Non Hodgkin Lymphoma:

Non Hodgkin Lymphoma: Non Hodgkin Lymphoma, often referred to as NHL, is a cancer originating in the lymphocytes, a type of blood cell, which are integral to the body s immune system. Non Hodgkin Lymphoma accounts for approximately 4% of all cancers in the United States. SEER data (Surveillance, Epidemiology and End Results) program of the National Institutes of Health estimates cases to be diagnosed in 2015 at 71,850 (39, 850 males and 32,00 females). Deaths in 2015 are expected be around 19,790, including 11,480 men and 8,310 women. Ninety five percent of Non Hodgkin Lymphoma is diagnosed in adults. This report is limited to adult cases only. The most common age range for the development of NHL is 65 74, with the average age being 66. Our immune system is very complex and consists of immune protecting cells, organs and lymph system. There are two types of lymphocytes that are key to the immune system, B lymphocytes and T lymphocytes. The B lymphocytes, or B cells are involved in the making of antibodies, which attach themselves to foreign substances, like germs or viruses, and they facilitate the destruction of these cells in the body. The T lymphocytes, or T cells are also involved in the immune system. Various types of T cells protect the body by directly or indirectly destroying various bacteria, fungi or viruses. The B cells and T cells are part of the Lymphatic system, often called the lymph system, which also includes lymph vessels, lymphoid tissues and related organs like the spleen and bone marrow. The lymph vessels run through the body, almost parallel to the blood vessels. They carry lymph fluid, lymphocytes and help clear the body of infection, and debris. Lymph nodes are organs located throughout the body and are connected by the lymph vessels. Lymph nodes can be felt in the neck, armpit or axilla and groin, but are located in other parts of the body. Lymph nodes enlarge when the body is fighting infection and are found normally when someone has a cold or other infection. However, enlarged lymph nodes are the most common sign of Lymphoma and are part of any diagnosis of NHL.

The spleen, thymus, adenoids, tonsils, bone marrow and parts of the stomach and intestines are organs that are part of this system and make lymphocytes, antibodies or lymphoid tissue. Non Hodgkin Lymphoma: Subtypes There are many different types of Non Hodgkin Lymphoma. This is an extensive list, but there are rare types not necessarily included in this summary. NHL B Cell Lymphomas B Cell Lymphomas comprise nearly 85% of all presentations of Non Hodgkin Lymphoma in the U.S. The table below summarizes their occurrence and characteristics. Table 1. B Cell Lymphoma Type Occurrence Characteristics Diffuse Large B cell The most common type Fast growing, responds Lymphoma (DLBCL) of NHL, approximately 1/3 of cases present with this diagnosis well to treatment. 75% of patients have a complete response after initial treatment. Primary Mediastinal B Approximately 2% of all Subtype of DLBCL. cell Lymphoma (a DLBCL sub type) frequently in young patients, under 40. About 2/3 of the patients are women Intravasular Large B cell Lymphoma (a DLBCL sub type) lymphomas. Occurs more Involves fibrosis tissue in the cells. Fast growing, responds well to treatment. Rare Subtype of DLBCL Lymphoma cells are found inside the blood vessels only and not in other organs common to lymphoma

B Cell Lymphoma Type Occurrence Characteristics Follicular Lymphoma Approximately 20% of all lymphomas Rare in young people, average age at diagnosis is about 60 years. Cells grow in a circular pattern. Slow growing May convert to a fast growing DLBCL Small Lymphocytic Approximately 5 10% of Slow growing Lymphoma (SLL), and all lymphomas are SLL Cancer cells are mainly in the lymph nodes and spleen Mantle Cell Lymphoma Marginal zone B cell lymphomas Extranodal marginal zone B cell lymphoma, also known as mucosaassociated lymphoid tissue (MALT) (a subtype of Marginal zone B cell lymphoma) Approximately 5% of all lymphomas More common in men Average age at diagnosis is about 60 years. Approximately 5 10% of all lymphomas Most common of the marginal zone B cell lymphomas Average age at diagnosis is about 60 years. Usually slow growing. 3 main sub types Initiate outside the lymph nodes Linked to Helicobacter pylori, the bacteria causing stomach ulcers May originate in other organs Usually confined and does not metastasize Nodal Marginal zone B Rare Ususally stays in the Cell lymphoma Found most often in older lymph nodes (a subtype of Marginal women Slow growing zone B cell lymphoma) Splenic marginal zone B cell lymphoma (a subtype of Marginal zone B cell lymphoma) Rare Most often elderly and male Slow growing Usually in spleen and bone marrow only.

