymphoma, the
events outlined above will not be addressed further in this report.

# TNF and Carcinogenesis

The role of TNF in carcinogenicity and tumor surveillance has not been
completely established. Early cell culture studies indicated that TNF is
cytotoxic for certain tumor cell lines (Old et al, 1985; Creasey et al,
1986; Palladino et al, 1987), but subsequent studies revealed that, for
certain types of malignancies, TNF may act as a growth factor (Filella
et al, 1996; Brach et al, 1992; Freedman et al, 1992; Moore et al, 1999;
Warzocha et al, 1998; Naylor et al, 1993) and may even enhance the
metastatic potential of certain tumors (Malik et al, 1990).

Over-production of TNF in B-cell chronic lymphocytic leukemia and hairy
cell leukemia has been associated with more severe disease progression
and decreased patient survival (Foa et al, 1990; Barak et al, 1999).
Highly metastatic lymphoma cells have been shown to have even greater
metastatic potential when co-administered with recombinant TNF (Orosz et
al, 1993). These results suggest that therapeutic TNF antagonism could
potentially be beneficial in patients with lymphoproliferative
disorders.

Early studies evaluating the effect of ENBREL^^ on cultured cells
revealed no increase in the frequency of gene injury or gene mutations
that may be predictive of greater cancer risk. In addition, animal
studies with ENBREL^^ have not revealed findings to suggest a higher
than background risk for the development of malignancies. Please refer
to BLA 98-0286.

# Lymphoma in Rheumatoid Arthritis 

There are multiple risk factors for the development of lymphoma. These
include underlying disease, disease severity and medication exposures.

Appendix 2 summarizes epidemiologic studies of lymphoma incidence in
various RA populations, compared to the incidence expected
(observed/expected, or standardized incidence ratio, SIR). Although the
observed RA SIRs vary, most studies reveal an increased incidence of
lymphoma in RA. In a review of all published literature between 1966 and
1998 evaluating the incidence of cancer associated with RA therapies,
Beauparlant et al (1999) conclude that the increased risk of lymphoma in
patients with RA is generally recognized to be two to three times that
observed in the general population.

Reports of juxta-articular lymphoma in patients with RA suggest a link
between inflammation and transformation (Goodlad et al, 1999). Both
Prior et al (1985) and Wolfe (1998) reported that the risk for
development of lymphoma in RA increases with severity of disease.
Baecklund et al (1998) performed a case control analysis indicating that
lymphoma risk increases substantially with greater RA disease activity.

The contribution of DMARDs to the incidence of hematologic malignancies
in RA patients remains controversial. Lymphomas (some reversible) have
been described in patients receiving both methotrexate (Georgescu et al,
1997; Sibilia et al, 1998) and azathioprine (Larval et al, 1994), but
Wolfe (1998) suggested that methotrexate therapy is not clearly
associated with increased lymphoma risk. Cyclosporine has also been
associated with lymphoma (Penn, 1987) and the Epstein-Barr virus has
also been implicated in methotrexate-associated lymphomas (Kamel et al,
1993).

In conclusion, there are multiple factors that augment lymphoma risk
including underlying disease, disease severity, and medication
exposures. These risk factors are particularly pertinent to the patient
population treated with ENBREL^^ and need to be considered when
interpreting lymphoma incidence.

# Lymphoma Observations from Pharmacovigilance

## Clinical Trial Observations

Lymphoma reports from clinical trials with ENBREL^^ will be represented
by the standardized incidence ratio (SIR, the ratio of observed to
expected cases). All "expected" numbers were calculated using the
National Cancer Institute Surveillance, Epidemiology, and End Results
(SEER) database (11 Registries, 1992-99) using age, gender, and
race-specific rates to predict the number of cases within the cohort of
patients in clinical trials. Note that these expected numbers represent
expectations for the United States general population and do not account
for potential variations in rates that may exist among patients in
diverse geographical regions, nor do they account for the increased risk
known to exist in the RA population as described in Section 6.0. The
confidence intervals were calculated under the assumption of a Poisson
distribution for the observed cases (Breslow et al, 1987). The following
data represent worldwide Amgen and Wyeth rheumatoid arthritis, juvenile
rheumatoid arthritis, and psoriatic arthritis clinical studies performed
with ENBREL^^. The vast majority of the clinical experience is from
rheumatoid arthritis clinical trials.

The only precise representation of lymphoma incidence can be determined
in clinical trials as there is complete accounting for observed cases in
the numerator, and total patient-year experience in the denominator is
accurately available. The expected number of cases takes into
consideration the age, gender, and race distribution of the treated
population. In calculating the SIR, the numerator (observed cases)
includes all cases observed during ENBREL^^ clinical trial experience
(including 30 days after discontinuation of study drug) through December
31, 2002. The denominator (expected cases) is calculated from an
estimation of the total experience in ENBREL^^ clinical trials to the
end of December 2002 (representing 8295 patient-years of therapy, Table
7-).

