Diagnostic , Myeloma, CLL April 13, 2018 Irwindeep Sandhu Division of University of Alberta CFPC CoI Templates: Slide 1 Faculty/Presenter Disclosure

• Speaker: Dr. Irwindeep Sandhu Hematology • Relationships with commercial interests: – Grants/Research Support: – Speakers Bureau/Honoraria: Celgene, Janssen, Gilead, Amgen, Novartis, Takeda – Consulting Fees: – Other: Trials: Celgene, Janssen, Gilead, Amgen, Novartis, Takeda, Boehringer Ingelheim, Roche/Genetech, CCTG, Celator/Jazz, Ambit, GlaxoSmithKline, Pfizer, Myeloma Canada Reseach Network Disclosures

• Salary support: University of Alberta + Dept of Medicine AFP – Honorarium: Celgene, Janssen, Gilead, Amgen, Novartis, Takeda • Trials: Celgene, Janssen, Gilead, Amgen, Novartis, Takeda, Boehringer Ingelheim, Roche/Genetech, CCTG, Celator/Jazz, Ambit, GlaxoSmithKline, Pfizer, Myeloma Canada Reseach Network CFPC CoI Templates: Slide 2 Disclosure of Commercial Support

• This Program is funded through AHS Operational Funding. • This Program has not received financial support. • This Program has not received in-kind support. • Dr. Irwindeep Sandhu is presenting at this Program on a voluntary basis. • Potential for conflict(s) of interest: None

• Off-label drugs: Nil Disclosures • Interaction • Broad principles

• Fueled by comments last year Lymphoproliferative diseases: Objectives Lymphoma update

Myeloma Update

Chronic Lymphocytic Update HELP: Alberta Central/North

Rapid North calls Hematology on call for other questions (NOTE NOT THE CCI)

We do NOT get the faxes….We are NOT part of Cancer Care or the Cross Cancer Institute Fax 780-407-2680 Referrals: 780-248-1112 Mature lymphoid disorders

lymphoma

CLL myeloma

Image: Wikimedia Commons, Mikael Haggstrom (http://upload.wikimedia.org/wikipedia/commons/4/4a/Hematopoiesis_simple.png) Lymphoid system

BLOOD

BONE

MARROW OTHER EXTRA- LYMPHATIC AREAS

SPLEEN LYMPH NODES Lymphoproliferative neoplasms (LPNs) Heterogeneous group of diseases characterized by infiltration of lymph nodes, spleen, bone marrow and other tissues by abnormal clonal proliferation of lymphoid cells

BLOOD

BONE

MARROW ABNORMAL OTHER LYMPHOCYTES EXTRA- LYMPHATIC AREAS

SPLEEN LYMPH NODES Lymph nodes Normal architecture, distribution and size • Abnormal if: – ↑Number – ↑Size (>1- 1.5cm) – Hard/firm www.digherbs.com/lymphatic-diseases.html consistency – Unusual location – Alteration in architecture www.ca.wikipedia.org/wiki/Fitxer:Lymph_node_regio – Infiltration by ns.jpg Medulla abnormal cells www.faculty.une.edu/com/abell/histo/histolab3b.htm Lymph nodes Causes of CAUSES LOCALIZED GENERALIZED Infections (bacterial more common) ( and mycobacteria)

Neoplasm Neoplasm (solid tumors, lymphoma/LPN) (lymphoma/LPN, solid tumors)

Local Inflammation (lupus, sarcoidosis, …) Local reaction (insect bite, cutaneous problem) Other (, serum sickness, drugs such as antiepileptics, …) Lymphoma Presentation Cytopenia - From bone marrow involvement or - Immune destruction (e.g. ITP) BLOOD Mass in testis, skin, kidneys, etc. BONE MARROW ABNORMAL OTHER LYMPHOCYTES EXTRA- LYMPHATIC AREAS

SPLEEN LYMPH NODES

Splenomegaly Lymphadenopathy Abdominal or mediastinal mass - Can compress vessels or kidneys/ ureters Lymphoma Presentation

• Constitutional symptoms () • Weight loss (10%) • (unexplained) • Sustained drenching night sweats • Recurrent infections • Physical examination – Inspect for asymmetry, erythema, or local skin lesions – Palpate for location, size, tenderness, consistency, and mobility versus matting • Smooth suggests reactive hyperplasia • Tender suggests acute infectious/ inflammatory process • Stony hard suggests malignant infiltration by carcinoma • Firm and rubbery suggests malignant infiltration by lymphoma • Fixed and matted suggests malignancy, lymphoma, chronic (e.g.: ), and/or sarcoid Case

17F to GP 7eral week Hx new PainLESS, 1x1 cm lump Right side neck. Nil elsewhere No infections, anorexia, constitutional Sx,B Sx ++Progressive Fatigue over 4 months.