B Cell Lymphoma Type Occurrence Characteristics Burkitt Lymphoma 1 2% of all Lymphomas Endemic type is rare in the US 90% of patients are male Usually diagnosed around age of 30 Burkitt like lymphoma type usually starts in the abdomen, or reproductive organs Slow growing Lymphoplasmacytic Lymphoma 1 2% of all lymphomas Found primarily in spleen, lymph nodes and bone marrow Hairy Cell Leukemia (HCL) Rare Cells have a hairy Despite the name, often Men more likely to be appearance considered a Lymphoma diagnosed than women Average age at diagnosis is 50 Usually found in the spleen, bone marrow and blood Slow growing Primary Central nervous Rare Poor outlook system (CNS) Lymphoma More common in people with immune system disorders Found in the brain, spinal cord, tissues around the spinal cord and eye.

T Cell Lymphomas T Cell Lymphoma Type Occurrence Characteristics Precursor T lymphoblastic lymphoma Peripheral T cell lymphomas Cutaneous T cell lymphomas (mycosis fungoides, Sezary syndrome and others Adult T cell Lymphoma Smoldering (Adult T cell Lymphoma subtype) Chronic (Adult T cell Lymphoma subtype) Comprises about 1% of all lymphomas Most often young adults Males develop more frequently than females Rare About 5% of all lymphomas Rare in the US More common in Japan, Africa and the Caribbean Rare in the US More common in Japan, Africa and the Caribbean Rare in the US More common in Japan, Africa and the Caribbean May present as leukemia or lymphoma Often starts in the thymus gland, where T cell are made May present in the center of the chest (mediastinum) and impact breathing or blood return to the heart Develop from mature T cells Start in the skin Begins with infection by a virus called HTLV 1. Grows slowly Abnormal T cells without increased lymphocytes My involve the skin or lungs Grows slowly Increased total lymphocytes and T cells May involve skin, lungs, liver, spleen and lymph nodes

T Cell Lymphoma Type Occurrence Characteristics Acute (Adult T cell Lymphoma subtype) Rare in the US More common in Japan, Africa and the Caribbean Acts like acute leukemia Fast growing High lymphocyte and T cell counts Enlarged lymph nodes, liver and spleen Fever, night sweats and Lymphoma (Adult T cell Lymphoma subtype) Angioimmunoblastic T cell lymphoma Extranodal natural killer/t cell lymphoma, nasal type Enteropathy associated intestinal T cell lymphoma (EATL) Type I EATL Type II EATL Rare in the US More common in Japan, Africa and the Caribbean 3% of all lymphomas More common in older adults Rare More common in parts of Asia and South America Rare Rare More common in men than women Tends to occur in people in their 60 s and 70 s. Less common than EATL Type I weight loss occur Enlarged lymph nodes without increased lymphocytes or T cells Enlarged lymph nodes, liver and spleen Fever, night sweats and weight loss occur Involves upper airway passages, but can also affect the skin and digestive tract. Occurs in various places within the lining of the intestine. May experience nausea, vomiting and abdominal pain Aligned with glutensensitivity enteropathy (celiac disease or sprue). Is not linked to sprue

T Cell Lymphoma Type Occurrence Characteristics Anaplastic large cell lymphoma (ALCL) Peripheral T cell lymphoma unspecified About 2% of all lymphomas More common in young people, but does occur at ages 50+ About half of all T cell lymphomas Average age of acquiring is in the 60 s. Starts in the lymph nodes Spreads to the skin Fast growing Do not fit into other groups Fast growing

Total Cases of Non Hodgkin Lymphoma The Sac Sierra Region Treated 155 cases of Non Hodgkin Lymphoma in 2014. These cases were distributed over our four ACoS sites, with 13 at SAFH, 87 at SMCS, 43 at SRMC and 12 at SSMC. Graph 1 100 90 80 70 60 50 40 30 20 10 0 SAFH SMCS SRMC SSMC 2014 NHL Volumes

Risk Factors: Age, Gender, Race Presence Among the Sutter Health Sac Sierra Region Population Age: Like many cancers, age is correlated with the development of NHL. Average age for diagnosis is 65 74, with the average age being 66. Below is a graph demonstrating the distribution of Non Hodgkin Lymphoma patients seen within the SHSSR in 2014 by age at diagnosis. Graph 2 45 2014 Age Distribution of Patients with NHL 40 35 30 25 20 15 10 5 0 <20 20 29 30 39 40 49 50 59 60 69 70 79 80 89 =>90 SAFH SMCS SRMC SSMC SHSSR

