Aggressive

Non-Hodgkin’s Hodgkin Kami Maddocks, MD Lymphoma Disease Associate Professor of Clinical Medicine Division of Hematology Department of Internal Medicine The Ohio State University Wexner Medical Center The James Cancer Hospital and Low High Grade/ Solove Research Institute Grade/Indolent Aggressive 5 subtypes Lymphoma Lymphoma

Cellular Origin of Non- Cancer statistics, 2018 Hodgkin’s Lymphoma (U.S. and Europe) ------

CA: A Cancer Journal for Clinicians 4 JAN 2018 DOI: 10.3322/caac.21442 http://onlinelibrary.wiley.com/doi/10.3322/caac.21442/full#caac21442-fig-0001

1 Non-Hodgkin’s Hodgkin Disease Lymphoma • ~ 8,500 new cases (3,660 in females and 4,840 in males) • 4% of all cancers • ~ 1,050 deaths (430 females, 620 males) • 7th most common cancer in men & women • Most common in early adulthood but • ~ 74,680 people (41,730 males and 32,950 females) diagnosed bimodal • ~ 19,910 people will die of this disease (11,510 • Peak patients aged 15-34 and 8,400) • Risk rises again > 55 years old • Risk of developing NHL is 1 in 47 • One of the more common cancers among • ~ 10-15% of cases diagnosed in children children, teens and young adults but risk of and teenagers developing NHL increases throughout life with half the patients ≥ 65 years of age • 5-year relative survival rate for all comers is 86%

Risk Factors Screening

• Age • Chronic Infections • Benzene, herbicides and • Helicobacter pylori • Hepatitis C • Immune deficiency • EBV • Solid organ • HHV8 There is no routine screening for transplant • HTLV-1 • HIV/AIDS • Immunosuppressive NHL or Hodgkin disease • Congenital Medications Immunodeficiency • drugs • Autoimmune diseases • Radiation • RA • SLE • Sjogren’s • Celiac Disease

2 Patient Presentations How is Lymphoma Diagnosed? • Enlargement of a • An excisional biopsy is ideal • Symptoms from bulky lymphadenopathy • Fine needle aspirations are generally non- • Dependent on location – pain, dyspnea, diagnostic early satiety, renal dysfunction • Even if indicative of lymphoma, not • Abnormal blood counts necessarily of subtype • Some patients present with “B” symptoms • A core biopsy often does not obtain enough tissue for all diagnostic studies • Fevers, night sweats, weight loss • A bone marrow biopsy and aspirate can • Pruritus in Hodgkin Disease help make the diagnosis and is used in staging

Nodal versus Extranodal Evaluation and Staging Studies' • Laboratory studies including CBC with Lymphoid Tissues Non-lymphatic Tissue differential, lactate dehydrogenase (LDH), uric • Lymph nodes • Skin acid, liver function • HIV • Spleen • Cutaneous T-cell • Imaging • Thymus lymphoma • Chest X-ray (HD) • Mucosa-associated • Organs • Computed tomography (CT) scans • Positron emission tomography (PET) scans – lymphoid tissue (MALT) • GI tract all aggressive lymphomas • Marginal zone • Lung • Bone marrow biopsy and aspirate lymphoma of • Liver • Additional potential testing: mucosa associated • Hepatitis • Renal or adrenal • ESR (HD) tissue • Central nervous • Echocardiogram system • PFT’s with DLCO (HD) • Brain MRI and LP

3 Ann Arbor Staging System Ann Arbor Staging System Involvement of a single lymph node region or lymphoid Stage I structure, or involvement of a single extra lymphatic site (IE).

Involvement of two or more lymph node regions on the same Stage I Stage II Stage III Stage IV side of the diaphragm which may be accompanied by Stage II localized contiguous involvement of an extra lymphatic site

or organ (IIE).