O/E: no fever. Normal exam except node: rubbery, immobile, tender Monospot negative, TSH Normal, throat swab normal

2 months later: 2.0 x 1.5 cm. nil else

Mean Corpuscular Leukocytes Neutrophils Date Hemoglobin Platelets Volume (WBCs) (ANC) (MCV) May 6, 2019 121 g/L 83 fL 284 × 109/L 14.2 × 109/L 10.1 × 109/L

Normal Range 120 to 160 g/L 80 to 100 fL 140 to 450 × 109/L 4.0 to 11.0 × 109/L 1.8 to 7.5 × 109/L

Differential Lymphocytes Monocytes Eosinophils Basophils 2.1 × 109/L 0.8 × 109/L 1.2 × 109/L 0.1 × 109/L

Normal Range 1.2 to 5.2 × 109/L 0.0 to 1.0 × 109/L 0.0 to 0.7 × 109/L 0.0 to 0.3 × 109/L Abnormal lymph nodes How to investigate further • Biopsy, if persistent and cause unclear • Also if LN definitely abnormal (size, consistency, location), or if very suggestive of malignancy • Different types of biopsy Fine needle aspirate (FNA) Core biopsy Excisional biopsy

Better if lymphoma is suspected, © Copyright andto Use see Restrictions the Apply – http://homer.med.ualberta.ca?copyrightarchitecture Abnormal lymph nodes Different ways to biopsy

Fine needle Core biopsy Excisional aspirates biopsy

Obtains a few But not helpful to cells, okay to diagnose lymphoma Obtains tissue, not just Obtains entire node, best diagnose solid cells (i.e. better sample) modality to assess tumors architecture © Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright Case

• FNA: negative for Malignant Cells, but mixed population of lymphoid cells with active Follicular centre cells present. • 1 month later: drenching night sweats, SOBOE, Orthopnea, dry cough supine. • A chest x-ray :“abnormal soft tissue in the right paratracheal region, right tracheobronchial angle, and near the aortic arch.” • CT scan confirms enlarged bilateral cervical (measuring up to 1.8 cm), prevascular (measuring up to 2.5 cm), and para-tracheal (measuring up to 2.3 cm) lymph nodes. • An excisional lymph node biopsy identifies “classical , likely nodular sclerosing subtype.” HELP

Who to Biopsy General surgeon

Radiologist

LYMPHOMA Triage: Cross Cancer Institute New patient office. RN to assist coordination with Lymphoma Doctor on triage. Investigations

• Imaging: CT scans

• Blood: CBCd, LDH (proliferation), compression (liver, kidney), Calcium/Albumin • Infectious Disease: Hep B, C, HIV

• Infections: qIgG/A/M, SPEP Non-Hodgkin’s Lymphoma

• Large group of different lymphoid neoplasms

– Cell of Origin: » 90% B-cell » 10% T-cell

– Clinical behavior varies widely

© Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright B-cell NHL versus T-cell NHL Differences B-cell NHL T-cell NHL

Diagnosis •Pathology (B-cell markers) •Pathology (T-cell markers) •Clinical picture helps in establishing precise diagnosis Clinical •Mainly lymphadenopathy •More skin involvement presentation and/or •More immune findings •Sometimes extranodal •Often “weird” presentation disease •Almost always advanced disease Treatment •Potential for cure depends •Almost never curative on subtype (aggressive vs not) •Chemotherapy used to treat, •Chemotherapy and often with autologous stem cell immunotherapy (anti- transplant upfront if possible CD20) are used to treat •RT sometimes useful •RT sometimes useful Prognosis •Better •Poorer © Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright NHL Clinical Behavior Summary

AGGRESSIVE NHL INDOLENT NHL • Example: diffuse large B-cell • Example: lymphoma • More often symptomatic, can be fatal if untreated in • Often asymptomatic, weeks to months sometimes diagnoses • Higher likelihood of incidentally involvement of CNS and • Usually involves lymphoid other extranodal sites tissues only • Tumor lysis syndrome more frequent • Tumor lysis syndrome

infrequent© Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright Lymphoproliferative diseases: Objectives Lymphoma update