Gender: Non Hodgkin Lymphoma is more common among men that females, yet some types of NHL are more prevalent with females. Below is the distribution of patient seen in the SHSSR, 2014, by gender. Graph 3 SHSSR Gender Distribution at Time of Diagnosis 52% 48% Female Male Graph 4 SAFH Gender Distribution at Time of Diagnosis SMCS Gender Distribution at Time of Diagnosis 62% 38% Female Male 52% 48% Female Male SRMC Gender Distribution at Time of Diagnosis SSMC Gender Distribution at Time of Diagnosis 47% 53% Female Male 58% 42% Female Male

Race: Non Hodgkin Lymphoma is seen more often in Caucasians than African Americans and Asian Americans in the United States. There are some NHL s that are associated with specific countries or cultures (demonstrated in the Table 1.) Below is the distribution by Race of patients seen at SHSSR with a diagnosis of NHL in 2014 (Graph 5). 1% 1% 2% SHSSR 2014 5% 2%1% 88% White Black Filipino Asian Indian or Pakistaninos Japanese Pacific Islander NOS Unknown SAFH 2014 100% White 1% 1% 2% 4% 7% 85% SMCS 2014 White Black Filipino Asian Indian or Pakistaninos Japanese Pacific Islander NOS Unknown SRMC 2014 SSMC 2014 2% 2% White 96% Black Filipino Asian Indian or Pakistaninos Japanese 16% 17% 67% White Black Filipino

STAGING Cancers are diagnosed by many modalities, including but not limited to biopsy, physical symptoms, lab tests, x rays, CT s (computerized tomography), bone marrow evaluation, MRI (Magnetic Resonance Imaging) and other interventional diagnostic tests. When the physician has received all the relevant data, one is categorized as a particular stage of disease. For Non Hodgkin Lymphoma, there are four stages of disease, I, II, III, and IV. In general, the higher the number, the more advanced the disease. Additionally, each number is assigned either an A or B designation. Patients receiving a B designation have the presence of, 1) Unexplained fevers greater than 100.4 degrees, 2) Drenching night sweats and 3) Unexplained weight loss of more than 10% of usual body weight. Patients receiving an A designation have the absence of B symptoms. Per the American Joint Committee on Cancer, the Anatomic Staging for Non Hodgkin Lymphoma is listed below. Table 2 Stage I Stage II Stage III Stage IV Involvement of a single lympahatic site (i.e., nodal region, Waldeyer s ring, thymus or spleen) (I) or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma Involvement of two or more lymph node regions on the same side of the diaphragm (II); or localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with r without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by an Arabic numeral, as in for example II3. Involvement of lymph node regions on both sides of the diaphragm (III), which also maybe accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE,S). Splenic involvement is designated by the letter S. Diffuse or disseminated involvement of one or more

extralymphatic organs, with or without associated lymph node involvement; or isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.

Below is the distribution of 2014 Non Hodgkin Patients by Stage at each site of the SHSSR. (Graph 6) 50 48 45 40 35 30 25 20 15 10 5 31 3 15 5 21 20 9 3 1A 1B 2A 2B 3A 3B 4A 4B 0 Unstaged SHSSR 2014 3.5 3 2.5 2 1.5 1 0.5 0 SAFH 2014 1A 1B 2A 2B 3A 3B 4A 40 35 30 25 20 15 10 5 0 SMCS 2014 1A 1B 2A 2B 3A 3B 4A 14 12 10 8 1A 1B 2A 3.5 3 2.5 2 1A 1B 2A 6 4 2 0 2B 3A 3B 1.5 1 0.5 0 2B 3A 3B SRMC 2014 4A SSMC 2014 4A

A comparison of SHSSR staging data to SEER staging data from 2008 2012 demonstrates very similar distribution of stage between these data. 50% Percent of Cases by Stage SEER Data 2008 2012 7% 28% 15% Localized Regional Distant Unknown 59% Percent of Cases by Stage SHSSR 2008 2012 5% 20% 16% Localized Regional Distant Unknown 56% Percent of Cases by Stage SAFH 2008 2012 10% 22% 12% Localized Regional Distant Unknown 63% Percent of Cases by Stage SMCS 2008 2012 4% 17% 16% Localized Regional Distant Unknown 52% Percent of Cases by Stage SRMC 2008 2012 7% 25% 16% Localized Regional Distant Unknown 58% Percent of Cases by Stage SSMC 2008 2012 2% 20% 20% Localized Regional Distant Unknown