Involvement of lymph node regions on both sides of the diaphragm which may also be accompanied by involvement Stage III of the spleen (IIIS) or by localized contiguous involvement of an extra lymphatic site or organ (IIIE). Diffuse or disseminated involvement of one or more extra Stage IV lymphatic organs or tissues, with or without lymph node involvement. * The absence or presence of fever (> 38C), unexplained weight loss (> 10% body weight), or night sweats should be donated by the suffix letters A or B, respectively.

Subtypes Diffuse Large B-cell NHL

• Non-Hodgkin’s Lymphoma • Epidemiology • Most common, constitutes 30-40% of adult NHL • Diffuse Large Lymphoma • Usually presents in middle aged and older • adults, male predominance • Median age 7th decade • • Peripheral T Cell Lymphoma • Clinical Features • 30-40% of cases present with early stage • Hodgkin Lymphoma disease • Usually symptomatic and not incidental • Symptoms noticed over weeks to a few months • 1/3 cases arise from low grade process

4 Diffuse Large B-cell NHL Diffuse Large B-cell NHL

• Rapid growth (weeks) enlarging tumor • Laboratory abnormalities • Usually rapidly enlarging, symptomatic mass • Cytopenias if disease involvement of BM or at a single nodal or extranodal site enlarged spleen • bulky palpable mass(es) • Elevated lactate dehydrogenase • thoracic and abdominal adenopathy without • Elevated uric acid superficial lymph nodes • Spontaneous tumor lysis • Extranodal extension or involvement common • Most common extranodal site is gastrointestinal region, but CNS, bone, thyroid, testis, lung, kidney, and liver involvement all occur • Symptoms • Dependent on site of disease involvement • “B” symptoms (fevers, sweats, weight loss)

Hodgkin Presentation Hodgkin Presentation • Painless adenopathy • Cough, SOB, DOE in patients with mediastinal • 75% neck, left > right disease • 25% axillary • Hemoptysis rarely • 10% inguinal and iliac • Usually tracks • Rarely, alcohol ingestion can induce pain in • Subdiaphragmatic presentations uncommon node • 1/3 have B-symptoms (fever, NS, weight loss) • Pruritus very common • Frequently cause of FUO in older males, very • Can predate lymphadenopathy by months, difficult to diagnose in these patients as they can delay diagnosis as patient travels to and often have stage IV disease and small nodes from dermatologists • Intense, refractory to topical and oral antihistamines

5 Treatment Toxicities • Chemotherapy based • R-CHOP • R-CHOP standard chemotherapy in most • Infusion reactions, cytopenias, infections, diffuse large B cell lymphoma need for transfusion, GI toxicity • , , , (nausea/vomiting/diarrhea/constipation/muco sitis), alopecia, anorexia, peripheral and neuropathy, cardiotoxicity, small risk of • ABVD standard chemotherapy in Hodgkin secondary malignancy including acute Disease leukemia • doxorubicin, bleomycin, vinblastine and • ABVD dacarbazine • Cytopenias, infections, alopecia, muscle • More aggressive/intensive regimens used in cramps, GI toxicity some of the other rare but more aggressive (nausea/vomiting/diarrhea/constipation/muco sitis), phlebitis, peripheral neuropathy, lymphomas cardiotoxicity, pulmonary toxicity • XRT in select cases • Radiation • Early/limited stage Diffuse Large B cell • Dependent on location – local symptoms lymphoma • Fatigue, cytopenias, skin burn/irritation • Select cases of Early Stage HD • CAD or CHF (HD – mediastinal) • Bulky Hodgkin Disease • Secondary malignancies

Lymphoma Emergencies Infectious Complications

• Presentation • Most common cause of morbidity and • Cord Compression mortality in the cancer patient • SVC Syndrome • Neutropenia major risk factor for infection • CNS Lymphoma • Hematologic diseases associated with • Spontaneous Tumor Lysis inherent immune defects • Treatment • Neutropenic Fever