Table 7-. SIR for Lymphoma Cases in ENBREL^^ Clinical Trials

  ----------------- ------------- ----------- ----------------------------
  Number of Cases   Expected\*    SIR         95 % Confidence Intervals

  6                 2.59          2.31        0.85-5.03
  ----------------- ------------- ----------- ----------------------------

\*Expected in the US general population and does not account for
increased risk in RA patients.

Three additional cases of lymphoma have been reported in patients
previously exposed to ENBREL^^ in clinical trials, but the events
occurred beyond 30 days after discontinuation of ENBREL^^. As it is not
possible to accurately estimate the additional time exposure represented
by these events, one cannot perform an SIR analysis.

The calculations above demonstrate that the SIR for lymphoma (comparing
patients in ENBREL^^ in clinical trials to the general U.S. population)
is 2.31, which is comparable to the reported SIR of 2--3 in all
rheumatoid arthritis patients relative to the general population
(Beauparlant et al,1999).

## Post-Marketing Safety Surveillance

Through November 2, 2002, after four years of worldwide commercial
experience, over 150,000 patients have received over 230,000
patient-years of ENBREL^^ therapy, and the observed worldwide lymphoma
reporting rate is 0.3 per 1000 patient-years of therapy. Some of these
cases were described in a recent publication (Brown et al, 2002).
Analysis of the reporting rate (reports per patient year of therapy) at
each six-month interval since ENBREL^^ approval indicates that the
reporting rate is stable over time, with no increase over the course of
four years (Figure 7-).

Figure 7-. Lymphoma Reporting Rates by Time Interval

for U.S. Post-Marketing Experience

![](media/image2.wmf){width="5.749305555555556in"
height="3.984722222222222in"}

Many of the previously described risk factors for lymphoma have been
noted in ENBREL^^ patients. The majority of patients who have reported
lymphoma have confounding risk factors including severe RA, Sjögren's
syndrome, and medication exposures such as methotrexate, azathioprine
and cyclosporine.

## Lymphoma Histopathologic Subtypes Compared to RA and Non-RA Controls

Analysis of the distribution of Hodgkin's disease and non-Hodgkin's
lymphoma (NHL) from both ENBREL^^ clinical trials and post-marketing
reports reveals that 86% of cases were NHL and 14% were Hodgkin's
disease, a proportion similar to that observed in the SEER database.

Further characterization of all non-Hodgkin's lymphomas reports (Table
7-) reveals that the distribution of histopathologic subtypes is
consistent with that previously reported in the general population and
in the RA population (Kamel et al, 1999). This contrasts with the
increased proportion of large B-Cell lymphomas and large T-cell
lymphomas associated with immunosuppression after transplantation
(Oertel et al, 2002).

Table 7-. Distribution of Histologic Subtypes of Non-Hodgkin\'s
Lymphoma: Comparison of Reports in Patients Receiving ENBREL^^ with RA
and Non-RA Controls

+-------------------------------+--------------+-----------+-----------+
| > REAL Classification\*       | Lymphoma     |           |           |
|                               | Cases From:  |           |           |
+-------------------------------+--------------+-----------+-----------+
|                               | Patients     | RA\       | Non-RA    |
|                               | Receiving    | Contr     | Contr     |
|                               | E            | ols\*\*\* | ols\*\*\* |
|                               | NBREL^^\*\* |           |           |
|                               |              | (%)       | (%)       |
|                               | (%)          |           |           |
+-------------------------------+--------------+-----------+-----------+
| > Diffuse large B-cell        | 43%          | 38%       | 43%       |
+-------------------------------+--------------+-----------+-----------+
| > Mantle                      | 5%           | 0%        | 2%        |
+-------------------------------+--------------+-----------+-----------+
| > Peripheral T-cell           | 8%           | 2%        | 4%        |
+-------------------------------+--------------+-----------+-----------+
| > Follicular                  | 16%          | 33%       | 27%       |
+-------------------------------+--------------+-----------+-----------+
| > Small lymphocytic           | 22%          | 14%       | 12%       |
| > lymphoma/B-cell chronic     |              |           |           |
| > lymphocytic leukemia        |              |           |           |
+-------------------------------+--------------+-----------+-----------+
| > Waldenstrom\'s              | 5%           | NA        | NA        |
| > Macroglobulinemia           |              |           |           |
+-------------------------------+--------------+-----------+-----------+
| > Marginal zone               | 0%           | 7%        | 0%        |
+-------------------------------+--------------+-----------+-----------+
| > Mycosis fungoides           | 0%           | 2%        | 10%       |
+-------------------------------+--------------+-----------+-----------+
| > Other                       | NA           | 2%        | 2%        |
+-------------------------------+--------------+-----------+-----------+
| \* REAL = Revised             |              |           |           |
| European-American Lymphoma    |              |           |           |
| Classification                |              |           |           |
|                               |              |           |           |
| \*\*Reports through November  |              |           |           |
| 2, 2002\                      |              |           |           |
| \*\*Kamel, et al. J Rheum     |              |           |           |
| 1999; 26:1676-80              |              |           |           |
+-------------------------------+--------------+-----------+-----------+

# Communication and Education

Rheumatic diseases are common and frequently severe, and can be
associated with unacceptable discomfort, progressive disability, and
increased mortality. It is widely recognized that ENBREL^^ has been a
substantial contribution to the lives of many patients with rheumatic
disorders.

