diagnostic lymphoma, multiple myeloma, cll...can mention “peripheral blood, solid organs, skin,...
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Diagnostic Lymphoma, Myeloma, CLLApril 13, 2018Irwindeep Sandhu
Division of HematologyUniversity of Alberta
Faculty/Presenter Disclosure
• Speaker: Dr. Irwindeep SandhuHematology
• 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
CFPC CoI Templates: Slide 1
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
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
CFPC CoI Templates: Slide 2
Disclosures
• Interaction • Broad principles
• Fueled by comments last year
Lymphoproliferative diseases: Objectives
Lymphoma update
Myeloma Update
Chronic Lymphocytic Leukemia Update
HELP: Alberta Central/North
Rapid North callsHematology 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 InstituteFax 780-407-2680Referrals: 780-248-1112
Mature lymphoid disorders
Image: Wikimedia Commons, Mikael Haggstrom (http://upload.wikimedia.org/wikipedia/commons/4/4a/Hematopoiesis_simple.png)
myeloma
CLL
lymphoma
Lymphoid system
BLOOD
BONE MARROW
SPLEEN LYMPH NODES
OTHEREXTRA-
LYMPHATIC AREAS
LYMPHOCYTES
Lymphoproliferative neoplasms (LPNs)
BLOOD
BONE MARROW
SPLEEN LYMPH NODES
OTHEREXTRA-
LYMPHATIC AREAS
ABNORMAL LYMPHOCYTES
Heterogeneous group of diseases characterized by infiltration of lymph nodes, spleen, bone marrow and other tissues by abnormal clonal proliferation of lymphoid cells
Lymph nodesNormal architecture, distribution and size
• Abnormal if:– ↑Number– ↑Size (>1-
1.5cm)– Hard/firm
consistency– Unusual
location– Alteration in
architecture– Infiltration by
abnormal cellswww.ca.wikipedia.org/wiki/Fitxer:Lymph_node_regio
ns.jpg
www.digherbs.com/lymphatic-diseases.html
www.faculty.une.edu/com/abell/histo/histolab3b.htm
Medulla
Lymph nodesCauses of lymphadenopathy
CAUSESLOCALIZED GENERALIZED
Infections (bacterial more common)
Neoplasm (solid tumors, lymphoma/LPN)
Local inflammation
Local reaction(insect bite, cutaneous problem)
Infections (virus and mycobacteria)
Neoplasm(lymphoma/LPN, solid tumors)
Inflammation(lupus, sarcoidosis, …)
Other(hyperthyroidism, serum sickness, drugs such as antiepileptics, …)
Lymphoma Presentation
BLOOD
BONE MARROW
SPLEEN LYMPH NODES
OTHEREXTRA-
LYMPHATIC AREAS
ABNORMAL LYMPHOCYTES
Splenomegaly Lymphadenopathy Abdominal or mediastinal mass- Can compress vessels or kidneys/ ureters
Cytopenia- From bone marrow involvement or- Immune destruction (e.g. ITP)
Mass in testis, skin, kidneys, etc.
• Constitutional symptoms (B symptoms)• Weight loss (10%)• Fever (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
infection (e.g.: tuberculosis), and/or sarcoid
Lymphoma Presentation
Case
17F to GP 7eral week Hx new PainLESS, 1x1 cm lump Right side neck.Nil elsewhereNo 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
Date Hemoglobin
Mean Corpuscular
Volume (MCV)
Platelets Leukocytes (WBCs)
Neutrophils (ANC)
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 Lymphocytes2.1 × 109/L
Monocytes0.8 × 109/L
Eosinophils1.2 × 109/L
Basophils0.1 × 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
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Abnormal lymph nodesHow to investigate further
• Biopsy, if persistent and cause unclear• Also if LN definitely abnormal (size, consistency,
location), or if signs and symptoms very suggestive of malignancy
• Different types of biopsyCore biopsy Excisional biopsyFine needle aspirate (FNA)
Better if lymphoma is suspected, to see the architecture
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Abnormal lymph nodesDifferent ways to biopsy
Obtains a few cells, okay to
diagnose solid tumors
Core biopsy Excisional biopsy
Fine needle aspirates
But not helpful to diagnose lymphoma Obtains tissue, not just
cells (i.e. better sample)Obtains entire node, best
modality to assess architecture
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 Hodgkin lymphoma, likely nodular sclerosing subtype.”