6 Neutropenia Neutropenic Fever • Chemotherapy induced, bone marrow • Fever • Single oral temperature 38.3 C (101) or higher involvement and heavily pretreated • 38.0 C (100.4) or higher for an hour • Correlation between neutrophil count (both • Neutropenia duration and rate of decline) and frequency • ANC less than 500/mcL • ANC less than 1000/mcL with a predicted and severity of infection decline in the next 48 hours • 20% patients ANC ≤ 100 bloodstream • Weakness, hypotension, syncope, pain, localized symptoms infection • Mortality highest among • Infectious complications combination of • Initial neutrophil counts ≤ 100 • Prolonged neutropenia (≥ 7 days) neutropenia, disruption of mucosal • Delay in treatment with broad spectrum barriers, microbial flora shifts antibiotics

Neutropenic Fever Evaluation and Treatment • Exam with localizing signs (vascular access, mucosal membranes) • 2/3 patients with fever have occult infection • CBC with differential, Chemistry Panel, Liver Function, Urinalysis/culture, Blood cultures, Chest x-ray • most common early pathogen • Intravenous antibiotic therapy • IV broad spectrum monotherapy usually sufficient • Coag negative staph, S. aureus, viridans • Anti-pseudomonal cephalosporin (cefepime or strep, entrerococci ceftazidime) • Piperacillin/tazobactam • E. coli, klebsiella, enterobacter, pseudomonas • Imipenem/cilastatin or meropenem • HSV, RSV, influenza • Vancomycin consideration • Apparent catheter related infections • Antibiotic-resistant bacteria, yeast, other fungi, • Gram-positive bacteremia common causes of subsequent infections • Known colonization with MRSA • Soft tissue infection • Candida, aspergillus • Clinically unstable • Double gram-negative coverage • High risk for pseudomonas infections • Clinically unstable

7 Evaluation and Treatment Follow-up • Persistent febrile neutropenia • Anti-fungal coverage after 4 days • Hematologic follow up every 3 months • CT scans to investigate for source • Treatment duration dependent on infection for 2 years, every 4-6 months from but should continue until ANC recovers to ≥ years 3-5 and then yearly dependent 500 on patient preference • Removal of vascular access • Physical exam and blood tests • Immediate in unstable patient (CBC, LDH in NHL, sedimentation • Fungal or mycobacterial bloodstream rate in HD if initially elevated infections • S. aureus, P. aeruginosa and VRE strongly consider

Survivor Survivorship • Many survivors experience physical and/or psychosocial effects of cancer and its treatment

• Some evident during anti-cancer therapy (long-term effects) “ An individual is considered a cancer survivor from the time of diagnosis, • Some manifest months or years after therapy (late effects) through the balance of his or her life” • Recent review suggests 50% of survivors suffer from late effects of cancer therapy

• Incidence increases with longer follow up time

• May occur less with new therapies and standards

8 Standards for Survivorship Long-term effects • Prevention of new and recurrent cancers and • Long-term physical effects other late effects • Cardiac effects, reproduction, pain, fatigue • Surveillance for cancer spread, recurrence or • Male and female sexual dysfunction second cancers • Cognitive decline • Secondary Malignancies • Assessment of late psychosocial and medical • 2-10% of patients develop effects • Dependent on chemotherapeutic agents and • Intervention for consequences of cancer and treatment • Psychosocial issues • Anxiety, depression, sleep disorders • Coordination of care between primary care • Employment, finances, insurance providers and specialists to ensure all health • Exercise needs are met

Secondary Malignancies Screening for second malignancy • AGE APPROPRIATE SCREENING and SKIN • Multifactorial (decreased immune surveillance, treatment related, virally mediated) EXAMS • Solid tumors most common • Referral to dermatology • Colonoscopy, prostate, mammogram, PAP smear • XRT > combined modality > chemotherapy alone • SMOKING CESSATION • Breast and lung cancer most common (esp in HD) • Risk of secondary acute leukemia in both HD and • Yearly chest imaging in patients with NHL and risk of secondary NHL in HD history of smoking or chest irradiation • Higher risk with chemotherapy • Annual breast screening 5-8 years after • Alkylating agents completion of therapy or age 40 if history • Highest risk 5-10 years of chest or axillary radiation • Topoisomerase II inhibitors, anthracyclines • MRI for those receiving between the • Highest risk 2-3 years ages of 10-30