Myeloma Update

Chronic Lymphocytic Leukemia Update Primary plasma cell disease

Smoldering MGUS Myeloma

Active Myeloma

Amyloidosis

POEMS Langren, O et al. Blood 2009; 113 (22) 5412-5417. Weiss BM et al. Blood 2009; 113 (22): 5418-5422. Antibody production

• Two parts - heavy chain and light chain • During production, type of antibody changes with progressive deletion of genetic code • IgG > IgA > IgM > IgD 70% 20% 10% 1% (~% of plasma cell problems) • Light chain similar K > L 3 : 1 • Detection: Serum protein electrophoresis Urine protein electrophoresis Serum free kappa/lambda light chain ratio Quantitative Immunoglobulin levels Monoclonal plasma cell

Monoclonal (“M”) peak Free light chain Assay

UPEP Paraprotein end organ damage

• Burden of disease (large amount) C – In bones: • bone pain, fractures, high Ca2+ R – In marrow: crowds out other guys: A • Anemia, thrombocytopenia, neutropenia • Ab filter through Kidney B • sCr high, paraproteinuria • Plasma cell proliferation in one spot • Plasmacytoma • Peripheral neuropathy New Definition!

• End organ damage – Bone disease: CT(low dose total body) vs Xray, total spine vs body MRI, FDG PET – Removal of Cr as criteria; use of CrCL – Anemia: no set limit: lowering of 20g/L • Free Light Chain ratio > 100 • Bone Marrow Plasma cells > 60% • MRI bone marrow plasmacytoma > 1 Rajkumar V et al. Lancet Oncol 15 (12) November. e538-e548

No Bone Scans for Myeloma!!! Plasma cell dyscrasia is a continuum from mgus to myeloma

Bone marrow plasma count classifies disease

MGUS Myeloma

5% 10% 60%

Normal if Smoldering if no end organ disease both Kappa and Myeloma if + end organ disease lambda present

Plasma cell % MGUS progression !

Non IgM: 1% per year IgM: 1.5% per year Light chain: 0.3% per year Plasmacytoma: 10% over 3 yrs (need Normal MRI spine/pelvis and bone imaging) if BMBx no clonality (IHC) 60% (bone) or 20% (soft tissue) within 3 yrs if BMBx: less than 10% clonal cells, FLC ratio

Rajkumar V et al. Lancet Oncol 15 (12) November. e538-e548 MGUS Risk Stratification • Noted 1% transformation • Can further stratify with high risk features • Non-IgG M protein (ex IgA) • M protein > 15 g/L (smoldering) • Abnormal free light chain ratio • Assists in timing of follow up testing. Score Relative risk Risk progression 20 Absolute risk progression 20 yrs, yrs (%) accounting for death from other causes (%)

0 1 5 2 1 5.4 21 10 2 10.1 37 18 3 20.8 58 27

Katzmann Blood August 1, 2005 vol. 106 no. 3 812-817 Workup of MGUS

• R/O myeloma, try to diagnose other condition • Cbcd --> cytopenia, rouleaux • sCr --> renal failure • SPEP +IFE --> M protein quantity • UPEP +IFE --> to detect presence, quantity • Ca, Albumin, IgG/M/A levels • Skeletal survey • Serum free kappa/lambda light chain ratio Causes of myeloma

• Pain: • Opiods/muscle relaxants • Chemotherapy (steroids/bortezomib) • Pamidronate • Khyphoplasty • Physical Braces: OT assist • Radiation: watch the stem cells… Multiple Myeloma

• New drugs you are seeing:

• Carfilzomib: Cardiac dysfunction/dypsnea in 13% • Afib, HTN, Headaches, nausea

• Daratumumab: $$$, infusion reaction, soon SC

• Ixazomib: pill Bortezomib, CYP3A4 Geriatric assessment

Activities of Daily Living • Bathing (tub bath, shower, sponge bath) Independent Dependent • Dressing (taking clothes from the wardrobe/drawers and 0 1 getting dressed) 0 1 • Toileting (going to the toilet room, using toilet, arranging 0 1 clothes) 0 1 • Transferring 0 1 • Continence 0 1 • Feeding Total ADL:______Instrumental Activity of Daily Living (IADL) High risk: 5 or more • Ability to use telephone • Shopping Independent Dependent • Food preparation 0 1 • Housekeeping 0 1 • Laundry 0 1 • Mode of Transportation 0 1 • Responsibility for own medication 0 1 • Ability to handle finances 0 1 0 1 0 1