HELP
Who to BiopsyGeneral 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
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• Large group of different lymphoid neoplasms
– Cell of Origin:» 90% B-cell» 10% T-cell
– Clinical behavior varies widely
Non-Hodgkin’s Lymphoma
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B-cell NHL T-cell NHL
Diagnosis •Pathology (B-cell markers) •Pathology (T-cell markers)•Clinical picture helps in establishing precise diagnosis
Clinical presentation
•Mainly lymphadenopathy and/or splenomegaly•Sometimes extranodaldisease
•More skin involvement•More immune findings•Often “weird” presentation•Almost always advanced disease
Treatment •Potential for cure depends on subtype (aggressive vsnot)•Chemotherapy and immunotherapy (anti-CD20) are used to treat •RT sometimes useful
•Almost never curative
•Chemotherapy used to treat, often with autologous stem cell transplant upfront if possible•RT sometimes useful
Prognosis •Better •Poorer
B-cell NHL versus T-cell NHLDifferences
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NHL Clinical Behavior Summary
AGGRESSIVE NHL• Example: diffuse large B-cell
lymphoma• More often symptomatic,
can be fatal if untreated in weeks to months
• Higher likelihood of involvement of CNS and other extranodal sites
• Tumor lysis syndrome more frequent
INDOLENT NHL• Example: follicular
lymphoma
• Often asymptomatic, sometimes diagnoses incidentally
• Usually involves lymphoid tissues only
• Tumor lysis syndrome infrequent
Lymphoproliferative diseases: Objectives
Lymphoma update
Myeloma Update
Chronic Lymphocytic Leukemia Update
Primary plasma cell disease
MGUS
AmyloidosisPOEMSplasmacytoma
Smoldering Myeloma
Active Myeloma
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 > L3 : 1
• Detection: Serum protein electrophoresisUrine protein electrophoresisSerum free kappa/lambda light chain ratioQuantitative Immunoglobulin levels
Monoclonal plasma cell
Monoclonal (“M”) peak
Free light chain Assay
UPEP
Paraprotein end organ damage
• Burden of disease (large amount)– In bones:
• bone pain, fractures, high Ca2+
– In marrow: crowds out other guys:• Anemia, thrombocytopenia, neutropenia
• Ab filter through Kidney• sCr high, paraproteinuria
• Plasma cell proliferation in one spot• Plasmacytoma
• Peripheral neuropathy
CRAB
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 > 1Rajkumar 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
Plasma cell %
5% 10% 60%
Normal if both Kappa and lambda present
Smoldering if no end organ disease
Myeloma if + end organ disease
MyelomaMGUS
MGUS progression !
Non IgM: 1% per yearIgM: 1.5% per yearLight chain: 0.3% per yearPlasmacytoma: 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 ratioRajkumar 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
yrs (%)Absolute risk progression 20 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 27Katzmann 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 assessmentActivities of Daily Living• Bathing (tub bath, shower, sponge bath)• Dressing (taking clothes from the wardrobe/drawers and
getting dressed)• Toileting (going to the toilet room, using toilet, arranging
clothes)• Transferring• Continence• Feeding
Instrumental Activity of Daily Living (IADL)• Ability to use telephone• Shopping• Food preparation• Housekeeping• Laundry• Mode of Transportation• Responsibility for own medication• Ability to handle finances
Independent Dependent0 10 10 10 10 10 1
Total ADL:______________High risk: 5 or more
Independent Dependent0 10 10 10 10 10 10 10 1
Total IADL:______________High risk: 6 or more.
Palumbo et al Blood Mar 26 2015 vol 125 13
Antonio Palumbo et al. Blood 2015;125:2068-2074©2015 by American Society of Hematology
Equal prognostic ability asMore expensive geneticTesting
Result: lessen the DoseIntensity
Start at lesser doseEx Dexamethasone 20mg
Bortezeomib 1.3 mg/m2
Lenalidomide 10 or 15mg
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: goodb) Second primary cancers: age appropriate
screen + skinc) 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
Image: Wikimedia Commons, Mikael Haggstrom (http://upload.wikimedia.org/wikipedia/commons/4/4a/Hematopoiesis_simple.png)
myeloma
CLL
lymphoma
Lymphoid system
BLOOD
BONE MARROW
SPLEEN LYMPH NODES
OTHEREXTRA-
LYMPHATIC AREAS
ABNORMAL LYMPHOCYTES
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Case: 75M routine visit
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• The most frequent cause of persistent peripheral blood lymphocytosis
• Happens mainly in elderly
• Diagnosis• Blood smear shows mature lymphocytes and smudge cells (NO
BLASTS- otherwise, ACUTE leukemia)• Flow cytometry 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
Chronic lymphocytic leukemia (CLL)
American Society of Hematology Image Bank
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BloodQualitative evaluation of lymphocytes
BLOOD SMEAR FLOW CYTOMETRY
www.en.wikipedia.comCell suspension with
monoclonal antibodies
Laser detects monoclonalantibodies
Light detects cellular size
Machine analyses
CD4
CD4
CD4
CD8
CD8
CD8
CD8
CD4 T-cell
Anti-CD4 monoclonal antibody
Cells and monoclonal antibodies
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
• Ibrutinib: 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