Clinical trial experience for over nine years and practice experience
for over four years have consistently demonstrated that, in the great
majority of patients treated, ENBREL^^ acts rapidly and is remarkably
effective in reducing clinical signs and symptoms of inflammatory
arthritis, even in patients with long-standing disease who have had
inadequate responses to methotrexate and other DMARDs (Moreland 1997;
Moreland 1999; Weinblatt 1999). ENBREL^^ frequently permits durable
reduction or discontinuation of corticosteroids (Moreland et al, 2001)
and methotrexate (Kremer et al, 2002) and thus may permit avoidance of
adverse effects associated with other medications. It is widely
recognized that ENBREL^^, with its unique mechanism of action, provides
substantial benefit to the lives of many patients with rheumatic
disorders.

Since approval, there have been reports of adverse events, some serious,
in patients who have received ENBREL^^ therapy. Amgen established a
comprehensive pharmacovigilance program to investigate the background
rates for many of these events and to further characterize the clinical
experience with ENBREL^^. The pharmacovigilance program is strengthened
by the ENLIVEN program which allows direct communication with over
70,000 patients on an ongoing basis. Comprehensive education and
communication efforts are summarized in Table 8-.

Table 8-. Summary of ENBREL^^ Safety Education and Communication
Initiatives

+-----------------------------------------------------------------------+
| -   Multiple product label revisions                                  |
+-----------------------------------------------------------------------+
| -   Corresponding changes in patient package inserts                  |
+-----------------------------------------------------------------------+
| -   Letters to Health Care Professionals: May 1999, October 2000      |
+-----------------------------------------------------------------------+
| -   Ongoing ENLIVEN program for patient education and outreach; this  |
|     periodic newsletter contains safety information                   |
+-----------------------------------------------------------------------+
| -   1-888-4ENBREL telephone access for product information            |
+-----------------------------------------------------------------------+
| -   Collaboration with the American College of Rheumatology for       |
|     "Hotline" announcements                                           |
+-----------------------------------------------------------------------+
| -   Collaboration with investigators preparing publications           |
|     concerning safety issues                                          |
+-----------------------------------------------------------------------+
| -   Safety abstracts submitted to national meetings                   |
+-----------------------------------------------------------------------+
| -   RADIUS RA observational study: opportunity for rheumatologists to |
|     share observations and analyze practice data with colleagues and  |
|     investigators                                                     |
+-----------------------------------------------------------------------+

# Summary and Conclusions

After more than nine years of ENBREL^^ clinical trial experience and
more than four years of commercial experience, with proactive
pharmacovigilance of adverse events reports including lymphomas, the
numbers and types of lymphomas remain within the range that would be
expected for the population considered for ENBREL^^ treatment. Though a
causal relationship between ENBREL^^ therapy and lymphoma has not been
established, Amgen and Wyeth remain committed to ongoing
pharmacovigilance.

To summarize:

-   The reporting rates of lymphoma from ENBREL^^ post-marketing safety
    surveillance and the SIRs observed in ENBREL^^ clinical trials are
    consistent with the background rates expected in rheumatoid
    arthritis patients.

-   The distribution of lymphoma histologic subtypes from reports in the
    ENBREL^^ database is consistent with that previously reported in
    the general population and the RA population.

-   Greater disease severity, which confers greater lymphoma risk, may
    be present in patients receiving biologic therapies.

-   Patients receiving biologic therapies may have greater exposure to
    prior DMARD therapies, which may independently confer greater risk
    of developing lymphoma.

-   The ENBREL^^ benefit/risk ratio remains strongly favorable.