Total IADL:______High risk: 6 or more. Palumbo et al Blood Mar 26 2015 vol 125 13 Equal prognostic ability as More expensive genetic Testing

Result: lessen the Dose Intensity

Start at lesser dose Ex Dexamethasone 20mg

Bortezeomib 1.3 mg/m2

Lenalidomide 10 or 15mg

Antonio Palumbo et al. Blood 2015;125:2068-2074 ©2015 by American Society of Hematology Bone Marrow transplant

• Stats edmonton: 24% increase in referrals from last year (autologous)

• If putting patients in: need 2-3 months prior to planned transplant

• Transplant service: review until day +100 • 780 – 432 – 8677 Office Assistance

• Exposure to radiation: CAD early

• Immune system cancers: hole in the immune system a) Infection: good b) Second primary cancers: age appropriate screen + skin c) Osteoporosis Lymphoproliferative diseases: Objectives Lymphoma update

Myeloma Update

Chronic Lymphocytic Leukemia Update HELP

• We need assistance!

• Malignant heme service UofA/CCI Lymphoproliferative diseases: Objectives Lymphoma update

Myeloma Update

Chronic Lymphocytic Leukemia Update Mature lymphoid disorders

lymphoma

CLL myeloma

Image: Wikimedia Commons, Mikael Haggstrom (http://upload.wikimedia.org/wikipedia/commons/4/4a/Hematopoiesis_simple.png) Lymphoid system

BLOOD

BONE

MARROW ABNORMAL OTHER LYMPHOCYTES EXTRA- LYMPHATIC AREAS

SPLEEN LYMPH NODES Case: 75M routine visit

© Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright Chronic lymphocytic leukemia (CLL) • The most frequent cause of persistent peripheral blood • Happens mainly in elderly • Diagnosis • Blood smear shows mature lymphocytes and smudge cells (NO BLASTS- otherwise, ACUTE leukemia) • profile (from peripheral blood) confirms the clinical suspicion • Bone marrow is always involved (but biopsy is not necessary for diagnosis) • Subtype of Non-Hodgkin lymphoma

American Society of Hematology Image Bank © Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright Blood Qualitative evaluation of lymphocytes BLOOD SMEAR FLOW CYTOMETRY Light detects Cells and cellular size CD8 monoclonal antibodies

CD4

CD8

CD4 Laser detects Machine monoclonal analyses antibodies CD8

Anti-CD4 CD8 monoclona l antibody CD4

CD4 T-cell Cell suspension with www.en.wikipedia.com © Copyrightmonoclonal and Use Restrictions antibodies Apply – http://homer.med.ualberta.ca?copyright Chronic Lymphocytic Leukemia

• Type of indolent NHL • In addition to high lymphocytes in blood may also cause: – Lymphadenopathy – Hepatomegaly and/or splenomegaly – Cytopenias • Due to massive bone marrow involvement OR • Hemolytic anemia and/or immune-mediated thrombocytopenia – B symptoms – Recurrent infections • Not curable • Treatment when symptomatic – Choice of chemotherapy agent(s) depends on age/frailty as well as disease characteristics Issue #1

• Infection: WBC increase! Double/triple/5x higher!

• Just watch and wait, monitor weekly

• Doubling time only counts if baseline > 30 initially!! Issue #2

• Watch the other counts!

• Autoimmune cytopenias: ITP or hemolytic anemia.

• Call if hemolysis seen/suspected: • Coombs +, haptoglobin absent, LDH/retic/Bili Issue #3

• New medicines: • Venetoclax: Tumour lysis syndrome

• : causes BLEEDING/BRUISING – Avoid antiplatelet agents unless needed (ie cardiac stents) – Anticoagulants better (likely) Ibrutinib

• Highly effective • “empties” lymph nodes/marrow  blood • Causes lymphocytosis for a few weeks after start

• Rash • Myalgias Chronic Lymphocytic Leukemia

• No live vaccines (Shingles): Shingrix • Give: prevnar then pneumovax; yearly Flu

• Avoid vaccine if rituximab 6 months prior Lymphoproliferative diseases: Objectives Lymphoma update

Myeloma Update

Chronic Lymphocytic Leukemia Update HELP

• We need assistance!

• Malignant heme service UofA/CCI