9 Cardiovascular disease Hypothyroidism • Mediastinal irradiation and anthracycline-based chemotherapy • 50% of long-term survivors, greatest with • Radiation-induced toxicity usually > 5-10 years neck or upper mediastinal irradiation after completion of therapy • Thyroid exam • Coronary disease and cardiomyopathy • Yearly thyroid function tests • Annual blood pressure monitoring and aggressive management of risk factors • Baseline stress test or echocardiogram (chest irradiation) and carotid ultrasound (neck irradiation) 10 years after therapy

Myelosuppression Resources

• Usually resolves with time from therapy • Leukemia and Lymphoma Society • Some delayed myelosuppression • Concern if new cytopenias develop • Appropriate immunizations and prevention • Lymphoma Research Foundation of infection

10 Stem cell transplant in How do you define aggressive lymphomas “cured”?

Indolent lymphoma Indolent Non-Hodgkin Lymphoma • A heterogeneous group of malignancies derived from mature B lymphocytes • Overview the common subtypes • Follicular lymphoma Beth Christian, MD • Marginal zone lymphoma, 3 varieties Associate Professor of Clinical Internal Medicine • Lymphoplasmacytic lymphoma Division of Hematology The Ohio State University Wexner Medical Center

11 Non-Hodgkin Lymphoma Precursor B-cell: bone marrow

Naïve B-cell: peripheral blood

Germinal Center B-cell: Lymph node, follicular region Follicular lymphoma

Memory B-cell: Lymph node, Perifollicular region • 4% new cancer cases Marginal zone lymphoma Lymphoplasmacytic lymphoma • 5 year overall survival (2007-2013) was 71% seer.cancer.gov

Pathologic Diagnosis Indolent Lymphoma

• Characterized by slow growth over years • Morphology • Appearance of the malignant cells • Severe symptoms are uncommon • Pattern of involvement within a lymph • Advanced stage indolent lymphoma is not node cured with standard therapy • Immunophenotype or pattern of antigens • Therapy for advanced stage indolent expressed on the cell surface lymphoma is given with the goal of treating • or preventing complications of the disease • • Cytogenetics

12 Indolent Lymphoma – Complications

• Increased risk of infection • Importance of immunizations: pneumococcal, influenza • Avoidance of live vaccines Follicular Lymphoma • Hypogammaglobulinemia • Increase risk of secondary malignancies • Age-appropriate cancer screening • Complications of treatment • Risk of cardiovascular disease • Radiation

Follicular Lymphoma Follicular lymphoma - Pathology • 2nd most common non-Hodgkin lymphoma, 20% • Grade 1-2, 3A,and 3B – number of • 70% of indolent lymphoma centroblasts • Median age of diagnosis = 60 years • Symptoms: enlarged lymph nodes, • Immunophenotype: monotypic uncommon to have severe symptoms immunoglobulin light chain, CD20, CD19, associated with disease CD10, and BCL-2 • Bone marrow involvement at diagnosis • Cytogenetics: t(14;18) 60-70% • “B symptoms” at diagnosis 20% Indolent lymphoma can transform into aggressive lymphoma • Fevers, night sweats, or weight loss

13 Follicular Lymphoma – Treatment Follicular Lymphoma - Treatment Treatment decisions are primarily made to • Early Stage – radiation or observation improve the quality of a patient’s life: • Advanced Stage Questions: “Watch and Wait” – Criteria for treatment 1. How can life be made better with • Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm treatment? • Any nodal or extranodal tumor mass with a 2. Is the benefit of treatment greater than diameter of ≥7 cm the side effects? • B symptoms 3. What treatment is the right one at this • Splenomegaly point in the patient’s course? • Pleural effusions or peritoneal ascites • Cytopenias or leukemic involvement

