diagnostic lymphoma, multiple myeloma, cll...can mention “peripheral blood, solid organs, skin,...

$: Diagnostic Lymphoma, Multiple Myeloma, CLL...Can mention “Peripheral blood, solid organs, skin, and central nervous system involved, but less commonly than lymph nodes and\ഠbone$
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

Presenter

Presentation Notes

This slide must be visually presented to the audience AND verbalized by the speaker.

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

Presenter

Presentation Notes

This slide must be visually presented to the audience AND verbalized by the speaker.

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

Presenter

Presentation Notes


Lymphoid system

BLOOD

BONE MARROW

SPLEEN LYMPH NODES

OTHEREXTRA-

LYMPHATIC AREAS

LYMPHOCYTES

Presenter

Presentation Notes

10) We can find abnormal lymphocytes in LPN in all these lymphoid “organs”... Let’s see how and when to suspect that LPN is involveing one of these sites…

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

Presenter

Presentation Notes

Can mention “Peripheral blood, solid organs, skin, and central nervous system involved, but less commonly than lymph nodes and bone marrow” 10) We can find abnormal lymphocytes in LPN in all these lymphoid “organs”... Let’s see how and when to suspect that LPN is involveing one of these sites…

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

Presenter

Presentation Notes

12) We all have LN throughout our body; they normally are encapsulated and contain germinal centres in the many nodules seen in the cortex of the LN. Some of them can be seen on imaging and palpated on P/E, but they should normally be soft in consistency and mobile, and measure no more than 1-1.5 cm. Abnormal LN can be defined as increased size and/or number of LN seen or palpated, abnormal consistency, LN palpated in location that is unusual (supraclavicular, epitrochlear, popliteal, ...). They are sometimes found to be involved by a disease even though they seemed normal on imaging and on P/E (abnormal architecture, or infiltration by abnormal cells). That is because before a LN gets enlarged, it needs to be affected by a significant number of abnormal cells (so when initially infiltrated by a few cells, it is normal in size but abnormal if you look carefully at it under the microscope)

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, …)

Presenter

Presentation Notes

13) Both benign and malignant causes can be seen when an increased number of LN and/or large LN are seen It is easier to evaluate the likely cause if we look at the clinical picture (localized vs generalized). Infections can cause LN-if bacterial, usually localized, vs generalized if viral (EBV, CMV, HIV, ...) or mycobacteria, and also in the case of toxoplasmosis. Neoplasm can cause both scenarios. Local inflammation and skin problems can induced localized LN, and some systemic disease can be associated with generalized Ln (lupus, sarcoidosis, Castleman, hyperthyroidism, and drugs...) Adequate history and P/E is essential to evaluation of a patient with lymphadenopathy

Lymphoma Presentation

BLOOD

BONE MARROW

SPLEEN LYMPH NODES

OTHEREXTRA-

LYMPHATIC AREAS


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.

Presenter

Presentation Notes

25) Now…the bone marrow

• 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

Presenter

Presentation Notes

38) Clinical Presentation of patient with lymphoma can be varied; it includes : …

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

© Copyright and Use Restrictions Apply – http://homer.med.ualberta.ca?copyright

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

Presenter

Presentation Notes

17) We already have defined what an abnormal LN is, and if there is no obvious cause and LN is persistent (more than a month or 2) or enlarging (or if the cause is obviously neoplastic-very large, very firm and or supraclavicular location), A BIOPSY WILL BE NEEDED. A sample can be obtained by 3 different ways, and an excisional biopsy is preferred when a LPN is suspected. Here is why


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

Presenter

Presentation Notes

14) FNA, small needle, small sample; core biopsy, bigger needle or trocar, bigger sample; excisional LN biopsy, all the LN is available for analysis- and architecture can be assessed

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


• Large group of different lymphoid neoplasms

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

– Clinical behavior varies widely

Non-Hodgkin’s Lymphoma

Presenter

Presentation Notes

55) If we summarize about NHL… It includes a lot of different disease; B-cell NHL are far more common than T-cell NHL, it is a disease of the older with slight male predominance, and widespread disease is frequent, and it is not rare to see extranodal and bone marrow involvement in patient with NHL (compared to HD)


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

Presenter

Presentation Notes

57) What are the differences between T cell NHL and B cell NHL? We talked about pathology, but clinical presentation also helps (more skin involvement and immune findings in T cell NHL). Treatment is almost never curative for T cell NHL, and prognosis is generally bad for T cell NHL. Because T-cell NHL are very rare, that’s all you need to know about it!