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APPENDIX 1

Appendix 1. Post-Approval Studies with ENBREL^^

+--------+------------+-----+----+-----+-----------------------------+
| Pr     | Title      | Sta | N  | Du  | Comments                    |
| otocol |            | tus | o. | rat |                             |
| \#     |            |     | of | ion |                             |
|        |            |     | Pa | of  |                             |
|        |            |     | ti | St  |                             |
|        |            |     | en | udy |                             |
|        |            |     | ts |     |                             |
+--------+------------+-----+----+-----+-----------------------------+
| 016    | Open-label | En  | 6  | ≥ 5 | Includes patients from      |
| .0018† | extension  | rol | 39 | ye  | initial licensing studies   |
|        | treatment  | led |    | ars | who have received ENBREL^^ |
|        | for        |     |    |     | continuously for up to 6    |
|        | DMARD-     |     |    |     | years with serial safety    |
|        | refractory |     |    |     | and efficacy observations.  |
|        | RA         |     |    |     |                             |
|        | patients   |     |    |     |                             |
|        | in         |     |    |     |                             |
|        | previous   |     |    |     |                             |
|        | trials     |     |    |     |                             |
|        | (various)  |     |    |     |                             |
+--------+------------+-----+----+-----+-----------------------------+
| 016    | Open-label | En  | 4  | ≥ 5 | Patients in this study have |
| .0023† | extension  | rol | 69 | ye  | received ENBREL^^ for up   |
|        | treatment  | led |    | ars | to 5 years with serial      |
|        | for early  |     |    |     | safety and efficacy         |
|        | RA         |     |    |     | observations.               |
|        | patients   |     |    |     |                             |
|        | (from      |     |    |     |                             |
|        | Protocol   |     |    |     |                             |
|        | 016.0012)  |     |    |     |                             |
+--------+------------+-----+----+-----+-----------------------------+
| 016    | Registry   | Enr | 6  | 3   | Safety, including effects   |
| .0026† | of         | oll | 00 | ye  | on growth and development   |
|        | ENBREL^^  | ing | \* | ars | parameters, among those who |
|        | for        |     |    |     | receive ENBREL^^ will be   |
|        | patients   |     |    |     | compared to a similar       |
|        | with JRA   |     |    |     | cohort of patients with     |
|        |            |     |    |     | polyarticular course or     |
|        |            |     |    |     | systemic JRA who are        |
|        |            |     |    |     | receiving methotrexate.     |
+--------+------------+-----+----+-----+-----------------------------+
| 016    | Dou        | Enr | 1  | 16  | Patients must have at least |
| .0029† | ble-blind, | oll | ,0 | we  | 1 documented comorbidity,   |
|        | r          | ing | 00 | eks | including diabetes mellitus |
|        | andomized, |     | \* |     | (at least 200 pts),         |
|        | placebo-   |     |    |     | pulmonary disease (e.g.     |
|        | controlled |     |    |     | asthma or COPD), pneumonia  |
|        | study of   |     |    |     | within previous year,       |
|        | ENBREL^^  |     |    |     | history of recurrent        |
|        | in RA      |     |    |     | bronchitis, sinusitis, or   |
|        | patients   |     |    |     | UTI. Study monitored by a   |
|        | with       |     |    |     | data safety monitoring      |
|        | comorbid   |     |    |     | board.                      |
|        | disorders  |     |    |     |                             |
+--------+------------+-----+----+-----+-----------------------------+
| 016    | Safety and | Enr | 75 | ≤   | Safety of ENBREL^^ in      |
| .0031† | efficacy   | oll | \* |  13 | pediatric patients with     |
|        | study of   | ing |    | mon | systemic onset JRA.         |
|        | ENBREL^^  |     |    | ths | Patients may be eligible    |
|        | in         |     |    |     | for registry (016.0026).    |
|        | children   |     |    |     |                             |
|        | with       |     |    |     |                             |
|        | systemic   |     |    |     |                             |
|        | onset JRA  |     |    |     |                             |
+--------+------------+-----+----+-----+-----------------------------+
| 01     | RA DMARD   | En  | 5  | ≥ 5 | Prospective, observational; |
| 6.0034 | in         | rol | ,0 | ye  | RADIUS 1 is designed to     |
|        | tervention | led | 00 | ars | systematically collect and  |
|        | and        |     | \* |     | document use patterns,      |
|        | u          |     |    |     | effectiveness, and safety   |
|        | tilization |     |    |     | of DMARD treatments         |
|        | study      |     |    |     | currently used in the       |
|        | (RADIUS 1) |     |    |     | management of RA.           |
+--------+------------+-----+----+-----+-----------------------------+
| †      |            |     |    |     |                             |
| p      |            |     |    |     |                             |
| ost-ap |            |     |    |     |                             |
| proval |            |     |    |     |                             |
| comm   |            |     |    |     |                             |
| itment |            |     |    |     |                             |
| with   |            |     |    |     |                             |
| the    |            |     |    |     |                             |
| FDA    |            |     |    |     |                             |
| Page 1 |            |     |    |     |                             |
| of 3   |            |     |    |     |                             |
|        |            |     |    |     |                             |
| \*     |            |     |    |     |                             |
| enro   |            |     |    |     |                             |
| llment |            |     |    |     |                             |
| goal   |            |     |    |     |                             |
+--------+------------+-----+----+-----+-----------------------------+

Appendix 1. Post-Approval Studies with ENBREL^^ (Continued)