Treatment Milestones in Follicular Lymphoma - Treatment Follicular Lymphoma Initial Therapy • Chemotherapy with an anti-CD20 monoclonal FDA Approvals Early era: CHOP, CVP • Maintenance therapy with an anti-CD • 1997 – rituximab, the first monoclonal antibody • Rituximab • 2002 – ibritumomab tiuxetan (Zevalin®) • 2008 – bendamustine Relapse(s) • 2014 – idelalisib • Chemotherapy with an anti-CD20 monoclonal antibody • 2016 – obinutuzumab • Immunomodulatory drug - lenalidomide* • 2017 – rituximab plus hyaluronidase - subQ • PI3 Kinase inhibitors – idelalisib, copanlisib copanlisib • Stem cell transplant

2018… * Off label use

14 Rituximab Rituximab • First monoclonal antibody approved for • A major advance in the treatment of follicular treatment lymphoma • Chimeric – both mouse and human components • First targeted treatment • Binds to CD20 on B-cells, normal and malignant • Side effects • Antibody-dependent cell-mediated cytotoxicity • Infusion reactions • Natural killer cells recognize the antibody • Rash, potentially severe bound to the cancer cell and release • Increased risk for infections cytokines and cytotoxic granules • Hepatitis B reactivation • Complement-dependent cytotoxicity • Model for the development of all monoclonal • The antibody activates complement and the antibody therapy membrane attack complex destroys the cell • Obinutuzumab • Depletes B-cells for up to 6 months

Follicular Lymphoma Marginal Zone Lymphoma

• The prognosis of follicular lymphoma continues to improve • A chronic disease, requiring intermittent MALT, gastric treatment MALT, non-gastric Splenic MZL • Median overall survival ~ 20 years Nodal MZL • Allogeneic stem cell transplant is a potentially treatment • Clinical Trials

15 Marginal Zone Lymphoma Marginal Zone Lymphoma Associated with chronic immune stimulation • 5% non-Hodgkin lymphoma • H pylori – gastric • Extranodal marginal zone lymphoma of • Hashimoto’s thyroiditis - thyroid mucosa-associated lymphoid tissue • Sjogren’s syndrome - salivary glands, lymphoma = MALT lymphoma: ocular adnexa most common type 70% • Chlamydia psittaci – ocular adnexa • Splenic MZL – 20% • Campylobacter jejuni – small intestine • Nodal MZL – 10% • Hepatitis C – splenic

Gastric MALT Lymphoma MALT Lymphoma • The majority are localized and associated • Non gastric sites: salivary glands, skin, lacrimal with H. pylori glands, orbit and conjunctiva, lung, thyroid, upper airway, breast, other GI sites, liver • Eradication of H. pylori can result in • Stage I-II remission and cure of the lymphoma • 10 year recurrence free survival: 76% • Median time to complete response = 15 • 10 year cause specific survival: 98% months • Transformation is uncommon, <10% • Up to 1/3 associated with t(11;18), unlikely • Localized disease is commonly treated with to respond to antibiotics radiation • Local radiation is an alternative therapy • Up to 1/3 of patients will present with or develop disseminated disease

16 Splenic Marginal Zone Lymphoma SMZL - Treatment • Median age diagnosis – 69 years Indicated for cytopenias or symptomatic • Splenic enlargement with localized LAD splenomegaly • Bone marrow / peripheral blood • Treatment of Hepatitis C involvement 95% • Splenectomy – historical • Often associated with a monoclonal • Rituximab* – response rate ~ 90% protein • Autoimmune complications • Chemotherapy with rituximab* • AIHA • Ibrutinib • ITP • Cold agglutinin disease • Cryoglobulinemia * Off label use

Marginal Zone Lymphoma Nodal MZL

• Ibrutinib – the first and only FDA approved • 1% of NHL, 10% of MZL therapy (2017) • Median age of diagnosis: 50-64 years • Bruton’s tyrosine kinase inhibitor • Bone marrow involvement in • Side effects approximately 1/3 • Increased bleeding risk • Association with Hepatitis C • Diarrhea • Transformation occurs in approximately • Rash 15% • Atrial fibrillation • Infection