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

Presenter

Presentation Notes

59) Let’s talk about aggressive or very aggressive B NHL… patients are sicker/more symptomatic, with more extraGG and CNS disease, but intent of treatment is CURATIVE. Treatment involves aggressive chemotherapy and immunotherapy, and needs to be started quickly (more so if Burkitt’s) because patient will die within weeks to months if left untreated As far as complications are concerned, tumor lysis syndrome happens quite often, esp if Burkitt’s because the cells are rapidly dividing and thus rapidly killed and releasing bad substances. Definition is … treatment is… 61) Now let’s talk about Indolent B NHL, the most frequent being FL. It is not curable, and patient can live for years and years with it, without necessarily needing treatment. We thus treat them only when symptomatic (as treatment can be worse than the disease itself!!!). We can use RT alone, Chemo-immunotherapy, with or without RT, … We do not see TLS very often, but we know patient with indolent B NHL can see their disease become more aggressive (TRANSFORMATION). It is suspected when (…), and if we perform a biopsy again, the pathologist will see that cells have a different aspect and a higher proliferation rate; it needs to be treated quickly as prognosis is no longer good and patients could now die within weeks to months.


Lymphoma update

Myeloma 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

Presenter

Presentation Notes

Long-term outcomes. (A) OS, (B) PFS, and (C) cumulative incidence of hematologic adverse events, (D) nonhematologic adverse events, and (E) discontinuation in the intention-to-treat population.

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


Lymphoma update

Myeloma Update


HELP

• We need assistance!

• Malignant heme service UofA/CCI


Lymphoma update

Myeloma Update


Mature lymphoid disorders


myeloma

CLL

lymphoma

Presenter

Presentation Notes


Lymphoid system

BLOOD

BONE MARROW

SPLEEN LYMPH NODES

OTHEREXTRA-

LYMPHATIC AREAS


Presenter

Presentation Notes

28) Last but not the least, the blood. Big organ, and very easily accessible so great area to study the presence of LPN and identify what is going on IF INVOLVED (which is rarely the case but in leukemiaa!)


Case: 75M routine visit

Presenter

Presentation Notes

96) First step : lab work. How would you describe his CBC/diff? (increased WBC, with absolute lymphocytosis)


• 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

Presenter

Presentation Notes

35)The most frequent disease that should be suspected when PB lymphocytes are persistently elevated is CLL...


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

Presenter

Presentation Notes

32) QUALITATIVE = ABNORMAL OR NOT, regardless of numeration. When lymphocytes are increased or when it is thought the patient has LPN or NHL, looking at the lymphocytes QUALITATIVELY is important. We can look at the aspect of the lymphocytes (morphology, on a blood smear) and/or at the surface markers that are present (helpful to quantify T and B cells, and see if those B and T cells express abnormal markers that could be a sign that they are neoplastic)A simple way of assessing markers at the surface of the cells (here, the lymphocytes) is to perform flow cytometry. Although it can done on various samples (usually, a pathologist will make that call or the clinician should remind the lab to do it in specific cases when LPN is suspected –for eg on pleural fluid, on nodes, …), it is easy to do on blood when LPN is suspected based on the presence of PB lymphocytosis and has to be ordered by the clinician. How it works is the cells are put in contact with monoclonal antibodies that will attach to Ag on the surface of cells if present. We usually identify t cell by tagging them with an anti-CD3 if they are T, anti-CD19/20 if B cells, then can look at various CD expression on each of these B or T cells. That way, the percentage of B and T cells in the blood is determined, and other markers can be looked at. Because we only have a few B cells in circulation normally, any excessive amount of B cells will be looked at, trying to assess if they are clonal (all the same) and trying to identify the disease according to the specific CD expression.

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


Lymphoma update

Myeloma Update


HELP

• We need assistance!

• Malignant heme service UofA/CCI

diagnostic lymphoma, multiple myeloma, cll...can mention “peripheral blood, solid organs, skin,...

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