<table style="width:100%;">
<colgroup>
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 43%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2">Protocol #</td>
<td colspan="2">Title</td>
<td colspan="2">Status</td>
<td colspan="2">No. of Patients</td>
<td colspan="2">Duration of Study</td>
<td>Comments</td>
</tr>
<tr class="even">
<td colspan="2">016.0035</td>
<td colspan="2">RA DMARD intervention and utilization study (RADIUS
2)</td>
<td colspan="2">Enrolling</td>
<td colspan="2">5,000*</td>
<td colspan="2">≥ 5 years</td>
<td>Prospective, observational; RADIUS 2 is designed to systematically
collect and document use patterns, effectiveness, and safety profile of
ENBREL<sup></sup> in the management of RA in clinical practice. Will
compare experience with ENBREL<sup></sup> use in Radius 2 to experience
with other DMARDs in RADIUS 1.</td>
</tr>
<tr class="odd">
<td>016.0620†</td>
<td colspan="2">Three month open label safety trial of
ENBREL<sup></sup> plus hydroxychloroquine, sulfasalazine, or injectable
gold in patients with RA</td>
<td colspan="2">Enrolled</td>
<td colspan="2">120*</td>
<td colspan="2">3 months</td>
<td colspan="2">Prospective study to evaluate the safety of
ENBREL<sup></sup> in combination with other DMARDs.</td>
</tr>
<tr class="even">
<td>0881A1–301-EU‡</td>
<td colspan="2">Open-label safety study of etanercept in patients with
rheumatoid arthritis</td>
<td colspan="2">Enrolled</td>
<td colspan="2">549</td>
<td colspan="2">Up to 4 years</td>
<td colspan="2">Includes patients from initial European double-blind
studies.</td>
</tr>
<tr class="odd">
<td>EU registry‡</td>
<td colspan="2">European RA patient registry</td>
<td colspan="2">Enrolling</td>
<td colspan="2">2000*</td>
<td colspan="2"></td>
<td colspan="2">Prospectively collects both safety and efficacy
information with registries conducted in the United Kingdom, Sweden, and
the Netherlands</td>
</tr>
<tr class="even">
<td colspan="11"><p>† post-approval commitment with the FDA Page 2 of
3</p>
<p>‡ post-approval commitment with the EMEA</p>
<p>* enrollment goal</p></td>
</tr>
</tbody>
</table>

Appendix 1. Post-Approval Studies with ENBREL^^ (Continued)

  ---------------- ----------------- ---------- ---------- -------------- -------------------------------
  Protocol \#      Title             Status     No. of     Duration of    Comments
                                                Patients   Study          

  0881A1-308-EU‡   A double-blind    Enrolled   686        12 months with This study will compare the
                   study evaluating                        double-blind   combination of ENBREL^^ and
                   the efficacy and                        extension      methotrexate to ENBREL^^ alone
                   safety of the                                          and methotrexate alone with
                   combination of                                         respect to efficacy and safety
                   etanercept and                                         in RA patients who have failed
                   methotrexate in                                        previous DMARD therapy.
                   comparison to                                          Radiographic progression of
                   etanercept and                                         disease will be evaluated.
                   methotrexate                                           Standard safety and efficacy
                   alone in                                               assessments will be performed.
                   rheumatoid                                             
                   arthritis                                              

  0881A1-309-EU‡   A 6-month,        Enrolled   260        6 months with  This study will compare the
                   double-blind                            double-blind   combination of ENBREL^^ and
                   comparison of                           extension      sulphasalazine to ENBREL^^
                   etanercept,                                            alone and sulphasalazine alone
                   sulphasalazine,                                        with respect to efficacy and
                   and the                                                safety in RA patients who have
                   combination of                                         failed previous DMARD therapy.
                   etanercept and                                         Standard safety and efficacy
                   sulphasalazine in                                      assessments will be performed.
                   patients with                                          
                   active rheumatoid                                      
                   arthritis                                              
                   receiving                                              
                   sulphasalazine                                         

  ‡ post-approval                                                         
  commitment with                                                         
  the EMEA Page 3                                                         
  of 3                                                                    
  ---------------- ----------------- ---------- ---------- -------------- -------------------------------