Survivorship Statistics for Non Hodgkin Lymphoma. The SEER data (Surveillance, Epidemiology and End Results) program of the National Institutes of Health, provides a national statistical data base to evaluate survivorship percentages of patients diagnosed with Non Hodgkin Lymphoma. The most recent data available is from 2008 2012. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5 Year Relative Survival Rate SEER Data 2008 2012 Localized Regional Distant Unstaged Compare this with the SHSSR Survival Data 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5 Year Relative Survival Rate SHSSR 2008 2012 Localized Regional Distant Unstaged

Below is the data by Facility, including SAFH, SMCS, SRMC, and SSMC 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5 Year Relative Survival Rate SAFH 2008 2012 Localized Regional Distant Unstaged 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5 Year Relative Survival Rate SMCS 2008 2012 Localized Regional Distant Unstaged 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5 Year Relative Survival Rate SRMC 2008 2012 Localized Regional Distant Unstaged 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5 Year Relative Survival Rate SSMC 2008 2012 Localized Regional Distant Unstaged TREATMENT Non Hodgkin Lymphoma is a disease primarily treated by chemotherapy and monoclonal antibodies. Surgery and Radiation play a role in some NHL types in early stage disease. Some patients may benefit from bone marrow transplant as a treatment modality. The Sutter Health Sac Sierra Region and four ACoS hospitals, Sutter Auburn Faith Hospital, Sutter Medical Center, Sacramento, Sutter Roseville Medical Center and Sutter Solano Medical Center are fortunate to be able to utilize the Bone and Marrow Transplant Program housed at Sutter Medical Center, Sacramento as part of the treatment resources for our patients.

The Bone and Marrow Transplant Center The Bone and Marrow Transplant Center for the Sutter Health Sac Sierra Region is housed at Sutter Medical Center, Sacramento. It opened in 1993. Currently, this unit has 16 beds. Our Blood and Marrow Transplant (BMT) Program supports fulfillment of a substantial community need and enhances community access with a full service program providing autologous, related, Haploidentical, matched unrelated allogeneic and cord blood transplants. An extensive number of diseases of the bone marrow may also result in consideration of BMT as a treatment modality. Those include, but are not limited to bone marrow failure, chronic leukemia, Hodgkin s disease, immune hematologic disorders, immunotherapy, Acute Leukemia, Multiple Myeloma, Myeloproliferative diseases and Non Hodgkin s Lymphoma. The BMT Program partners with National Marrow Donor Program (NMDP) to search for volunteer unrelated donors. The goal of the BMT Program is to achieve the highest standards of quality in all business units practice and operations without compromising patient safety. The BMT Program is accredited by the Foundation of Cellular Therapy (FACT) allogeneic and autologous transplants, Hematopoietic Stem Cell Collection of Peripheral Cells and Bone Marrow Harvest for patients diagnosed with leukemia, lymphoma, multiple myeloma and other blood disorders. Our team is led by Dr. Michael Carroll, M.D., Medical Director and Dr. Elias Kiwan, M.D. In addition, a large team of patient care coordinators, social workers, financial coordinators, nurses, quality assurance specialist, and patient advocates, who are familiar with the issues and care of transplant patients work together to provide a coordinated service to meet the needs of this unique patient population.

Dr. Michael Carroll, M.D., is the Medical Director of the Blood and Marrow Transplant Service for the Sutter Cancer Centers Valley Operating Unit. Dr. Carroll has been with Sutter Medical Group since 2008, building the program into a state of the art treatment center for patients. Dr. Carroll graduated from Stanford University School of Medicine, Completed his Internship and Residency at the University of Chicago and his Fellowship in Hematology/Oncology at the Johns Hopkins University School of Medicine. Dr. Carroll is a member of the American Society of Clinical Oncology and the American Society for Blood and Marrow Transplantation. Dr. Elias Nicolas Kiwan, MD, joined Sutter Medical Group in 2011 and expanded the Medical Oncology Team providing care to the patients within the Sutter Health Network requiring Blood and Marrow Transplant Services. Dr. Kiwan graduated from The Lebanese University Faculty of Medicine in Beirut Lebanon. He Completed his Internship and Residency at the University of Arkansas for Medical Sciences. Dr. Kiwan then completed his

Medical Oncology Hematology Fellowship and Research at the University of Arkansas for Medical Sciences, Bone marrow Transplant Unit. He is a member of the American Medical Association, American Society of Hematology and American Society of Clinical Oncology. He is fluent in English, French and Arabic. Information regarding management of patients with Non Hodgkin Lymphoma or the Bone and Marrow Transplant Center may be found at www.checksutterfirst.org. References will be added.