17 Nodal MZL – Pathology Nodal MZL -Treatment • Approach is similar to follicular lymphoma • Plasmacytic features in 20-40% • Localized disease – radiation • Higher portion of large blastoid cells and high Ki-67 can occur • Advance stage disease • CD19, CD20, CD79a, BCL2 • Watch and Wait • Frequent genetic abnormalities: • Rituximab and chemotherapy* • Gain chromosome 3 • Ibrutinib • 18q23 • Treatment for Hepatitis C

* Off label use

Lymphoplasmacytic Lymphoplasmacytic lymphoma & Lymphoma Waldenström macroglobulinemia (WM) • 1% of Non-Hodgkin Lymphoma • Median age diagnosis: 73 years • Male:Female 1.6:1 Waldenström macroglobulinemia • Lymphoplasmacytic lymphoma with an IgM monoclonal protein = Waldenström macroglobulinemia • Non-IgM associated LPL is very rare • Familial association

18 WM - Pathology WM – Signs/Symptoms Immunophenotype • Anemia – most common presentation • sIgM, CD19, CD20, CD22, CD79 • Elevated total protein and a monoclonal • Up to 20% can express CD5, CD10, or protein CD23 • Bone marrow involvement is very common Cytogenetics • Lymphadenopathy: 15% • Chromosome 6q deletions in up to • Splenomegaly: 10% half of patients • AIHA, ITP • MYD88 somatic mutations are present in >90% • Cryglobulinemia, Cold agglutinin disease

WM – Signs/Symptoms WM – Signs/Symptoms • Neuropathy IgM • 20% patients at presentation • Pentamer and the largest antibody • distal, symmetric, and slowly progressive sensorimotor peripheral neuropathy causing • Accumulation of IgM can result in paresthesias and weakness increased blood viscosity • : Anti-myelin-associated • IgM ~ 6000 mg/dL but can vary glycoprotein and GM1 ganglioside • There is no definitive viscosity level where • Renal complications • Direct infiltration symptoms occur but typically ~ 4 cP • Immune mediated glomerulonephritis • Use caution with PRBC transfusions – • Amyloid increasing hematocrit will increase • Skin involvement / vasculitis • Bing Neel Syndrome = CNS involvement viscosity

19 WM – Signs/Symptoms WM – Indications for Treatment Symptomatic hyperviscosity is an emergency • Anemia - Hemoglobin < 10 (11) g/dL 9 Symptoms: Treatment: • Platelets < 100 (120) x 10 /L • Visual – blurred vision, • Plasmapheresis • Symptomatic hyperviscosity retinal hemorrhage, • Treatment of the • Bulky adenopathy / organomegaly papilledema lymphoma • Moderate to severe neuropathy • Mucocutaneous – epistaxis, gingival bleeding • Amyloidosis • Neurologic – headache, • Cryoglobulinemia tinnitus, vertigo, seizures • Cold agglutinin disease

WM - Treatment Indolent Lymphoma: • Chemotherapy* Summary • Cyclophosphamide Common Signs / Symptoms of Indolent • Bendamustine Lymphoma • Anti-CD20 monoclonal antibodies – • Cytopenias rituximab* • Slowly progressive lymphadenopathy • Bruton’s tyrosine kinase inhibitor - • Splenomegaly ibrutinib • Elevated total protein with presence of a • Proteosome inhibitors – bortezomib, monoclonal protein carfilzomib* • New onset of autoimmune cytopenias • Stem cell transplant * Off label use

20 Indolent Lymphoma: Summary • The mainstay of therapy is to only treat when needed • The prognosis of indolent lymphomas is very good and improving over time • We are less reliant on traditional chemotherapy and have increasing options for treatment • Clinical trials – new options are on the horizon • Allogeneic stem cell transplant offers a potentially curative option

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