APPENDIX 2

Appendix 2. Epidemiologic Studies of Lymphoma in RA

+-----+----+--------+------+-------------+----------+---------------+
| **S | *  | **n    | *    | *           | **Stan   | **Comment**   |
| tud | *C | (patie | *Pat | *Observed** | dardized |               |
| y** | ou | nts)** | ient |             | I        |               |
|     | nt |        | -yea |             | ncidence |               |
|     | ry |        | rs** |             | Ratio**  |               |
|     | ** |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | F  | 46,101 | 213  | NHL (m) 13\ | NHL (m)  | National RA   |
| 78\ | in |        | ,911 | NHL (f) 25\ | 2.69\    | patient       |
| I   | la |        |      | HD (m) 5\   | NHL (f)  | registry      |
| som | nd |        |      | HD (f) 14   | 2.68\    |               |
| aki |    |        |      |             | HD (m)   |               |
|     |    |        |      |             | 2.19\    |               |
|     |    |        |      |             | HD (f)   |               |
|     |    |        |      |             | 3.08     |               |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | U  | 521    | 7    | All Lymph   | All      | Pop           |
| 85\ | SA |        | ,389 | (m) 2\      | Lymph    | ulation-based |
| K   |    |        |      | All Lymph   | (m)      | cohort        |
| atu |    |        |      | (f) 1       | 4.00\    |               |
| sic |    |        |      |             | All      |               |
|     |    |        |      |             | Lymph    |               |
|     |    |        |      |             | (f) 0.48 |               |
+-----+----+--------+------+-------------+----------+---------------+
| 1   | UK | 489    | N/A  | NHL 7\      | NHL      | Clin          |
| 985 |    |        |      | HD 2        | 24.0\    | ic-associated |
|     |    |        |      |             | HD 12.5  | RA patients   |
| Pr  |    |        |      |             |          |               |
| ior |    |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | UK | St     | Stud | Study 1.    | Study 1. | Study 1.      |
| 85\ |    | udy 1. | y 1. |             |          | Cohort seen   |
| S   |    | 489 RA | 5    | NHL 7       | NHL 24.1 | by one        |
| ymm |    | pts    | ,468 |             |          | physician     |
| ons |    |        |      | HD 2        | HD 12.5  |               |
|     |    | Study  |      |             |          | Study 2.      |
|     |    | 2.     |      | (Also 1     |          |               |
|     |    |        |      | CLL, which  |          | 10 from       |
|     |    | 30 RA  |      | the authors |          | Study 1, and  |
|     |    | pts    |      | do not      |          | 20 from       |
|     |    | who    |      | count as    |          | various UK    |
|     |    | dev    |      | NHL)        |          | hospitals     |
|     |    | eloped |      |             |          |               |
|     |    | l      |      | Study 2. 30 |          |               |
|     |    | ymphop |      |             |          |               |
|     |    | rolife |      |             |          |               |
|     |    | rative |      |             |          |               |
|     |    | malign |      |             |          |               |
|     |    | ancies |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | Sw | 11,683 | 101  | NHL 36\     | NHL      | Hospitalized  |
| 93\ | ed |        | ,000 | HD 12       | 1.88\    | RA patients   |
| G   | en |        |      |             | HD 2.34  |               |
| rid |    |        |      |             |          |               |
| ley |    |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| CLL |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| C   |    |        |      |             |          |               |
| hro |    |        |      |             |          |               |
| nic |    |        |      |             |          |               |
| ly  |    |        |      |             |          |               |
| mph |    |        |      |             |          |               |
| ocy |    |        |      |             |          |               |
| tic |    |        |      |             |          |               |
| leu |    |        |      |             |          |               |
| kem |    |        |      |             |          |               |
| ia; |    |        |      |             |          |               |
| HD  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Hod |    |        |      |             |          |               |
| gki |    |        |      |             |          |               |
| n's |    |        |      |             |          |               |
| di  |    |        |      |             |          |               |
| sea |    |        |      |             |          |               |
| se; |    |        |      |             |          |               |
| Ly  |    |        |      |             |          |               |
| mph |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| MM  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Mu  |    |        |      |             |          |               |
| lti |    |        |      |             |          |               |
| ple |    |        |      |             |          |               |
| my  |    |        |      |             |          |               |
| elo |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| N/A |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Not |    |        |      |             |          |               |
| a   |    |        |      |             |          |               |
| vai |    |        |      |             |          |               |
| lab |    |        |      |             |          |               |
| le; |    |        |      |             |          |               |
| NHL |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| N   |    |        |      |             |          |               |
| on- |    |        |      |             |          |               |
| Hod |    |        |      |             |          |               |
| gki |    |        |      |             |          |               |
| n's |    |        |      |             |          |               |
| lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| RA  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| R   |    |        |      |             |          |               |
| heu |    |        |      |             |          |               |
| mat |    |        |      |             |          |               |
| oid |    |        |      |             |          |               |
| art |    |        |      |             |          |               |
| hri |    |        |      |             |          |               |
| tis |    |        |      |             |          |               |
|     |    |        |      |             |          |               |
| P   |    |        |      |             |          |               |
| age |    |        |      |             |          |               |
| 1   |    |        |      |             |          |               |
| of  |    |        |      |             |          |               |
| 3   |    |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+

Appendix 2. Epidemiologic Studies of Lymphoma in RA (Continued)

+-----+----+--------+------+-------------+----------+---------------+
| **S | *  | **n    | *    | *           | **Stan   | **Comment**   |
| tud | *C | (patie | *Pat | *Observed** | dardized |               |
| y** | ou | nts)** | ient |             | I        |               |
|     | nt |        | -yea |             | ncidence |               |
|     | ry |        | rs** |             | Ratio**  |               |
|     | ** |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | Ca | 13,333 | N/A  | N/A         | Lymph/MM | \             |
| 93\ | na |        |      |             | RA (all) | *Hospitalized |
| Ten | da |        |      |             | 2.2\     | RA patients.  |
| nis |    |        |      |             | Lymph/MM | RA-RH= RA     |
|     |    |        |      |             | RA-RH    | patients.     |
|     |    |        |      |             | 4.1      | Hospitalized  |
|     |    |        |      |             |          | by a          |
|     |    |        |      |             |          | r             |
|     |    |        |      |             |          | heumatologist |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | D  | 20,699 | 144  | NHL 85\     | NHL 2.4\ | Hospitalized  |
| 96\ | en |        | ,421 | HD 14       | HD 3.4   | RA patients   |
| Me  | ma |        |      |             |          |               |
| lle | rk |        |      |             |          |               |
| mkj |    |        |      |             |          |               |
| aer |    |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| 19  | Ca | 862    | 14   | NHL 3\      | NHL 0.55 | Uni           |
| 97\ | na |        | ,998 | HD 0        |          | versity-based |
| Cib | da |        |      |             | HD 0     | rheumatic     |
| ere |    |        |      |             |          | disease unit  |
+-----+----+--------+------+-------------+----------+---------------+
| 2   | UK | 1      | 652  | NHL (m) 30\ | NHL (m)  | Scottish      |
| 000 |    | 24,143 | ,133 | NHL (f) 71\ | 2.39\    | national      |
| Tho |    |        |      | HD (m) 84\  | NHL (f)  | cohort        |
| mas |    |        |      | HD (f) 90   | 2.04\    |               |
|     |    |        |      |             | HD (m)   |               |
|     |    |        |      |             | 5.49\    |               |
|     |    |        |      |             | HD (f)   |               |
|     |    |        |      |             | 3.04     |               |
+-----+----+--------+------+-------------+----------+---------------+
| 20  | Fr | 2      | 8    | NHL (m) 6\  | NHL      | National      |
| 02\ | an | 7,000- | 1,00 | NHL (f) 12\ | (1       | study from 61 |
| Ma  | ce | 30,000 | 0-90 | HD (m) 5\   | .07-1.2) | French        |
| rie |    |        | ,000 | HD (f) 2    |          | departments   |
| tte |    |        |      |             | HD       | of            |
|     |    |        |      |             | (        | rheumatology  |
|     |    |        |      |             | 7.4-8.2) |               |
|     |    |        |      |             |          |               |
|     |    |        |      |             | (Depends |               |
|     |    |        |      |             | on which |               |
|     |    |        |      |             | n used)  |               |
+-----+----+--------+------+-------------+----------+---------------+
| CLL |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| C   |    |        |      |             |          |               |
| hro |    |        |      |             |          |               |
| nic |    |        |      |             |          |               |
| ly  |    |        |      |             |          |               |
| mph |    |        |      |             |          |               |
| ocy |    |        |      |             |          |               |
| tic |    |        |      |             |          |               |
| leu |    |        |      |             |          |               |
| kem |    |        |      |             |          |               |
| ia; |    |        |      |             |          |               |
| HD  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Hod |    |        |      |             |          |               |
| gki |    |        |      |             |          |               |
| n's |    |        |      |             |          |               |
| di  |    |        |      |             |          |               |
| sea |    |        |      |             |          |               |
| se; |    |        |      |             |          |               |
| DLB |    |        |      |             |          |               |
| CL: |    |        |      |             |          |               |
| D   |    |        |      |             |          |               |
| iff |    |        |      |             |          |               |
| use |    |        |      |             |          |               |
| la  |    |        |      |             |          |               |
| rge |    |        |      |             |          |               |
| B-c |    |        |      |             |          |               |
| ell |    |        |      |             |          |               |
| lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma, |    |        |      |             |          |               |
| Ly  |    |        |      |             |          |               |
| mph |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| MM  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Mu  |    |        |      |             |          |               |
| lti |    |        |      |             |          |               |
| ple |    |        |      |             |          |               |
| my  |    |        |      |             |          |               |
| elo |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| N/A |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Not |    |        |      |             |          |               |
| a   |    |        |      |             |          |               |
| vai |    |        |      |             |          |               |
| lab |    |        |      |             |          |               |
| le; |    |        |      |             |          |               |
| NHL |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| N   |    |        |      |             |          |               |
| on- |    |        |      |             |          |               |
| Hod |    |        |      |             |          |               |
| gki |    |        |      |             |          |               |
| n's |    |        |      |             |          |               |
| lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| RA  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| R   |    |        |      |             |          |               |
| heu |    |        |      |             |          |               |
| mat |    |        |      |             |          |               |
| oid |    |        |      |             |          |               |
| art |    |        |      |             |          |               |
| hri |    |        |      |             |          |               |
| tis |    |        |      |             |          |               |
|     |    |        |      |             |          |               |
| P   |    |        |      |             |          |               |
| age |    |        |      |             |          |               |
| 2   |    |        |      |             |          |               |
| of  |    |        |      |             |          |               |
| 3   |    |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+

Appendix 2. Epidemiologic Studies of Lymphoma in RA (Continued)

+-----+----+--------+------+-------------+----------+---------------+
| **S | *  | **n    | *    | *           | **Stan   | **Comment**   |
| tud | *C | (patie | *Pat | *Observed** | dardized |               |
| y** | ou | nts)** | ient |             | I        |               |
|     | nt |        | -yea |             | ncidence |               |
|     | ry |        | rs** |             | Ratio**  |               |
|     | ** |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| 20  | Sw | N/A    | N/A  | 296 Total   | N/A      | Swedish       |
| 02\ | ed |        |      |             |          | Hospital      |
| Bae | en |        |      | NHL 277     |          | Inpatient     |
| ckl |    |        |      |             |          | Register and  |
| und |    |        |      | DLBCL 52%   |          | Swedish       |
|     |    |        |      |             |          | Cancer        |
|     |    |        |      | HD 19       |          | Register      |
|     |    |        |      |             |          | study         |
+-----+----+--------+------+-------------+----------+---------------+
| 2   | US | Non-RA | No   | Non-RA      | 1.01     | Tennessee     |
| 002 |    | 5      | n-RA | 1,386       | (95% CI  | Medicaid      |
| Wat |    | 57,242 | 1    |             | =        | Cohort        |
| ter |    |        | ,967 | RA 28       | 0.       |               |
| son |    | RA     | ,956 |             | 69-1.47) |               |
|     |    | 10,700 |      | NHL 23      |          |               |
|     |    |        | RA   |             |          |               |
|     |    |        | 32   | HD 5        |          |               |
|     |    |        | ,979 |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+
| CLL |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| C   |    |        |      |             |          |               |
| hro |    |        |      |             |          |               |
| nic |    |        |      |             |          |               |
| ly  |    |        |      |             |          |               |
| mph |    |        |      |             |          |               |
| ocy |    |        |      |             |          |               |
| tic |    |        |      |             |          |               |
| leu |    |        |      |             |          |               |
| kem |    |        |      |             |          |               |
| ia; |    |        |      |             |          |               |
| HD  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Hod |    |        |      |             |          |               |
| gki |    |        |      |             |          |               |
| n's |    |        |      |             |          |               |
| di  |    |        |      |             |          |               |
| sea |    |        |      |             |          |               |
| se; |    |        |      |             |          |               |
| DLB |    |        |      |             |          |               |
| CL: |    |        |      |             |          |               |
| D   |    |        |      |             |          |               |
| iff |    |        |      |             |          |               |
| use |    |        |      |             |          |               |
| la  |    |        |      |             |          |               |
| rge |    |        |      |             |          |               |
| B-c |    |        |      |             |          |               |
| ell |    |        |      |             |          |               |
| lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma, |    |        |      |             |          |               |
| Ly  |    |        |      |             |          |               |
| mph |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| MM  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Mu  |    |        |      |             |          |               |
| lti |    |        |      |             |          |               |
| ple |    |        |      |             |          |               |
| my  |    |        |      |             |          |               |
| elo |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| N/A |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| Not |    |        |      |             |          |               |
| a   |    |        |      |             |          |               |
| vai |    |        |      |             |          |               |
| lab |    |        |      |             |          |               |
| le; |    |        |      |             |          |               |
| NHL |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| N   |    |        |      |             |          |               |
| on- |    |        |      |             |          |               |
| Hod |    |        |      |             |          |               |
| gki |    |        |      |             |          |               |
| n's |    |        |      |             |          |               |
| lym |    |        |      |             |          |               |
| pho |    |        |      |             |          |               |
| ma; |    |        |      |             |          |               |
| RA  |    |        |      |             |          |               |
| =   |    |        |      |             |          |               |
| R   |    |        |      |             |          |               |
| heu |    |        |      |             |          |               |
| mat |    |        |      |             |          |               |
| oid |    |        |      |             |          |               |
| a   |    |        |      |             |          |               |
| rth |    |        |      |             |          |               |
| rit |    |        |      |             |          |               |
| is  |    |        |      |             |          |               |
|     |    |        |      |             |          |               |
| P   |    |        |      |             |          |               |
| age |    |        |      |             |          |               |
| 3   |    |        |      |             |          |               |
| of  |    |        |      |             |          |               |
| 3   |    |        |      |             |          |               |
+-----+----+--------+------+-------------+----------+---------------+